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Sample records for b-cell chronic lymphocytic

  1. Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia

    Science.gov (United States)

    2016-04-26

    B-cell Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Diffuse Well-differentiated Lymphocytic Lymphoma; B Cell Lymphoma; Follicular Lymphoma,; Mantle Cell Lymphoma; Non-Hodgkin's Lymphoma; Waldenstrom Macroglobulinemia; Burkitt Lymphoma; B-Cell Diffuse Lymphoma

  2. Genetic features of B-cell chronic lymphocytic leukemia.

    Science.gov (United States)

    Stilgenbauer, S; Lichter, P; Döhner, H

    2000-03-01

    The genetic features of B-cell chronic lymphocytic leukemia (CLL) are currently being reassessed by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH). Conventional cytogenetic studies by chromosome banding are difficult in CLL mainly because of the low in vitro mitotic activity of the tumor cells, which leads to poor quantity and quality of metaphase spreads. Molecular genetic analyses are limited because candidate genes are known for only a few chromosomal aberrations that are observed in CLL. FISH was found to be a powerful tool for the genetic analysis of CLL as it overcomes both the low mitotic activity of the CLL cells and the lack of suitable candidate genes for analysis. Using FISH, the detection of chromosomal aberrations can be performed at the single cell level in both dividing and non-dividing cells, thus circumventing the need of metaphase preparations from tumor cells. Probes for the detection of trisomies, deletions and translocation breakpoints can be applied to the regions of interest with the growing number of clones available from genome-wide libraries. Using the interphase cytogenetic FISH approach with a disease specific set of probes, chromosome aberrations can be found in more than 80% of CLL cases. The most frequently observed abnormalities are losses of chromosomal material, with deletions in band 13q14 being the most common, followed by deletions in 11q22-q23, deletions in 17p13 and deletions in 6q21. The most common gains of chromosomal material are trisomies 12q, 8q and 3q. Translocation breakpoints, in particular involving the immunoglobulin heavy chain locus at 14q32, which are frequently observed in other types of non-Hodgkin's lymphoma, are rare events in CLL. Genes affected by common chromosome aberrations in CLL appear to be p53 in cases with 17p deletion and ataxia telangiectasia mutated (ATM), which is mutated in a subset of cases with 11q22-q23 aberrations. However, for the other frequently

  3. Cyclophosphamide, Alvocidib, and Rituximab in Treating Patients With High Risk B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2015-11-10

    Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  4. Chronic lymphocytic leukemia/small lymphocytic lymphoma: another neoplasm related to the B-cell follicle?

    Science.gov (United States)

    Tandon, Bevan; Swerdlow, Steven H; Hasserjian, Robert P; Surti, Urvashi; Gibson, Sarah E

    2015-01-01

    Although there has been increased attention paid to the critical nature of nodal involvement in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the B-cell compartment it is most closely related to and its relationship to the follicle remain uncertain. A clinicopathologic investigation of 60 extramedullary biopsies of LEF1+ CLL/SLL, including 29 cases with perifollicular/follicular (PF/F) growth, was therefore performed. A subset of PF/F cases demonstrated inner mantle zone preservation or intra-mantle zone growth. All PF/F and 16/31 other cases contained CD21+ follicular dendritic cells. No cytogenetic, IGHV mutational or gene usage differences were seen between PF/F and diffuse cases. PF/F cases were more often kappa positive (pa subset of bona fide CLL/SLL is related to the follicle, most likely the outer mantle zone, and that at least a subset of the diffuse cases may represent "later" disease. PMID:25860247

  5. Renal complications in chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis: the Mayo Clinic experience.

    Science.gov (United States)

    Strati, Paolo; Nasr, Samih H; Leung, Nelson; Hanson, Curtis A; Chaffee, Kari G; Schwager, Susan M; Achenbach, Sara J; Call, Timothy G; Parikh, Sameer A; Ding, Wei; Kay, Neil E; Shanafelt, Tait D

    2015-09-01

    While the renal complications of plasma cell dyscrasia have been well-described, most information in patients with chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis is derived from case reports. This is a retrospective analysis of patients with chronic lymphocytic leukemia or monoclonal B-cell lymphocytosis who underwent kidney biopsy for renal insufficiency and/or nephrotic syndrome. Between January 1995 and June 2014, 49 of 4,024 (1.2%) patients with chronic lymphocytic leukemia (n=44) or monoclonal B-cell lymphocytosis (n=5) had a renal biopsy: 34 (69%) for renal insufficiency and 15 (31%) for nephrotic syndrome. The most common findings on biopsy were: membranoproliferative glomerulonephritis (n=10, 20%), chronic lymphocytic leukemia interstitial infiltration as primary etiology (n=6, 12%), thrombotic microangiopathy (n=6, 12%), and minimal change disease (n=5, 10%). All five membranoproliferative glomerulonephritis patients treated with rituximab, cyclophosphamide and prednisone-based regimens had recovery of renal function compared to 0/3 patients treated with rituximab with or without steroids. Chronic lymphocytic leukemia infiltration as the primary cause of renal abnormalities was typically observed in relapsed/refractory patients (4/6). Thrombotic microangiopathy primarily occurred as a treatment-related toxicity of pentostatin (4/6 cases), and resolved with drug discontinuation. All cases of minimal change disease resolved with immunosuppressive agents only. Renal biopsy plays an important role in the management of patients with chronic lymphocytic leukemia or monoclonal B-cell lymphocytosis who develop renal failure and/or nephrotic syndrome. PMID:26088927

  6. Idelalisib therapy of indolent B-cell malignancies: chronic lymphocytic leukemia and small lymphocytic or follicular lymphomas

    Directory of Open Access Journals (Sweden)

    Madanat YF

    2016-03-01

    Full Text Available Yazan F Madanat,1 Mitchell R Smith,2 Alexandru Almasan,3 Brian T Hill2 1Department of Internal Medicine, 2Department of Hematology and Medical Oncology, Taussig Cancer Institute, 3Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Abstract: Chronic lymphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma are indolent B-cell lymphoproliferative disorders that mainly affect an older population. Although the majority of patients in need of treatment derive significant benefit from conventional chemotherapeutic agents as well as monoclonal antibodies, less toxic and more effective treatments are needed. Novel agents that inhibit the B-cell receptor signaling pathway have shown promising outcomes in these disorders. Idelalisib is a potent selective oral inhibitor of phosphatidylinositol 3-kinase delta and has shown significant clinical activity in B-cell malignancies. In this review, we summarize the clinical trial data using idelalisib as monotherapy or in combination with rituximab for the treatment of relapsed/refractory disease. The adverse effect profile includes autoimmune disorders such as transaminitis, colitis, and pneumonitis. Given the efficacy and manageable toxicity profile of idelalisib, it is being increasingly incorporated into the management of indolent B-cell malignancies. Keywords: idelalisib, PI3Kδ inhibitors, chronic lymphocytic leukemia, follicular lymphoma

  7. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Wiestner, Adrian

    2015-12-01

    Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton's tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton's tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic

  8. Engineered T Cells for the Adoptive Therapy of B-Cell Chronic Lymphocytic Leukaemia

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    Philipp Koehler

    2012-01-01

    Full Text Available B-cell chronic lymphocytic leukaemia (B-CLL remains an incurable disease due to the high risk of relapse, even after complete remission, raising the need to control and eliminate residual tumor cells in long term. Adoptive T cell therapy with genetically engineered specificity is thought to fulfil expectations, and clinical trials for the treatment of CLL are initiated. Cytolytic T cells from patients are redirected towards CLL cells by ex vivo engineering with a chimeric antigen receptor (CAR which binds to CD19 on CLL cells through an antibody-derived domain and triggers T cell activation through CD3ζ upon tumor cell engagement. Redirected T cells thereby target CLL cells in an MHC-unrestricted fashion, secret proinflammatory cytokines, and eliminate CD19+ leukaemia cells with high efficiency. Cytolysis of autologous CLL cells by patient's engineered T cells is effective, however, accompanied by lasting elimination of healthy CD19+ B-cells. In this paper we discuss the potential of the strategy in the treatment of CLL, the currently ongoing trials, and the future challenges in the adoptive therapy with CAR-engineered T cells.

  9. A high rate of telomeric sister chromatid exchange occurs in chronic lymphocytic leukaemia B-cells.

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    Medves, Sandrine; Auchter, Morgan; Chambeau, Laetitia; Gazzo, Sophie; Poncet, Delphine; Grangier, Blandine; Verney, Aurélie; Moussay, Etienne; Ammerlaan, Wim; Brisou, Gabriel; Morjani, Hamid; Géli, Vincent; Palissot, Valérie; Berchem, Guy; Salles, Gilles; Wenner, Thomas

    2016-07-01

    Cancer cells protect their telomere ends from erosion through reactivation of telomerase or by using the Alternative Lengthening of Telomere (ALT) mechanism that depends on homologous recombination. Chronic lymphocytic leukaemia (CLL) B cells are characterized by almost no telomerase activity, shelterin deregulation and telomere fusions. To characterize telomeric maintenance mechanisms in B-CLL patients, we measured their telomere length, telomerase expression and the main hallmarks of the ALT activity i.e. C-circle concentration, an extra-chromosomal telomere repeat (ECTR), and the level of telomeric sister chromatid exchange (T-SCE) rate. Patients showed relative homogenous telomere length although almost no TERT transcript and nearly no C-circle were evidenced. Nevertheless, compared with normal B cells, B-CLL cells showed an increase in T-SCE rate that was correlated with a strong down-regulation of the topoisomerase III alpha (TOP3A) expression, involved in the dissolution of Holliday Junctions (HJ), together with an increased expression of SLX1A, SLX4, MUS81 and GEN1, involved in the resolution of HJ. Altogether, our results suggest that the telomere maintenance mechanism of B-CLL cells do not preferentially use telomerase or ALT. Rather, the rupture of the dissolvasome/resolvasome balance may increase telomere shuffling that could homogenize telomere length, slowing telomere erosion in this disease. PMID:26970083

  10. Mutation Pattern of Paired Immunoglobulin Heavy and Light Variable Domains in Chronic Lymphocytic Leukemia B Cells

    KAUST Repository

    Ghiotto, Fabio

    2011-01-01

    B-cell chronic lymphocytic leukemia (CLL) patients display leukemic clones bearing either germline or somatically mutated immunoglobulin heavy variable (IGHV ) genes. Most information on CLL immunoglobulins (Igs), such as the definition of stereotyped B-cell receptors (BCRs), was derived from germline unmutated Igs. In particular, detailed studies on the distribution and nature of mutations in paired heavy- and light-chain domains of CLL clones bearing mutated Igs are lacking. To address the somatic hyper-mutation dynamics of CLL Igs, we analyzed the mutation pattern of paired IGHV-diversity-joining (IGHV-D-J ) and immunoglobulin kappa/lambda variable-joining (IGK/LV-J ) rearrangements of 193 leukemic clones that displayed ≥ 2% mutations in at least one of the two immunoglobulin variable (IGV ) genes (IGHV and/or IGK/LV ). The relationship between the mutation frequency in IGHV and IGK/LV complementarity determining regions (CDRs) and framework regions (FRs) was evaluated by correlation analysis. Replacement (R) mutation frequency within IGK/LV chain CDRs correlated significantly with mutation frequency of paired IGHV CDRs in λ but not κ isotype CLL clones. CDRs of IGKV-J rearrangements displayed a lower percentage of R mutations than IGHVs. The frequency/pattern of mutations in kappa CLL Igs differed also from that in κ-expressing normal B cells described in the literature. Instead, the mutation frequency within the FRs of IGHV and either IGKV or IGLV was correlated. Notably, the amount of diversity introduced by replaced amino acids was comparable between IGHVs and IGKVs. The data indicate a different mutation pattern between κ and λ isotype CLL clones and suggest an antigenic selection that, in κ samples, operates against CDR variation.

  11. Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification

    OpenAIRE

    Strati, Paolo; Shanafelt, Tait D.

    2015-01-01

    Monoclonal B lymphocytosis (MBL) is defined as the presence of a clonal B-cell population in the peripheral blood with fewer than 5 × 109/L B-cells and no other signs of a lymphoproliferative disorder. The majority of cases of MBL have the immunophenotype of chronic lymphocytic leukemia (CLL). MBL can be categorized as either low count or high count based on whether the B-cell count is above or below 0.5 × 109/L. Low-count MBL can be detected in ∼5% of adults over the age of 40 years when ass...

  12. MicroRNAs in the pathology of B-Cell Chronic Lymphocytic Leukemia

    International Nuclear Information System (INIS)

    In chronic lymphocytic leukemia (B-CLL), aberrations along the p53 axis lead to decreased overall survival and therapy resistance. Recent studies identified miR-34a as a major downstream target of p53. We monitored the expression of miR-34a during disease development in a murine B-CLL model. miR-34a was upregulated >20-fold during the leukemic but not during the preleukemic phase. In the human system, B-CLL cells also had 4.6-fold higher miR-34a expression as compared to B-cells of healthy controls. In B-CLL cells of patients with p53 aberrations miR-34a expression was consistently low. The broad distribution of miR-34a levels in p53 wild-type individuals prompted us to study the correlation between SNP309 in the intronic promoter of MDM2 and miR-34a expression. B-CLL cells of patients with the SNP309 GG genotype had significantly lower miR-34a expression levels as compared to patients with the TT genotype (P =0.002). Low miR-34a levels were able to predict shorter time to treatment (P = 0.003) and were associated with an abbreviated lymphocyte doubling time. Further, overexpression of miR-34a in primary B-CLL cells induced apoptosis. These findings suggest miR-34a as a possible therapeutic avenue and a sensitive indicator of the activity of the p53 axis in B-CLL. (author)

  13. B cell receptor pathway in chronic lymphocytic leukemia: specific role of CC-292

    Directory of Open Access Journals (Sweden)

    Arnason JE

    2014-01-01

    Full Text Available Jon E Arnason,1 Jennifer R Brown21Beth Israel Deaconess Medical Center, 2CLL Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Chronic lymphocytic leukemia (CLL is the most common adult leukemia. The current treatment paradigm involves the use of chemoimmunotherapy, when patients develop an indication for therapy. With this strategy, a majority of patients will obtain a remission, though cure remains elusive. While treatable, the majority of CLL patients will die of complications of their disease. Recent advances in the understanding of the importance of the B cell receptor (BCR pathway in CLL have led to the development of a number of agents targeting this pathway. In this review, we discuss recent developments in the targeting of the BCR pathway, with a focus on CC-292. CC-292 covalently binds to Bruton's tyrosine kinase, a key mediator of BCR signaling, and has demonstrated preclinical and clinical activity in CLL, with acceptable tolerability. Based on the success of CC-292 and other inhibitors of the BCR pathway, these agents are being investigated in combination with standard therapy, with the hope that they will increase the depth and length of response, without significant toxicity.Keywords: Bruton's tyrosine kinase inhibitor, ibrutinib

  14. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Agathangelidis, Andreas; Darzentas, Nikos; Hadzidimitriou, Anastasia;

    2012-01-01

    Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as...

  15. Modification of immunocytochemical ZAP-70 assay for potential clinical application in B-cell chronic lymphocytic leukemia

    OpenAIRE

    Jerzy Kawiak; Jacek Roliński; Agnieszka Bojarska-Junak

    2011-01-01

    The ZAP-70 protein is a member of the Syk/ZAP protein tyrosine kinase family, normally expressed in T cells and NK cells but not found in normal, mature B cells. The protein plays a critical role in the initiation of T-cell signaling. Leukemic cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) that expressed nonmutated immunoglobulin V genes were found to express levels of ZAP-70 protein that were comparable to those detected in T cells of healthy adults. The ZAP-70 protein ...

  16. Cellular Immunotherapy Following Chemotherapy in Treating Patients With Recurrent Non-Hodgkin Lymphomas, Chronic Lymphocytic Leukemia or B-Cell Prolymphocytic Leukemia

    Science.gov (United States)

    2016-07-29

    Post-transplant Lymphoproliferative Disorder; B-Cell Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma; Recurrent Lymphoplasmacytic Lymphoma

  17. Expression profile of Eph receptors and ephrin ligands in healthy human B lymphocytes and chronic lymphocytic leukemia B-cells.

    Science.gov (United States)

    Alonso-C, Luis M; Trinidad, Eva M A; de Garcillan, Beatriz; Ballesteros, Monica; Castellanos, Milagros; Cotillo, Ignacio; Muñoz, Juan J; Zapata, Agustin G

    2009-03-01

    Increasing information relates some Eph receptors and their ligands, ephrins (EFN), with the immune system. Herein, we found that normal B-cells from peripheral blood (PB) and lymph nodes (LN) showed a differential expression of certain Eph/EFN members, some of them being modulated upon in vitro stimulation including EFNA1, EFNA4, EphB6 and EphA10. In contrast, PB CLL B-cells showed a more heterogeneous Eph/EFN profile than their normal PB B-cell counterparts, expressing Eph/EFN members frequently found within the LN and activated B-cells, specially EFNA4, EphB6 and EphA10. Two of them, EphB6 and EFNA4 were further related with the clinical course of CLL patients. EphB6 expression correlated with a high content of ZAP-70 mRNA and a poor prognosis. High serum levels of a soluble EFNA4 isoform positively correlated with increasing peripheral blood lymphocyte counts and lymphadenopathy. These findings suggest that Eph/EFN might be relevant in normal B-cell biology and could represent new potential prognostic markers and therapeutic targets for CLL. PMID:18819711

  18. The ibrutinib B-cell proliferation inhibition is potentiated in vitro by dexamethasone: Application to chronic lymphocytic leukemia.

    Science.gov (United States)

    Manzoni, Delphine; Catallo, Régine; Chebel, Amel; Baseggio, Lucile; Michallet, Anne-Sophie; Roualdes, Olivier; Magaud, Jean-Pierre; Salles, Gilles; Ffrench, Martine

    2016-08-01

    New B-cell receptor-targeted therapies such as ibrutinib, a Bruton tyrosine kinase inhibitor, are now proposed for lymphoid pathologies. The putative benefits of its combination with glucocorticoids were evaluated here. We compared the effects of dexamethasone (DXM), ibrutinib and their in vitro combination on proliferation and metabolic stress markers in stimulated normal B-lymphocytes and in malignant lymphocytes from chronic lymphocytic leukemia (CLL) patients. In both cellular models, cell cycle progression was globally inhibited by DXM and/or ibrutinib. This inhibition was significantly amplified by DXM addition to ibrutinib and was related to a significant decrease in the expression of the cell cycle regulatory proteins CDK4 and cyclin E. Apoptosis increased especially with DXM/ibrutinib combination and was associated with a significant decrease in Mcl-1 expression. Treatment effects on metabolic stress were evaluated by DNA damage recognition after 53BP1 foci labeling. The percentage of cells with more than five 53BP1 foci decreased significantly with ibrutinib in normal and CLL lymphocytes. This decrease was strongly reinforced, in CLL, by DXM addition. Our data indicated that, in vitro, DXM potentiated antiproliferative effects of ibrutinib and decreased DNA damage in lymphoid B-cells. Thus their combination may be proposed for CLL treatment. PMID:27235717

  19. B cell receptor pathway in chronic lymphocytic leukemia: specific role of CC-292

    OpenAIRE

    Arnason JE; Brown JR

    2014-01-01

    Jon E Arnason,1 Jennifer R Brown21Beth Israel Deaconess Medical Center, 2CLL Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. The current treatment paradigm involves the use of chemoimmunotherapy, when patients develop an indication for therapy. With this strategy, a majority of patients will obtain a remission, though cure remains elusive. While treatabl...

  20. Immunoglobulin heavy chain variable region gene repertoire and B-cell receptor stereotypes in Indian patients with chronic lymphocytic leukemia.

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    Rani, Lata; Mathur, Nitin; Gogia, Ajay; Vishnubhatla, Sreenivas; Kumar, Lalit; Sharma, Atul; Dube, Divya; Kaur, Punit; Gupta, Ritu

    2016-10-01

    In chronic lymphocytic leukemia (CLL), the geographical bias in immunoglobulin heavy-chain variable (IGHV) gene usage lead us to analyze IGHV gene usage and B-cell receptor stereotypy in 195 patients from India. IGHV3, IGHV4, and IGHV1 families were the most frequently used. 20.5% sequences had stereotyped BCR and were clustered in 12 pre-defined and 6 novel subsets. Unmutated IGHV was significantly associated with reduced time to first treatment (p cases (p = 0.045) in early stage patients. Regarding subfamily usage, only IGHV1-69 expression was found to have statistically significant poor outcome (p = 0.017). Our results from the analysis of various molecular and clinical features suggest that the expression of specific IGHV gene influences the outcome in early stage CLL, and hence its assessment may be added to the clinical leukemia laboratory armamentarium. PMID:26942309

  1. Igs Expressed by Chronic Lymphocytic Leukemia B Cells Show Limited Binding-Site Structure Variability

    KAUST Repository

    Marcatili, P.

    2013-05-01

    Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three-dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated. Copyright © 2013 by The American Association of Immunologists, Inc.

  2. Intrinsic and extrinsic factors influencing the clinical course of B-cell chronic lymphocytic leukemia: prognostic markers with pathogenetic relevance

    Directory of Open Access Journals (Sweden)

    Gaidano Gianluca

    2009-08-01

    Full Text Available Abstract B-cell chronic lymphocytic leukemia (CLL, the most frequent leukemia in the Western world, is characterized by extremely variable clinical courses with survivals ranging from 1 to more than 15 years. The pathogenetic factors playing a key role in defining the biological features of CLL cells, hence eventually influencing the clinical aggressiveness of the disease, are here divided into "intrinsic factors", mainly genomic alterations of CLL cells, and "extrinsic factors", responsible for direct microenvironmental interactions of CLL cells; the latter group includes interactions of CLL cells occurring via the surface B cell receptor (BCR and dependent to specific molecular features of the BCR itself and/or to the presence of the BCR-associated molecule ZAP-70, or via other non-BCR-dependent interactions, e.g. specific receptor/ligand interactions, such as CD38/CD31 or CD49d/VCAM-1. A putative final model, discussing the pathogenesis and the clinicobiological features of CLL in relationship of these factors, is also provided.

  3. Modification of immunocytochemical ZAP-70 assay for potential clinical application in B-cell chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Jerzy Kawiak

    2011-08-01

    Full Text Available The ZAP-70 protein is a member of the Syk/ZAP protein tyrosine kinase family, normally expressed in T cells and NK cells but not found in normal, mature B cells. The protein plays a critical role in the initiation of T-cell signaling. Leukemic cells from patients with B-cell chronic lymphocytic leukemia (B-CLL that expressed nonmutated immunoglobulin V genes were found to express levels of ZAP-70 protein that were comparable to those detected in T cells of healthy adults. The ZAP-70 protein expression can be evaluated by flow cytometry and may be used as a prognostic marker in B-CLL patients. We modified the method of immunocytochemical assessment of ZAP-70 expression. The traditional two-step method with monoclonal anti-ZAP-70 antibody in the first step followed by FITC-conjugated goat anti-mouse IgG was changed for one-step method with monoclonal anti-ZAP-70 antibody labeled by Zenon Alexa Fluor 488. The method is simple and fast. The major advantage of Zenon labeling technique is its compatibility with simultaneous staining of surface antigens. The cells may be earlier immunostained for CD3, CD19 and/or CD5 to compare of the ZAP-70 kinase expression in B and T cells.

  4. Modification of immunocytochemical ZAP-70 assay for potential clinical application in B-cell chronic lymphocytic leukemia.

    Science.gov (United States)

    Bojarska-Junak, Agnieszka; Roliński, Jacek; Kawiak, Jerzy

    2005-01-01

    The ZAP-70 protein is a member of the Syk/ZAP protein tyrosine kinase family, normally expressed in T cells and NK cells but not found in normal, mature B cells. The protein plays a critical role in the initiation of T-cell signaling. Leukemic cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) that expressed nonmutated immunoglobulin V genes were found to express levels of ZAP-70 protein that were comparable to those detected in T cells of healthy adults. The ZAP-70 protein expression can be evaluated by flow cytometry and may be used as a prognostic marker in B-CLL patients. We modified the method of immunocytochemical assessment of ZAP-70 expression. The traditional two-step method with monoclonal anti-ZAP-70 antibody in the first step followed by FITC-conjugated goat anti-mouse IgG was changed for one-step method with monoclonal anti-ZAP-70 antibody labeled by Zenon Alexa Fluor 488. The method is simple and fast. The major advantage of Zenon labeling technique is its compatibility with simultaneous staining of surface antigens. The cells may be earlier immunostained for CD3, CD19 and/or CD5 to compare of the ZAP-70 kinase expression in B and T cells. PMID:15871558

  5. Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment.

    Science.gov (United States)

    Ten Hacken, Elisa; Burger, Jan A

    2016-03-01

    Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL. Novel small molecule inhibitors, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and the phosphoinositide-3-kinase delta (PI3Kδ) inhibitor idelalisib, target BCR signaling and have become the most successful new therapeutics in this disease. We here review the cellular and molecular characteristics of CLL cells, and discuss the cellular components and key pathways involved in the cross-talk with their microenvironment. We also highlight the relevant novel treatment strategies, focusing on immunomodulatory agents and BCR signaling inhibitors and how these treatments disrupt CLL-microenvironment interactions. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza. PMID:26193078

  6. Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Lanemo Myhrinder, Anna; Hellqvist, Eva; Bergh, Ann-Charlotte;

    2013-01-01

    ) and DNA/short tandem repeat (STR) fingerprinting. Innate B-cell features, i.e. natural Ab production and CD5 receptors, were present in most CLL cell lines, but in none of the normal LCLs. This panel of immortalized CLL-derived cell lines is a valuable reference representing a renewable source of...

  7. T-cell independent, B-cell receptor-mediated induction of telomerase activity differs among IGHV mutation-based subgroups of chronic lymphocytic leukemia patients

    OpenAIRE

    Damle, Rajendra N.; Temburni, Sonal; Banapour, Taraneh; Paul, Santanu; Mongini, Patricia K. A.; Allen, Steven L.; Kolitz, Jonathan E.; Rai, Kanti R; Chiorazzi, Nicholas

    2012-01-01

    Although B-cell chronic lymphocytic leukemia (B-CLL) clones with unmutated IGHV genes (U-CLL) exhibit greater telomerase activity than those with mutated IGHV genes (M-CLL), the extent to which B-cell receptor (BCR) triggering contributes to telomerase up-regulation is not known. Therefore, we studied the effect of BCR stimulation on modulating telomerase activity. The multivalent BCR ligand, dextran conjugated anti-μ mAb HB57 (HB57-dex), increased telomerase activity and promoted cell surviv...

  8. Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation.

    OpenAIRE

    Yeomans, Alison; Thirdborough, Stephen M.; Valle-Argos, Beatriz; Linley, Adam; Krysov, Sergey; Hidalgo, Marina Sanchez; Leonard, Elodie; Ishfaq, Muhammad; Wagner, Simon D.; Willis, Anne E.; Steele, Andrew; Stevenson, Freda; Forconi, Francesco; Coldwell, Mark J; Packham, Graham

    2015-01-01

    Antigenic stimulation via the B-cell receptor (BCR) is a major driver of the proliferation and survival of chronic lymphocytic leukemia (CLL) cells. However, the precise mechanisms by which BCR stimulation leads to accumulation of malignant cells remain incompletely understood. Here, we investigated the ability of BCR stimulation to increase messenger RNA (mRNA) translation, which can promote carcinogenesis by effects on both global mRNA translation and upregulated expression of specific onco...

  9. Serologic markers of effective tumor immunity against chronic lymphocytic leukemia include non-mutated B cell antigens

    OpenAIRE

    Marina, Ovidiu; Hainz, Ursula; Biernacki, Melinda A.; Zhang, Wandi; Cai, Ann; Duke-Cohan, Jonathan S.; Liu, Fenglong; Brusic, Vladimir; Neuberg, Donna; Kutok, Jeffery L.; Alyea, Edwin P.; Canning, Christine M.; Soiffer, Robert J.; Ritz, Jerome; Wu, Catherine J.

    2010-01-01

    Patients with chronic lymphocytic leukemia (CLL) who relapse after allogeneic transplant may achieve durable remission following donor lymphocytes infusion (DLI), demonstrating the potency of donor-derived immunity in eradicating tumor. We sought to elucidate the antigenic basis of the effective graft-versus-leukemia (GvL) responses associated with DLI for the treatment of CLL by analyzing the specificity of plasma antibody responses developing in two DLI-treated patients who achieved long-te...

  10. Tris (dibenzylideneacetone) dipalladium: a small-molecule palladium complex is effective in inducing apoptosis in chronic lymphocytic leukemia B-cells.

    Science.gov (United States)

    Kay, Neil E; Sassoon, Traci; Secreto, Charla; Sinha, Sutapa; Shanafelt, Tait D; Ghosh, Asish K; Arbiser, Jack L

    2016-10-01

    Here we tested impact of Tris (dibenzylideneacetone) dipalladium (Tris-DBA) on chronic lymphocytic leukemia (CLL) B-cell survival. Indeed, treatment of CLL B-cells with Tris-DBA induced apoptosis in a dose-dependent manner irrespective of IgVH mutational status. Further analyses suggest that Tris-DBA-induced apoptosis involves reduced expression of the anti-apoptotic proteins Bcl-xL, and XIAP with an upregulation of the pro-apoptotic protein BIM in CLL B-cells. Our findings also indicate that Tris-DBA targets the ribosomal protein (rp)-S6, an essential component of the Akt/mTOR signaling axis in CLL B-cells. Of interest, CLL bone marrow stromal cells were unable to protect the leukemic B cells from Tris-DBA-induced apoptosis in an in vitro co-culture system. Finally, co-administration of Tris-DBA and the purine nucleoside analog fludarabine (F-ara-A) augmented CLL B-cell apoptosis levels in vitro showing synergistic effects. In total, Tris-DBA is effective at inducing apoptosis in CLL B-cells even in the presence of stromal cells likely by targeting directly the signal mediator, rpS6. PMID:27189785

  11. B-Cell Chronic Lymphocytic Leukemia with 11q22.3 Rearrangement in Patient with Chronic Myeloid Leukemia Treated with Imatinib.

    Science.gov (United States)

    Lewandowski, Krzysztof; Gniot, Michał; Lewandowska, Maria; Wache, Anna; Ratajczak, Błażej; Czyż, Anna; Jarmuż-Szymczak, Małgorzata; Komarnicki, Mieczysław

    2016-01-01

    The coexistence of two diseases chronic myeloid leukemia (CML) and B-cell chronic lymphocytic leukemia (B-CLL) is a rare phenomenon. Both neoplastic disorders have several common epidemiological denominators (they occur more often in men over 50 years of age) but different origin and long term prognosis. In this paper we described the clinical and pathological findings in patient with CML in major molecular response who developed B-CLL with 11q22.3 rearrangement and Coombs positive hemolytic anemia during the imatinib treatment. Due to the presence of the symptoms of autoimmune hemolytic anemia and optimal CML response to the imatinib treatment, the decision about combined therapy with prednisone and imatinib was made. During the follow-up, the normalization of complete blood count and resolution of peripheral lymphadenopathy were noted. The hematologic response of B-CLL was diagnosed. The repeated FISH analysis of cultured peripheral blood lymphocytes showed 2% of cells carrying 11q22.3 rearrangement. At the same time, molecular monitoring confirmed the deep molecular response of CML. The effectiveness of such combination in the described case raises the question about the best therapeutic option in such situation, especially in patients with good imatinib tolerance and optimal response. PMID:27034682

  12. PEG10 Activation by Co-Stimulation of CXCR5 and CCR7 Essentially Contributes to Resistance to Apoptosis in CD19+CD34+ B Cells from Patients with B Cell Lineage Acute and Chronic Lymphocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    ChunsongHu; JeiXiong; LinjeiZhang; BaojunHuang; QiupingZhang; QunLi; MingzhenYang; YaouWu; QunWu; QianShen; QingpingGao; KejianZhang; ZhiminSun; JunyanLin; YouxinJin

    2004-01-01

    We investigated CD19+CD34+ and CD19+CD34 B cells from cord blood (CB) and typical patients with B cell lineage acute and chronic lymphocytic leukemia (B-ALL and B-CLL) in terms of expression and functions of CXCR5/CXCL13 and CCR7/CCL19. CXCR5 and CCR7 were selectively frequent expressed on B-ALL, B-CLL and CB CD19+CD34+ B cells, but not on CD19+CD34- B cells. Instead of induction of impressive chemotactic responsiveness, CXCL13 and CCL19 together induced significant resistance to TNF-α-mediated apoptosis in B-ALL and B-CLL but not CB CD19+CD34+ B cells. B-ALL and B-CLL CD19+CD34+ B cells expressed elevatedlevel of Paternally Expressed Gene 10 (PEG10), and CXCL13 and CCL19 together significantly up-regulated PEG10 expression in the cells. We found that CXCL13 and CCL19 together by means of activation of CXCR5 and CCR7 up-regulated PEG10 expression and function, subsequent stabilized caspase-3 and caspase-8 in B-ALL and B-CLL CD19+CD34+ B cells, and rescued the cells from TNF-α-mediated apoptosis. We suggested that normal lymphocytes, especially naive B and T cells, utilized CXCR5/CXCL13 and CCR7/CCL19 for migration, homing, maturation, and cell homeostasis as well as secondary lymphoid tissues organogenesis. Meanwhile certain malignant cells took advantages of CXCR5/CXCL13 and CCR7/CCL19 for infiltration, resistance to apoptosis, and inappropriate proliferation. Cellular & Molecular Immunology.

  13. PEG10 Activation by Co-Stimulation of CXCR5 and CCR7 Essentially Contributes to Resistance to Apoptosis in CD19+CD34+ B Cells from Patients with B Cell Lineage Acute and Chronic Lymphocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    Chunsong Hu; Qian Shen; Qingping Gao; Kejian Zhang; Zhimin Sun; Junyan Liu; Youxin Jin; Jinquan Tan; Jei Xiong; Linjei zhang; Baojun Huang; Qiuping Zhang; Qun Li; Mingzhen Yang; Yaou Wu; Qun Wu

    2004-01-01

    We investigated CD19+CD34+ and CD19+CD34- B cells from cord blood (CB) and typical patients with B cell lineage acute and chronic lymphocytic leukemia (B-ALL and B-CLL) in terms of expression and functions of CXCR5/CXCL13 and CCR7/CCL19. CXCR5 and CCR7 were selectively frequent expressed on B-ALL, B-CLL and CB CD19+CD34+ B cells, but not on CD19+CD34- B cells. Instead of induction of impressive chemotactic responsiveness, CXCL13 and CCL19 together induced significant resistance to TNF-α-mediated apoptosis in B-ALL and B-CLL but not CB CD19+CD34+ B cells. B-ALL and B-CLL CD19+CD34+ B cells expressed elevated level of Paternally Expressed Gene 10 (PEG10), and CXCL13 and CCL19 together significantly up-regulated PEG10 expression in the cells. We found that CXCL13 and CCL19 together by means of activation of CXCR5 and CCR7 up-regulated PEG10 expression and function, subsequent stabilized caspase-3 and caspase-8 in B-ALL and B-CLL CD19+CD34+ B cells, and rescued the cells from TNF-α-mediated apoptosis. We suggested that normal lymphocytes, especially na(I)ve B and T cells, utilized CXCR5/CXCL13 and CCR7/CCL19 for migration, homing, maturation, and cell homeostasis as well as secondary lymphoid tissues organogenesis.Meanwhile certain malignant cells took advantages of CXCR5/CXCL13 and CCR7/CCL19 for infiltration,resistance to apoptosis, and inappropriate proliferation.

  14. Concurrent epigenetic silencing of wnt/β-catenin pathway inhibitor genes in B cell chronic lymphocytic leukaemia

    International Nuclear Information System (INIS)

    The Wnt/β-catenin signalling is aberrantly activated in primary B cell chronic lymphocytic leukaemia (CLL). Epigenetic silencing of pathway inhibitor genes may be a mechanism for its activation. In this study, we investigated systematically and quantitatively the methylation status of 12 Wnt/β-catenin pathway inhibitor genes – CDH1, DACT1, DKK1, DKK2, DKK3, DKK4, SFRP1, SFRP2, SFRP3, SFRP4, SFRP5 and WIF1 – in the cell lines EHEB and MEC-1 as well as patient samples. Quantification of DNA methylation was performed by means of bisulphite pyrosequencing and confirmed by bisulphite Sanger sequencing. Gene expression was analysed by qPCR using GAPDH as internal control. E-cadherin and β-catenin protein quantification was carried out by microsphere-based immunoassays. Methylation differences observed between the patient and control groups were tested using generalised least squares models. For 10 genes, a higher methylation level was observed in tumour material. Only DKK4 exhibited similarly high methylation levels in both tumour and normal specimens, while DACT1 was always essentially unmethylated. However, also for these inhibitors, treatment of cells with the demethylating agent 5-aza-2´-deoxycytidine resulted in an induction of their expression, as shown by quantitative PCR, suggesting an indirect epigenetic control of activity. While the degree of demethylation and its transcriptional consequences differed between the genes, there was an overall high correlation of demethylation and increased activity. Protein expression studies revealed that no constitutive Wnt/β-catenin signalling occurred in the cell lines, which is in discrepancy with results from primary CLL. However, treatment with 5-aza-2´-deoxycytidine caused accumulation of β-catenin. Simultaneously, E-cadherin expression was strongly induced, leading to the formation of a complex with β-catenin and thus demonstrating its epigenetically regulated inhibition effect. The results suggest an

  15. Fludarabine Phosphate and Total-Body Irradiation Before Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia

    Science.gov (United States)

    2016-07-18

    B-Cell Prolymphocytic Leukemia; Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia

  16. CD137 is induced by the CD40 signal on chronic lymphocytic leukemia B cells and transduces the survival signal via NF-κB activation.

    Directory of Open Access Journals (Sweden)

    Yukana Nakaima

    Full Text Available CD137 is a member of the tumor necrosis factor receptor family that is expressed on activated T cells. This molecule provides a co-stimulatory signal that enhances the survival, and differentiation of cells, and has a crucial role in the development of CD8 cytotoxic T cells and anti-tumor immunity. Here we report that CD137 expression is also induced on normal or malignant human B cells by CD40 ligation by its ligand CD154. This CD137 induction was more prominent in chronic lymphocytic leukemia (CLL cells than in other types of B cells. CD137 stimulation on B cells by its ligand induced the nuclear translocation of p52 (a non-canonical NF-κB factor. In agreement with this finding, expression of the survival factor BCL-XL was upregulated. Consequently, the CD137 signal augmented the survival of CD154-stimulated CLL B cells in vitro. This unexpected induction of CD137 on B cells by CD40 signal may influence the clinical course of CLL.

  17. Safety, Tolerability, and Pharmacokinetics of Idelalisib in Japanese Adults With Relapsed or Refractory Indolent B-Cell Non-Hodgkin Lymphomas or Chronic Lymphocytic Leukemia

    Science.gov (United States)

    2016-05-16

    Chronic Lymphocytic Leukemia; Indolent Non-Hodgkin Lymphoma; Follicular Lymphoma; Small Lymphocytic Lymphoma; Lymphoplasmacytic Lymphoma (With or Without Waldenstrom Macroglobulinemia); Marginal Zone Lymphoma

  18. T-cell independent, B-cell receptor-mediated induction of telomerase activity differs among IGHV mutation-based subgroups of chronic lymphocytic leukemia patients.

    Science.gov (United States)

    Damle, Rajendra N; Temburni, Sonal; Banapour, Taraneh; Paul, Santanu; Mongini, Patricia K A; Allen, Steven L; Kolitz, Jonathan E; Rai, Kanti R; Chiorazzi, Nicholas

    2012-09-20

    Although B-cell chronic lymphocytic leukemia (B-CLL) clones with unmutated IGHV genes (U-CLL) exhibit greater telomerase activity than those with mutated IGHV genes (M-CLL), the extent to which B-cell receptor (BCR) triggering contributes to telomerase up-regulation is not known. Therefore, we studied the effect of BCR stimulation on modulating telomerase activity. The multivalent BCR ligand, dextran conjugated anti-μ mAb HB57 (HB57-dex), increased telomerase activity and promoted cell survival and proliferation preferentially in U-CLL cases, whereas the PI3K/Akt inhibitor LY294002 blocked HB57-dex induced telomerase activation. Although both U-CLL and M-CLL clones exhibited similar membrane proximal signaling responses to HB57-dex, telomerase activity and cell proliferation, when inducible in M-CLL, differed. B-CLL cells stimulated using bivalent F(ab')(2) -goat anti-μ antibody (goat anti-μ) exhibited higher membrane proximal response in U-CLL than M-CLL cells, whereas telomerase activity, cell survival, and proliferation were induced to lower levels than those induced by HB57-dex. In normal B lymphocytes, HB57-dex induced less protein phosphorylation but more cell proliferation and survival than goat anti-μ. Although both anti-BCR stimuli induced comparable telomerase activity, normal CD5(+) B cells preferentially exhibited higher hTERT positivity than their CD5(-) counterparts. These findings provide an understanding of how BCR-mediated signals impact telomerase modulation in IGHV mutation-based subgroups of B-CLL and normal B cells. PMID:22875913

  19. Multidimensional single-cell analysis of BCR signaling reveals proximal activation defect as a hallmark of chronic lymphocytic leukemia B cells.

    Directory of Open Access Journals (Sweden)

    M Lia Palomba

    Full Text Available PURPOSE: Chronic Lymphocytic Leukemia (CLL is defined by a perturbed B-cell receptor-mediated signaling machinery. We aimed to model differential signaling behavior between B cells from CLL and healthy individuals to pinpoint modes of dysregulation. EXPERIMENTAL DESIGN: We developed an experimental methodology combining immunophenotyping, multiplexed phosphospecific flow cytometry, and multifactorial statistical modeling. Utilizing patterns of signaling network covariance, we modeled BCR signaling in 67 CLL patients using Partial Least Squares Regression (PLSR. Results from multidimensional modeling were validated using an independent test cohort of 38 patients. RESULTS: We identified a dynamic and variable imbalance between proximal (pSYK, pBTK and distal (pPLCγ2, pBLNK, ppERK phosphoresponses. PLSR identified the relationship between upstream tyrosine kinase SYK and its target, PLCγ2, as maximally predictive and sufficient to distinguish CLL from healthy samples, pointing to this juncture in the signaling pathway as a hallmark of CLL B cells. Specific BCR pathway signaling signatures that correlate with the disease and its degree of aggressiveness were identified. Heterogeneity in the PLSR response variable within the B cell population is both a characteristic mark of healthy samples and predictive of disease aggressiveness. CONCLUSION: Single-cell multidimensional analysis of BCR signaling permitted focused analysis of the variability and heterogeneity of signaling behavior from patient-to-patient, and from cell-to-cell. Disruption of the pSYK/pPLCγ2 relationship is uncovered as a robust hallmark of CLL B cell signaling behavior. Together, these observations implicate novel elements of the BCR signal transduction as potential therapeutic targets.

  20. Cross-talk between chronic lymphocytic leukemia (CLL) tumor B cells and mesenchymal stromal cells (MSCs): implications for neoplastic cell survival.

    Science.gov (United States)

    Trimarco, Valentina; Ave, Elisa; Facco, Monica; Chiodin, Giorgia; Frezzato, Federica; Martini, Veronica; Gattazzo, Cristina; Lessi, Federica; Giorgi, Carlo Alberto; Visentin, Andrea; Castelli, Monica; Severin, Filippo; Zambello, Renato; Piazza, Francesco; Semenzato, Gianpietro; Trentin, Livio

    2015-12-01

    Leukemic cells from Chronic Lymphocytic Leukemia (CLL) patients interact with stromal cells of the surrounding microenvironment. Mesenchymal Stromal Cells (MSCs) represent the main population in CLL marrow stroma, which may play a key role for disease support and progression. In this study we evaluated whether MSCs influence in vitro CLL cell survival. MSCs were isolated from the bone marrow of 46 CLL patients and were characterized by flow cytometry analysis. Following co-culture of MSCs and leukemic B cells, we demonstrated that MSCs were able to improve leukemic B cell viability, this latter being differently dependent from the signals coming from MSCs. In addition, we found that the co-culture of MSCs with leukemic B cells induced an increased production of IL-8, CCL4, CCL11, and CXCL10 chemokines.As far as drug resistance is concerned, MSCs counteract the cytotoxic effect of Fludarabine/Cyclophosphamide administration in vivo, whereas they do not protect CLL cells from the apoptosis induced by the kinase inhibitors Bafetinib and Ibrutinib. The evidence that leukemic clones are conditioned by environmental stimuli suggest new putative targets for therapy in CLL patients. PMID:26517523

  1. Peptide vaccination induces profound changes in the immune system in patients with B-cell chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Michael Schmitt

    2011-04-01

    Full Text Available Although the immune status of chronic lymphocytic leukemia (CLL patients is mostly characterized by immunosuppression, there is an accumulation of in vivo (graft-versus-leukemia effect and in vitro (spontaneous remissions after infections data that indicates that CLL might be effectively targeted by T-cell based immunotherapy. Recently, we characterized receptor for hyaluronic acid mediated motility (RHAMM as a preferential target for immunotherapy of CLL. We also completed a RHAMM-derived peptide vaccination phase I/II clinical trial in CLL. Here, we present a detailed immunological analysis of six CLL patients vaccinated with HLA-A2 restricted RHAMM-derived epitope R3 (ILSLELMKL. Beside effective induction of R3-specific cytotoxic T-cells, peptide vaccination caused profound changes in different T-cell subsets as well as cytokines. We present longitudinal analyses of Th17, CD8+CD103+, CD8+CD137+ and IL-17 producing CD8+ T cells (CD8+IL- -17+ as well as important cytokines involved in regulation of immune response such as TGF-β, IL-10, IL-2 and TNF throughout the peptide vaccination period. (Folia Histochemica et Cytobiologica 2011, Vol. 49, No. 1, 161–167

  2. Expression of Functional Sphingosine-1 Phosphate Receptor-1 Is Reduced by B Cell Receptor Signaling and Increased by Inhibition of PI3 Kinase δ but Not SYK or BTK in Chronic Lymphocytic Leukemia Cells

    OpenAIRE

    Till, Kathleen J.; Andrew R Pettitt; Slupsky, Joseph R.

    2015-01-01

    BCR signaling pathway inhibitors such as ibrutinib, idelalisib, and fostamatinib (respective inhibitors of Bruton’s tyrosine kinase, PI3Kδ, and spleen tyrosine kinase) represent a significant therapeutic advance in B cell malignancies, including chronic lymphocytic leukemia (CLL). These drugs are distinctive in increasing blood lymphocytes while simultaneously shrinking enlarged lymph nodes, suggesting anatomical redistribution of CLL cells from lymph nodes into the blood. However, the mechan...

  3. Different frequencies and effects of ABCB1 T3435C polymorphism on clinical and laboratory features of B cell chronic lymphocytic leukemia in Kurdish patients.

    Science.gov (United States)

    Maroofi, Farzad; Amini, Sabrieh; Roshani, Daem; Ghaderi, Bayazid; Abdi, Mohammad

    2015-04-01

    Finding the effects of gene polymorphism on cancer pathogenesis is very desirable. The ATP-binding cassette is involved in drug metabolism, and the polymorphism of this gene may be an important risk factor in B cell chronic lymphocytic leukemia (B-CLL) or progression and/or response to chemotherapy agents. For the first time, the present study was aimed to evaluate the probable effects of ABCB1 T3435C polymorphism on clinical and laboratory features of Kurdish patients with B-CLL. This descriptive analytical case-control study was performed on 50 B-CLL patients and 100 healthy subjects. Serum levels of beta-2-microglobulin (B2M) and lactate dehydrogenase (LDH) and blood WBC, RBC, Plt and ESR were measured. The T3435C polymorphism of the ABCB1 gene was determined by PCR-RFLP. Concentration of serum and blood markers was significantly higher in the malignant group than in the benign subjects. The CC genotype had the highest frequency (66%) in the patient groups. There are no significant differences between the genotypes and type of treatment. Our results demonstrate the high frequency of C allele of ABCB1 T3435C in B-CLL patients with Kurdish ethnicity. We also show that this polymorphism has a significant risk factor in B-CLL. However, the effect of this polymorphism on clinical and laboratory characteristics of B-CLL patients was not significant. PMID:25586345

  4. Therapeutic potential of new B cell-targeted agents in the treatment of elderly and unfit patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Rai, Kanti R

    2015-01-01

    Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is primarily a disease of the elderly, with most patients ≥65 years of age and having at least one major comorbidity. Aggressive chemoimmunotherapy regimens recommended to achieve remission and improve survival in young, fit patients are often poorly tolerated in elderly and/or less physiologically fit ("unfit") patients, necessitating alternative treatment options. Although patient age, fitness, and comorbidities are key considerations in the selection of a treatment regimen, historically, clinical trials have been limited to young, fit patients by virtue of the ethical concerns associated with potential end organ toxic effects that could worsen comorbidities. However, the availability of new therapies promises a shift to a research paradigm that encompasses the identification of optimal treatments for elderly and unfit patients. Anti-CD20 monoclonal antibody therapy, which overall has improved response rates and survival in patients with CLL, has only recently been evaluated elderly and unfit patients. B cell-targeted agents such as the Bruton's tyrosine kinase inhibitor ibrutinib and the phosphatidylinositol 3-kinase inhibitor idelalisib are the first of a new generation of oral agents for CLL. Available clinical data suggest that these therapies have the potential to address the unmet need in elderly and unfit patients with CLL and result in clinical remission, and not merely symptom palliation and improved quality of life, which, by themselves, are also a reasonable goal. PMID:26170206

  5. Genetically Engineered Lymphocytes, Cyclophosphamide, and Aldesleukin in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or Indolent B-Cell Non-Hodgkin Lymphoma

    Science.gov (United States)

    2014-08-04

    B-cell Chronic Lymphocytic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  6. Relevance of stereotyped B-cell receptors in the context of the molecular, cytogenetic and clinical features of chronic lymphocytic leukemia.

    Directory of Open Access Journals (Sweden)

    Francesco Maura

    Full Text Available Highly homologous B-cell receptors, characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV genes and heavy-chain complementarity determining region-3 (HCDR3, are expressed in a recurrent fraction of patients affected by chronic lymphocytic leukemia (CLL. We investigated the IGHV status of 1131 productive IG rearrangements from a panel of 1126 CLL patients from a multicenter Italian study group, and correlated the presence and class of HCDR3 stereotyped subsets with the major cytogenetic alterations evaluated by FISH, molecular prognostic factors, and the time to first treatment (TTFT of patients with early stage disease (Binet A. Stereotyped HCDR3 sequences were found in 357 cases (31.7%, 231 of which (64.7% were unmutated. In addition to the previously described subsets, 31 new putative stereotypes subsets were identified. Significant associations between different stereotyped HCDR3 sequences and molecular prognostic factors, such as CD38 and ZAP-70 expression, IGHV mutational status and genomic abnormalities were found. In particular, deletion of 17p13 was significantly represented in stereotype subset #1. Notably, subset #1 was significantly correlated with a substantially reduced TTFT compared to other CLL groups showing unmutated IGHV, ZAP-70 or CD38 positivity and unfavorable cytogenetic lesions including del(17(p13. Moreover, subset #2 was strongly associated with deletion of 13q14, subsets #8 and #10 with trisomy 12, whereas subset #4 was characterized by the prevalent absence of the common cytogenetic abnormalities. Our data from a large and representative panel of CLL patients indicate that particular stereotyped HCDR3 sequences are associated with specific cytogenetic lesions and a distinct clinical outcome.

  7. In vitro and in vivo evaluation of direct rhenium-188-labeled anti-CD52 monoclonal antibody alemtuzumab for radioimmunotherapy of B-cell chronic lymphocytic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Decker, Mario de [Department of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent (Belgium); Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen, Groningen (Netherlands)], E-mail: mario.dedecker@health.wa.gov.au; Bacher, Klaus; Thierens, Hubert [Department of Medical Physics and Radiation Protection, Ghent University, Ghent (Belgium); Slegers, Guido [Department of Medical Imaging of Domestic Animals, Ghent University, Ghent (Belgium); Dierckx, Rudi A. [Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen, Groningen (Netherlands); Vos, Filip de [Department of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent (Belgium)

    2008-07-15

    Alemtuzumab (Campath, Berlex) is a humanized IgG1 rat monoclonal antibody directed against the cell surface CD52 antigen, found on lymphocytes and monocytes. It is being developed for the treatment of chronic lymphocytic leukemia (CLL), autoimmune disease and for the prevention of transplant rejection. This study focused on synthesis, quality control, in vitro evaluation and biodistrubution of {sup 188}Re-labeled alemtuzumab for radioimmunotherapy of B-cell CLL. {sup 188}Re-alemtuzumab was synthesized using a direct radiolabeling method. Reduction of the intramolecular disulfide bonds of the antibody was performed with tris-(carboxyethyl)-phosphine (Pierce), using a 1:60 molar excess. Reaction took place at room temperature for 20 min. A PD-10 desalting column was used to purify the reduced antibody from excess phospine. Complexation and transchelation of {sup 188}ReO{sub 4}{sup -} was achieved using sodium gluconate as weak chelator and SnCl{sub 2} as reducing agent. Quality control was done using instant thin-layer chromatography. Binding assays were performed on a CD52-positive cell line (HuT-78). Female NMRI mice were injected intravenously with 20 {mu}g radiolabeled alemtuzumab and killed at preset time intervals for biodistribution studies. Tissues were dissected, weighed and counted for determination of radioactivity. Data were expressed as percentage injected activity per gram of tissue (% IA/g tissue) or as percentage injected activity (% IA). {sup 188}Re-alemtuzumab was prepared achieving high radiochemical yields. Labeling efficiency of more than 95% can be obtained using optimal reaction conditions. {sup 188}Re-alemtuzumab showed good in vitro stability, remaining intact at 24 h after radiolabeling. In mice, {sup 188}Re-alemtuzumab showed high uptake in the blood (25.10{+-}1.36% IA at 1 h p.i.), followed by a biexponential clearance (t{sub 1/2{alpha}}=4.790 h and t{sub 1/2{beta}}=55.45 h). Increased uptake was observed in kidneys and heart (9

  8. Screening of YAC clones and building a map of the chromosome 13 region often deleted during chronic B-cell lymphocytic leucosis

    NARCIS (Netherlands)

    Brodyanskii, VM; Sulimova, GE; Udina, IG; Aitova, SS; Shaikhaev, GO; Sharikova, OA; Zakharev, VM; Fedorova, LI; Zelenin, AV; Eikhorn, S; Baush, C; Laland, M; Ross, M; Yankovskii, NK

    1995-01-01

    Pools of YAC clones from the ICRF library were analyzed by PCR using PBKpt, MGG15, and D13S25 markers that flank the chromosome 13 region often deleted during chronic lymphocytic leukemia. Ten clones were found and described. Nine mega-YAC clones from the CEPH library flanking the region of interest

  9. Assessment of expression of selected Bcl-2 family proteins in lymphoid infiltration in patients with B-cell chronic lymphocytic leukaemia treated with nucleoside analogues.

    Directory of Open Access Journals (Sweden)

    Janusz Kłoczko

    2008-12-01

    Full Text Available B-cell chronic lymphocytic leukaemia (B-CLL is characterized by clonal growth and accumulation of mature lymphoid cells due to disturbance in genetically regulated form of cell death called apoptosis. The intrinsic mechanism of apoptosis is controlled by Bcl-2 family proteins. Purine nucleoside analogues induce the apoptosis in cells in a state of quiescence. The aim of the study was to assess expression of selected Bcl-2 family proteins in neoplastic infiltration in bone marrow in patients with B-CLL treated with nucleoside analogues. The study comprised examination of bone marrow obtained routinely by trephine biopsy from 18 patients with B-CLL diagnosed before administration of purine nucleoside analogues treatment and after its completion. Expression of Bcl-2, Bcl-x and Bax proteins was examined. Lymphoid cells in bone marrow were present in all patients before administration of treatment. After treatment in two patients bone marrow was infiltrated in diffuse pattern, whereas other patients presented nodular pattern of infiltration. The difference between stage of infiltration before and after treatment was statistically significant (p<0.002. High percentage of infiltration cells with positive anti Bcl-2 reaction from 42.0% in one patient to 85.33+/-3.06% in four patients before treatment was observed. After treatment percentage of infiltration cells with positive anti Bcl-2 antibody reaction was from 33.0+/-18.38% in two patients to 99.0% in one patient. Positive correlation between stage of infiltration and expression of Bcl-2 protein was confirmed before and after treatment. Such correlations were not observed in case of Bax and Bcl-x. Strong staining of immunohistochemical reaction of cells in lymphoid infiltration with Bcl-2 antibody was confirmed. There was a difference between Bcl-/Bax ratio before and after treatment. Immunohistochemical assessment of expression of Bcl-2 family proteins in cells of lymphoid infiltration in bone

  10. Polyclonal B-cell lymphocytosis with binucleated lymphocytes (PPBL

    Directory of Open Access Journals (Sweden)

    Xavier Troussard

    2008-10-01

    Full Text Available Xavier Troussard1, Edouard Cornet1, Jean-François Lesesve2, Carine Kourel3, Hossein Mossafa31Laboratoire d’Hématologie Côte de Nacre, Université Caen Basse Normandie Caen, Registre Régional des Hémopathies Malignes de Basse Normandie, France; 2Laboratoire d’Hématologie, Vandoeuvre-Les-Nancy Cedex, France; 3Département de Génétique Humaine, Laboratoire pasteur-Cerba, Cergy-Pontoise, FranceFor the Groupe Français d’Hématologie cellulaire (GFHCAbstract: Persistent polyclonal B-cell lymphocytosis (PPBL is a rare and recently described entity. The review of the literature show PPBL is diagnosed predominantly but not exclusively in women, usually smokers. PPBL is recognized by a moderate, chronic and absolute lymphocytosis (>4 × 109/l in the peripheral blood. In 10% of cases without lymphocytosis, the PPBL diagnosis has to be suggested by peripheral blood examination showing in all cases atypical binucleated lymphocytes. A polyclonal serum IgM is also associated and HLA-DR7 expression is present in most cases. Contrary to B-cell chronic lymphoproliferative disorders (B-CLPD, peripheral B cells are polyclonal with kappa and lambda light-chain expression and no clonal rearrangement of immunoglobulin heavy chain genes is usually demonstrated. The detection of an extra isochromosome for the long arm of chromosome 3 +i(3(q10 has to be considered as a specific marker of PPBL. We performed conventional cytogenetic analysis (CCA in 111 patients with typical PPBL we followed-up more than 4 years. +i(3q was detected in 34% (33/98, PCC in 8% (8/98 and both abnormalities in 31% (30/98. CCA showed neither +i(3q nor PCC in 28% (27/98. Fluorescence in situ hybridization (FISH was also performed in 84 cases and +i(3q was detected in 71% (60/84. When combining both procedures in 84 patients, +i(3q was detected in 17 patients with negative CCA and was confirmed in 43 patients with positive CCA. CCA and FISH were both negative in 24 cases. Whether

  11. [Chronic lymphocytic leukemia].

    Science.gov (United States)

    Aoki, Sadao

    2016-03-01

    Currently, several novel drugs are available for chronic lymphocytic leukemia (CLL) in Western countries. Of these drugs, those that inhibit the B-cell receptor (BCR) signaling pathway are the most promising. Ibrutinib inhibits BTK in the BCR pathway and can be administered orally. The results of several clinical trials suggest that ibrutinib is highly effective against relapsed/resistant (RR) and treatment-naïve CLL. Furthermore, ibrutinib shows equivalent efficacy on CLL with the 17p deletion. Idelalisib, which also blocks the BCR pathway, inhibits PIK3delta and induces CLL cell death. Clinical trials have shown outstanding efficacy of idelalisib against RR-CLL, especially when administered with antiCD20 antibodies. This drug is also effective against CLL with the 17p deletion. ABT-199 is another novel drug; it inhibits BCL2 signaling, not the BCR pathway, and can be administered orally. The efficacy of ABT-199 against RR-CLL has been demonstrated in a number of clinical trials. These drugs have only mild toxicity and can be used for patients in poor general condition. Unfortunately, none of these drugs have yet been approved in Japan. Rapid resolution of the 'drug lag' problem is necessary. PMID:27076234

  12. Stages of Chronic Lymphocytic Leukemia

    Science.gov (United States)

    ... ALL Treatment Childhood AML Treatment Research Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version General Information About Chronic Lymphocytic Leukemia Go to Health Professional Version Key Points Chronic ...

  13. Association between gene and miRNA expression profiles and stereotyped subset #4 B-cell receptor in chronic lymphocytic leukemia.

    Science.gov (United States)

    Maura, Francesco; Cutrona, Giovanna; Mosca, Laura; Matis, Serena; Lionetti, Marta; Fabris, Sonia; Agnelli, Luca; Colombo, Monica; Massucco, Carlotta; Ferracin, Manuela; Zagatti, Barbara; Reverberi, Daniele; Gentile, Massimo; Recchia, Anna Grazia; Bossio, Sabrina; Rossi, Davide; Gaidano, Gianluca; Molica, Stefano; Cortelezzi, Agostino; Di Raimondo, Francesco; Negrini, Massimo; Tassone, Pierfrancesco; Morabito, Fortunato; Ferrarini, Manlio; Neri, Antonino

    2015-01-01

    In this study we investigated specific biological and clinical features associated with chronic lymphocytic leukemia (CLL) patients carrying stereotyped BCR subset #4 (IGHV4-34) among a prospective cohort of 462 CLL/MBL patients in early stage (Binet A). All subset #4 patients (n = 16) were characterized by the IGHV mutated gene configuration, and absence of unfavorable cytogenetic lesions, NOTCH1 or SF3B1 mutations. Gene and miRNA expression profiling evidenced that the leukemic cells of subset #4 cases showed significant downregulation of WDFY4, MF2A and upregulation of PDGFA, FGFR1 and TFEC gene transcripts, as well as the upregulation of miR-497 and miR-29c. The transfection of miR-497 mimic in primary leukemic CLL cells induced a downregulation of BCL2, a known validated target of this miRNA. Our data identify biological characteristics associated with subset #4 patients, providing further evidence for the putative role of BCR in shaping the features of the tumor cells in CLL. PMID:25860243

  14. Small B cell lymphocytic lymphoma presenting as obstructive sleep apnea

    Directory of Open Access Journals (Sweden)

    Chang Weng-Cheng

    2004-07-01

    Full Text Available Abstract Background Most lymphomas that involve the tonsil are large B cell lymphomas. Large B-cell lymphoma is a high grade malignancy which progresses rapidly. Tonsillar lymphoma usually presents as either a unilaterally enlarged palatine tonsil or as an ulcerative and fungating lesion over the tonsillar area. Small lymphocytic lymphomas (SLL of the Waldeyer's ring are uncommon. Case presentation We report a 41-year-old male who presented with a ten-year history of snoring. Physical examination revealed smooth bilateral symmetrically enlarged tonsils without abnormal surface change or cervical lymphadenopathy. Palatal redundancy and a narrowed oropharyngeal airway were also noted. The respiratory disturbance index (RDI was 66 per hour, and severe obstruction sleep apnea (OSA was suspected. No B symptoms, sore throat, odynophagia or dysphagia was found. We performed uvulopalatopharyngoplasty (UPPP and pathological examination revealed incidental small B-cell lymphocytic lymphoma (SLL. Conclusion It is uncommon for lymphoma to initially present as OSA. SLL is an indolent malignancy and is not easy to detect in the early stage. We conclude that SLL may be a contributing factor of OSA in the present case.

  15. Monoclonal Antibody Therapy in Treating Patients With Chronic Lymphocytic Leukemia, Lymphocytic Lymphoma, Acute Lymphoblastic Leukemia, or Acute Myeloid Leukemia

    Science.gov (United States)

    2013-06-03

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

  16. 非经典性NF-κB活性在慢性B淋巴细胞白血病中的作用%Function of alternative NF-κB activity in B-cell chronic lymphocytic leukemia cells

    Institute of Scientific and Technical Information of China (English)

    徐晶晶; 周鹏; 国风

    2014-01-01

    Objective To investigate the function of alternative NF-κB activity in B-cell chronic lymphocytic leukemia cells (B-CLL).Methods The mRNA expression of individual NF-κB subunits in CD5+CD19+ cells (CLL B-cells) from bone marrow (BM) of 56 patients with B-CLL was analyzed by quantitative RT-PCR.An ELISA-based NF-κB family transcription factor activity assay was performed to quantify the κB DNA-binding activity in nuclear extracts from CLL B-cells.Cell death of CLL-B cells was determined by PI staining,RelA and RelB expression at protein level of CLL B-cells by Western blot analyses.Results The expression levels of RelA,p50,RelB and p52 mRNA in CLL B-cells were all higher than that of normal B cells with statistical significance (P<0.05).RelA was activated in almost all the patients detected while RelB activity was induced in part of samples.The average RelA activity in CLL B-cells was increased compared to that in normal B cells while the average RelB activity was similar to that of normal B cells.When cultured in vitro for 24,48 and 72 hours,the frequencies of cell death of CLL B-cells from RelA+/RelB-group were (35.54±4.43)%,(50.92±8.44)%,and (49.24±8.16)%,respectively;that of the RelA+/RelB+ group were (20.65±2.37)%,(18.17± 1.36)%,and (26.55±4.08)%,respectively.When the cells from RelA+/RelB-group were co-cultured with bone marrow stromal cells (hBMSCs),the frequencies of cell death of CLL B-cells were decreased compared to that of the cells cultured alone,while the frequencies of cell death of RelA+/RelB-CLL B-cells were higher than that of CLL B-cells from RelA+/ RelB+ group when co-cultured with hBMSCs.RelA and RelB expression in CLL-B cells from the RelA+/RelB-group was induced after co-cultured with hBMSCs for 48h.RelB was reduced in the cytoplasm and increased in the nucleus in CLL-B cells from the RelA+/RelB+ group.Conclusion The alternative NF-κB was indeed activated and presented heterogenous in CLL B-cells from BM.Activation of

  17. Pembrolizumab Alone or With Idelalisib or Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Other Low-Grade B-Cell Non-Hodgkin Lymphomas

    Science.gov (United States)

    2016-04-18

    Recurrent Chronic Lymphocytic Leukemia; Recurrent Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Lymphoplasmacytic Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Nodal Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent Splenic Marginal Zone Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Refractory Follicular Lymphoma; Refractory Lymphoplasmacytic Lymphoma; Refractory Nodal Marginal Zone Lymphoma; Refractory Small Lymphocytic Lymphoma; Refractory Splenic Marginal Zone Lymphoma; Richter Syndrome; Waldenstrom Macroglobulinemia

  18. Deregulation of the carbohydrate (chondroitin 4) sulfotransferase 11 (CHST11) gene in a B-cell chronic lymphocytic leukemia with a t(12;14)(q23;q32).

    Science.gov (United States)

    Schmidt, Helmut H; Dyomin, Vadim G; Palanisamy, Nallasivam; Itoyama, Takahiro; Nanjangud, Gouri; Pirc-Danoewinata, Hendrati; Haas, Oskar A; Chaganti, R S K

    2004-09-01

    The t(12;14)(q23;q32) breakpoints in a case of B-cell chronic lymphocytic leukemia (B-CLL) were mapped by fluorescence in situ hybridization (FISH) and Southern blot analysis and cloned using an IGH switch-gamma probe. The translocation affected a productively rearranged IGH allele and the carbohydrate (chondroitin 4) sulfotransferase 11 (CHST11) locus at 12q23, with a reciprocal break in intron 2 of the CHST11 gene. CHST11 belongs to the HNK1 family of Golgi-associated sulfotransferases, a group of glycosaminoglycan-modifying enzymes, and is expressed mainly in the hematopoietic lineage. Northern Blot analysis of tumor RNA using CHST11-specific probes showed expression of two CHST11 forms of abnormal size. 5'- and 3'-Rapid Amplification of cDNA Ends (RACE) revealed IGH/CHST11 as well as CHST11/IGH fusion RNAs expressed from the der(14) and der(12) chromosomes. Both fusion species contained open reading frames making possible the translation of two truncated forms of CHST11 protein. The biological consequence of t(12;14)(q23;q32) in this case presumably is a disturbance of the cellular distribution of CHST11 leading to deregulation of a chondroitin-sulfate-dependent pathway specific to the hematopoietic lineage. PMID:15273723

  19. Ibrutinib (PCI-32765) in Chronic Lymphocytic Leukemia

    OpenAIRE

    Jain, Nitin; O’Brien, Susan

    2013-01-01

    B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are currently being studied as potential therapeutic targets. These include Lyn, Syk, PI3 and Bruton tyrosine (BTK). Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of BTK. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation. In addition, it also affects CLL cell migration and homing. Early clinic...

  20. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Herman, S E M; Niemann, C U; Farooqui, M;

    2014-01-01

    Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further...

  1. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study

    DEFF Research Database (Denmark)

    Coiffier, B.; Lepretre, S.; Pedersen, L.M.;

    2008-01-01

    Safety and efficacy of the fully human anti-CD20 monoclonal antibody, ofatumumab, was analyzed in a multicenter dose-escalating study including 33 patients with relapsed or refractory chronic lymphocytic leukemia. Three cohorts of 3 (A), 3 (B), and 27 (C) patients received 4, once weekly, infusio...

  2. What Is Chronic Lymphocytic Leukemia?

    Science.gov (United States)

    ... Topic Normal bone marrow, blood, and lymphoid tissue What is chronic lymphocytic leukemia? Cancer starts when cells ... body, including the lymph nodes, liver, and spleen. What is leukemia? Leukemia is a cancer that starts ...

  3. Treatment Options by Stage (Chronic Lymphocytic Leukemia)

    Science.gov (United States)

    ... ALL Treatment Childhood AML Treatment Research Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version General Information About Chronic Lymphocytic Leukemia Go to Health Professional Version Key Points Chronic ...

  4. Treatment Option Overview (Chronic Lymphocytic Leukemia)

    Science.gov (United States)

    ... ALL Treatment Childhood AML Treatment Research Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version General Information About Chronic Lymphocytic Leukemia Go to Health Professional Version Key Points Chronic ...

  5. Selective loss of B-cell phenotype in lymphocyte predominant Hodgkin lymphoma.

    NARCIS (Netherlands)

    Tedoldi, S.; Mottok, A.; Ying, J.; Paterson, J.C.; Cui, Y.; Facchetti, F.; Krieken, J.H.J.M. van; Ponzoni, M.; Ozkal, S.; Masir, N.; Natkunam, Y.; Pileri, S.; Hansmann, M.L.; Mason, D.; Tao, Q.; Marafioti, T.

    2007-01-01

    The neoplastic Reed-Sternberg cells characteristic of classical Hodgkin's lymphoma (cHL) are of B-cell origin but they almost always show striking loss of a range of B-cell-associated molecules. In contrast, the neoplastic cells found in lymphocyte predominant Hodgkin's lymphoma (LPHL) (L&H cells) a

  6. Genetically Engineered Lymphocyte Therapy in Treating Patients With B-Cell Leukemia or Lymphoma That is Resistant or Refractory to Chemotherapy

    Science.gov (United States)

    2015-07-31

    Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  7. Levels of expression of CD19 and CD20 in chronic B cell leukaemias.

    Science.gov (United States)

    Ginaldi, L; De Martinis, M; Matutes, E; Farahat, N; Morilla, R; Catovsky, D

    1998-01-01

    AIMS: To investigate whether the antigen levels of the B cell lineage markers CD19 and CD20 can distinguish between normal and neoplastic B cells or characterise distinct expression patterns among the chronic B cell leukaemias. METHODS: Peripheral blood cells from 70 patients with B cell disorders and 17 healthy donors were analysed by quantitative flow cytometry. Direct immunofluorescence staining was performed with phycoerythrin conjugated CD19 and CD20 monoclonal antibodies. Standard microbeads with different capacities to bind mouse immunoglobulins were used to convert the mean fluorescence intensity (MFI) values into number of antigen molecules/cell, expressed as antibody binding capacity (ABC). RESULTS: CD19 and CD20 ABC values in leukaemic B cells differed from those of normal blood B lymphocytes. The results identified distinct profiles of CD19 and CD20 expression in the various types of B cell leukaemias. In all leukaemias studied except hairy cell leukaemia (HCL), CD19 expression was significantly lower than the mean (SD) value in normal B cells (22 (7) x 10(3) molecules/cell), as follows: chronic lymphocytic leukaemia (CLL), 13 (7) x 10(3); B prolymphocytic leukaemia (B-PLL), 16 (9) x 10(3); splenic lymphoma with villous lymphocytes (SLVL), 15 (11) x 10(3); mantle cell lymphoma (MCL), 10 (7) x 10(3). In HCL there was strong CD19 expression (38 (16) x 10(3)). In contrast, the level of expression of membrane CD20 was higher than the mean (SD) value in normal B cells (94 (16) x 10(3) molecules/cell) in MCL (123 (51) x 10(3)); B-PLL (129 (47) x 10(3)); SLVL (167 (72) x 10(3)); and HCL (312 (110) x 10(3)); while it was significantly lower (65 (11) x 10(3)) in CLL compared with normal B cells and the other B cell leukaemias. CONCLUSIONS: Quantitative determination of CD19 and CD20 may provide useful diagnostic information for the study of B lymphoproliferative disorders. PMID:9708202

  8. Smudge cells in peripheral blood smears did not differentiate chronic lymphocytic leukemia from other B-cell chronic lymphoprolipherative diseases Sombras nucleares no esfregaço do sangue periférico não diferenciam a leucemia linfocítica crônica das outras doenças linfoproliferativas B crônicas

    Directory of Open Access Journals (Sweden)

    Daniel M. Matos

    2009-01-01

    Full Text Available Smudge cells has been classically associated with chronic lymphocytic leukemia (CLL, but they are found in peripheral blood tests for other chronic B-cell lymphoproliferative diseases (CLD. We investigated whether the percentage of smudge cells in peripheral blood smears can be used in the clinical practice to differentiate CLL from other B-cell CLD. The peripheral blood smears of 63 patients with the diagnosis of CLL and 62 with other B-cell CLD were analyzed. Three hundred cells (both lymphoid cells and smudge cells were counted for each peripheral blood smear. A comparison of the percentage of smudge cells between the two groups was performed and, subsequently, 5 cut-off values were fixed (10%, 20%, 30%, 40% and 50% of smudge cells with the aim of defining cases as "positive" or "negative" for smudge cells and verifying whether there are any differences between CLL and the other B-cell CLD. The percentage of smudge cells in patients with CLL (median 26%, 4%-86% was higher than in patients with B-cell CLD (median 14%, 1%-64%. However, none of the cut-off values tested presented suitable values of sensitivity, specificity and positive predictive value to separate the two groups. As it is necessary to have a single cut-off value with high sensitivity, specificity and positive predictive value to infer the diagnosis of CLL in the clinical practice, we concluded that smudge cells are not fitting to differentiate CLL from other B-cell CLD.As sombras nucleares têm sido classicamente associadasà leucemia linfocítica crônica (LLC, embora possam ser encontradas nos esfregaços do sangue periférico de outras doenças linfoproliferativas B crônicas (DLBC. Nesse estudo, nós investigamos se a porcentagem de sombras nucleares nos esfregaços do sangue periférico pode ser utilizada na prática clínica da hematologia para diferenciar a LLC das outras DLBC. Foram analisados os esfregaços do sangue periférico de 63 pacientes com o diagnóstico de LLC

  9. Impaired removal of Vβ8(+) lymphocytes aggravates colitis in mice deficient for B cell lymphoma-2-interacting mediator of cell death (Bim)

    OpenAIRE

    Leucht, K; Caj, M; Fried, M; Rogler, G; Hausmann, M.

    2013-01-01

    We investigated the role of B cell lymphoma (BCL)-2-interacting mediator of cell death (Bim) for lymphocyte homeostasis in intestinal mucosa. Lymphocytes lacking Bim are refractory to apoptosis. Chronic colitis was induced in Bim-deficient mice (Bim(-/-) ) with dextran sulphate sodium (DSS). Weight loss and colonoscopic score were increased significantly in Bim(-/-) mice compared to wild-type mice. As Bim is induced for the killing of autoreactive cells we determined the role of Bim in the re...

  10. Autoimmune Cytopenias in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Giovanni D'Arena

    2013-01-01

    Full Text Available The clinical course of chronic lymphocytic leukemia (CLL may be complicated at any time by autoimmune phenomena.The most common ones are hematologic disorders, such as autoimmune hemolytic anemia (AIHA and immune thrombocytopenia (ITP. Pure red cell aplasia (PRCA and autoimmune agranulocytosis (AG are, indeed, more rarely seen. However, they are probably underestimated due to the possible misleading presence of cytopenias secondary to leukemic bone marrow involvement or to chemotherapy cytotoxicity. The source of autoantibodies is still uncertain, despite the most convincing data are in favor of the involvement of resting normal B-cells. In general, excluding the specific treatment of underlying CLL, the managementof these complications is not different from that of idiopathic autoimmune cytopenias or of those associated to other causes. Among different therapeutic approaches, monoclonal antibody rituximab, given alone or in combination, has shown to be very effective.

  11. [The genetic landscape of chronic lymphocytic leukemia].

    Science.gov (United States)

    Marosvári, Dóra; Alpár, Donát; Király, Attila Péter; Rajnai, Hajnalka; Reiniger, Lilla; Bödör, Csaba

    2016-06-01

    Chronic lymphocytic leukemia (CLL) is the most frequent mature B-cell non-Hodgkin's lymphoma in the Western countries. The recent next-generation sequencing (NGS) studies lead to an exponential increase in our knowledge of the pathogenesis and progression of CLL. Whole genome and exome sequencing studies revealed a remarkable inter- and intra-patient genetic heterogeneity with a significant therapy-induced clonal evolution in the majority of the patients. Driver mutations were identified in components of various signalling pathways and cellular processes with notable prognostic and therapeutic relevance. Interestingly, these studies revealed only a few genes mutated in at least 15-20% of the patients with a larger number of genes mutated in a smaller proportion of patients. This improved understanding of the genomic landscape of CLL has opened new avenues for a more precise patient stratification and rational application of novel, more effective targeted therapies. PMID:27275638

  12. Quantification of newly produced B and T lymphocytes in untreated chronic lymphocytic leukemia patients

    Directory of Open Access Journals (Sweden)

    Caimi Luigi

    2010-11-01

    Full Text Available Abstract Background The immune defects occurring in chronic lymphocytic leukemia are responsible for the frequent occurrence of infections and autoimmune phenomena, and may be involved in the initiation and maintenance of the malignant clone. Here, we evaluated the quantitative defects of newly produced B and T lymphocytes. Methods The output of B and T lymphocytes from the production and maturation sites was analyzed in chronic lymphocytic leukemia patients and healthy controls by quantifying kappa-deleting recombination excision circles (KRECs and T-cell receptor excision circles (TRECs by a Real-Time PCR assay that simultaneously detects both targets. T-lymphocyte subsets were analyzed by six-color flow cytometric analysis. Data comparison was performed by two-sided Mann-Whitney test. Results KRECs level was reduced in untreated chronic lymphocytic leukemia patients studied at the very early stage of the disease, whereas the release of TRECs+ cells was preserved. Furthermore, the observed increase of CD4+ lymphocytes could be ascribed to the accumulation of CD4+ cells with effector memory phenotype. Conclusions The decreased number of newly produced B lymphocytes in these patients is likely related to a homeostatic mechanism by which the immune system balances the abnormal B-cell expansion. This feature may precede the profound defect of humoral immunity characterizing the later stages of the disease.

  13. B-Cell Hematologic Malignancy Vaccination Registry

    Science.gov (United States)

    2015-09-15

    Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Waldenstrom Macroglobulinemia; Lymphocytosis; Lymphoma, Non-Hodgkin; B-Cell Chronic Lymphocytic Leukemia; Hematological Malignancies

  14. Chronic Lymphocytic Leukemia: Inception to Cure: Are We There?

    OpenAIRE

    Lad, Deepesh P.; Malhotra, Pankaj; Varma, Subhash

    2012-01-01

    There have been remarkable advances in our understanding of the biology and therapeutics of chronic lymphocytic leukemia. B cell receptor signaling and micro-environment in CLL biology have been the most modern areas of research. In CLL therapeutics, we have come a long way from alkylating agents to chemo-immunotherapy. Despite this there remain significant lacunae in the disease biology that has hindered our quest to achieve the ultimate in CLL: Cure. This review aims to summarize the past, ...

  15. Immunological aspects in chronic lymphocytic leukemia (CLL) development

    OpenAIRE

    García-Muñoz, Ricardo; Galiacho, Verónica Roldan; Llorente, Luis

    2012-01-01

    Chronic lymphocytic leukemia (CLL) is unique among B cell malignancies in that the malignant clones can be featured either somatically mutated or unmutated IGVH genes. CLL cells that express unmutated immunoglobulin variable domains likely underwent final development prior to their entry into the germinal center, whereas those that express mutated variable domains likely transited through the germinal center and then underwent final development. Regardless, the cellular origin of CLL remains ...

  16. Curcumin and Cholecalciferol in Treating Patients With Previously Untreated Stage 0-II Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2016-02-16

    Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia

  17. Vorinostat, Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2016-05-04

    Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  18. Allogeneic cellular immunotherapy for chronic B-cell leukemia

    OpenAIRE

    Hoogendoorn, Mels

    2007-01-01

    Allogeneic stem cell transplantation (SCT) following reduced-intensity conditioning (RIC) as treatment modality has curative potential in patients suffering from chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL), illustrating susceptibility of these leukemic cells for the graft-versus-leukemia (GvL) effect. However, effectiveness of this therapy is limited due to low immunogenicity of leukemic cells and the lack of specificity resulting in concurrent development of graft-versus...

  19. DNA apoptosis and stability in B-cell chronic lymphoid leukaemia: implication of the DNA double-strand breaks repair system by non homologous recombination

    International Nuclear Information System (INIS)

    After an introduction presenting the diagnosis and treatment of chronic lymphoid leukaemia, its molecular and genetic characteristics, and its cellular origin and clonal evolution, this research thesis describes the apoptosis (definition and characteristics, cancer and chemotherapy, apoptotic ways induced by gamma irradiation), the genotoxic stresses, the different repair mechanisms for different damages, and the DNA repair processes. It reports how human chronic lymphocytic leukaemia B cells can escape DNA damage-induced apoptosis through the non-homologous end-joining DNA repair pathway, and presents non-homologous end-joining DNA repair as a potent mutagenic process in human chronic lymphocytic leukaemia B cells

  20. Stromal control of chronic lymphocytic leukemia cells

    Directory of Open Access Journals (Sweden)

    Seke Etet PF

    2013-09-01

    Full Text Available Paul Faustin Seke Etet,1 Armel Herve Nwabo Kamdje,2 Jeremie Mbo Amvene,2 Yousef Aldebasi,3 Mohammed Farahna,1 Lorella Vecchio41Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia; 2Department of Medicine, University of Ngaoundere, Ngaoundere, Cameroon; 3Department of Optometry, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia; 4Laboratory of Cytometry, Institute of Molecular Genetics, CNR, University of Pavia, Pavia, ItalyAbstract: In the ongoing efforts to develop therapies against chronic lymphocytic leukemia (CLL, stromal factors allowing malignant cells to escape spontaneous and chemotherapy-mediated apoptosis, giving way to relapses, have been abundantly investigated. Bone marrow adherent cell types, collectively referred to as stromal cells, appear to be key players in such escape, mainly because CLL malignant cells, which rapidly undergo spontaneous apoptosis when cultured in vitro, survive, migrate, and resist cytotoxic agents in co-culture with bone marrow stromal cells. CLL displays variable clinical courses according to well-defined prognostic factors induced on malignant B-cells (CLL cells or expressed by the transformed bone marrow stromal microenvironment. Particularly, a critical pathogenic role is played by proinflammatory factors, adhesion molecules, and signaling molecules involved in cell fate and stemness, such as Notch, Wnt, sonic Hedgehog, phosphoinositide 3-kinase (PI3K, protein kinase B (Akt, and the B-cell CLL/lymphoma 2 (Bcl-2 family of regulator proteins. As herein discussed, these molecules probably form a complex network favoring CLL cell survival, proliferation, and chemoresistance to anticancer therapy. Characterizing the sets of signaling pathways involved in the interactions between stromal cells and CLL cells may provide new tools for CLL clinical phenotyping and for re-sensitizing chemotherapy resistant cells

  1. Ultraviolet-induced DNA excision repair in human B and T lymphocytes. 3. Repair in lymphocyte from chronic lymphocytic leukaemia

    International Nuclear Information System (INIS)

    This study examined the capacity of lymphocytes from individuals with chronic lymphocytic leukaemia (CLL) to undertake ultraviolet (u.v.)-induced DNA repair in comparison to control and age-matched purified B and T lymphocytes. The technique was independent of incorporation of radioactive precursor, i.e. by the recovery of normal sedimentation behaviour of nucleoid bodies obtained from these cells by lysis in high salt and non-ionic detergent. Recovery of normal sedimentation was associated with restoration of DNA supercoiling. CLL cells were found to be as sensitive to u.v. and to repair at similar rates as age-matched B controls. They were considerably more sensitive than young B cells and repaired less efficiently. Reasons for previous reported discrepancies in CLL repair were discussed. (author)

  2. [Chronic B-cell lymphoproliferative disorders with hairy cells].

    Science.gov (United States)

    Troussard, Xavier; Cornet, Édouard

    2015-01-01

    The standardized blood smear examination is the first step in the diagnosis of a B-cell chronic lymphoproliferative disorder and can guide further investigations. In the laboratory, the identification of hairy cells on blood smear is a matter of daily practice. Hairy cell proliferations represent heterogeneous entities and their respective diagnoses can be difficult. If hairy cell leukemia (HCL) and splenic marginal zone lymphoma (SMZL) represent separate entities, the variant form of HCL (HCLv) and splenic diffuse red pulp small B-cell lymphoma (SDRPL) remain provisional entities in the 2008 WHO classification. We discuss the main clinical and biological characteristics of these four entities and appropriate means to characterize, identify and distinguish from each other; standardized blood smear examination, multiparameter flow cytometry analysis, analysis of the repertoire of immunoglobulins heavy chains genes and their mutational status (mutated or unmutated profile), molecular analyses: BRAF gene V600E mutation in HCL and MAP2K1 gene mutations in HCLv. We also discuss the main therapeutic aspects with emphasis on the new targeted drugs that enter into force in the therapeutic arsenal. PMID:25858127

  3. Idelalisib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma.

    Science.gov (United States)

    Barrientos, Jacqueline C

    2016-09-01

    Idelalisib is a first-in-class selective oral PI3Kδ inhibitor for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma, a predominantly elderly population with high comorbidity. The drug promotes apoptosis in primary CLL cells ex vivo, independent of common prognostic markers and inhibits CLL cell homing, migration and adhesion to cells in the microenvironment. Idelalisib has shown efficacy with acceptable safety as monotherapy and combination therapy in relapsed/refractory CLL. Idelalisib has clinical activity in patients with CLL with del(17p). The development of other novel B-cell-targeted agents provides the opportunity to evaluate additional idelalisib treatment combinations for their potential to further improve outcomes in CLL/small lymphocytic lymphoma. PMID:27324214

  4. Selective loss of B-cell phenotype in lymphocyte predominant Hodgkin lymphoma.

    Science.gov (United States)

    Tedoldi, S; Mottok, A; Ying, J; Paterson, J C; Cui, Y; Facchetti, F; van Krieken, J H J M; Ponzoni, M; Ozkal, S; Masir, N; Natkunam, Y; Pileri, Sa; Hansmann, M-L; Mason, Dy; Tao, Q; Marafioti, T

    2007-12-01

    The neoplastic Reed-Sternberg cells characteristic of classical Hodgkin's lymphoma (cHL) are of B-cell origin but they almost always show striking loss of a range of B-cell-associated molecules. In contrast, the neoplastic cells found in lymphocyte predominant Hodgkin's lymphoma (LPHL) (L&H cells) are traditionally thought of as possessing the full repertoire of features associated with germinal centre B cells (eg BCL-6 expression, 'ongoing' Ig gene mutation). In the present paper, we report an extensive phenotypic analysis of L&H cells which revealed down-regulation of a number of markers associated with the B-cell lineage (eg CD19, CD37) and with the germinal centre maturation stage (eg PAG, LCK). The promoter methylation status of three of these down-regulated genes (CD10, CD19, and LCK) was further studied in microdissected L&H cells, and this revealed that their promoters were unmethylated. In contrast, these genes showed promoter methylation in cell lines derived from CHL. Further investigation of the mechanisms responsible for the deregulation of these molecules in L&H cells may provide new insights into the genetic abnormalities underlying LPHL. PMID:17935142

  5. Addition of Rice Bran Arabinoxylan to Curcumin Therapy May Be of Benefit to Patients With Early-Stage B-Cell Lymphoid Malignancies (Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Stage 0/1 Chronic Lymphocytic Leukemia): A Preliminary Clinical Study.

    Science.gov (United States)

    Golombick, Terry; Diamond, Terrence H; Manoharan, Arumugam; Ramakrishna, Rajeev

    2016-06-01

    Hypothesis Prior studies on patients with early B-cell lymphoid malignancies suggest that early intervention with curcumin may lead to delay in progressive disease and prolonged survival. These patients are characterized by increased susceptibility to infections. Rice bran arabinoxylan (Ribraxx) has been shown to have immunostimulatory, anti-inflammatory, and proapoptotic effects. We postulated that addition of Ribraxx to curcumin therapy may be of benefit. Study design Monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) or stage 0/1 chronic lymphocytic leukemia (CLL) patients who had been on oral curcumin therapy for a period of 6 months or more were administered both curcumin (as Curcuforte) and Ribraxx. Methods Ten MGUS/SMM patients and 10 patients with stage 0/1 CLL were administered 6 g of curcumin and 2 g Ribraxx daily. Blood samples were collected at baseline and at 2-month intervals for a period of 6 months, and various markers were monitored. MGUS/SMM patients included full blood count (FBC); paraprotein; free light chains/ratio; C-reactive protein (CRP)and erythrocyte sedimentation rate (ESR); B2 microglobulin and immunological markers. Markers monitored for stage 0/1 CLL were FBC, CRP and ESR, and immunological markers. Results Of 10 MGUS/SMM patients,5 (50%) were neutropenic at baseline, and the Curcuforte/Ribraxx combination therapy showed an increased neutrophil count, varying between 10% and 90% among 8 of the 10 (80%) MGUS/SMM patients. An additional benefit of the combination therapy was the potent effect in reducing the raised ESR in 4 (44%) of the MGUS/SMM patients. Conclusion Addition of Ribraxx to curcumin therapy may be of benefit to patients with early-stage B-cell lymphoid malignancies. PMID:27154182

  6. T and B cells and PHA response of peripheral lymphocytes among atomic bomb survivors

    International Nuclear Information System (INIS)

    Little is known about immune compretence in atomic bomb survivors. The following results were observed from this study. T and B cells showed no change in proportion by age or exposure dose. The percentage of T cells was slightly lower in malignant tumor patients than in the control group. However, it was significantly higher in the group with chromosomal aberrations than in the control group. Phytohemagglutinin (PHA) response of peripheral lymphocytes decreased significantly with age in the 0 rad control group and the 200+ rad exposure group, particularly so in the latter. The malignant tumor group also showed lower PHA response than the control group. The PHA response of the chromosomal aberration group was significantly depressed compared with that of the control group. (author)

  7. Not all IGHV3-21 chronic lymphocytic leukemias are equal

    DEFF Research Database (Denmark)

    Baliakas, Panagiotis; Agathangelidis, Andreas; Hadzidimitriou, Anastasia;

    2015-01-01

    An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in...

  8. Do We Know What Causes Chronic Lymphocytic Leukemia?

    Science.gov (United States)

    ... Topic Can chronic lymphocytic leukemia be prevented? Do we know what causes chronic lymphocytic leukemia? The exact ... genes -- the instructions for how our cells function. We look like our parents because they are the ...

  9. Stromal-cell and cytokine-dependent lymphocyte clones which span the pre-B- to B-cell transition.

    Science.gov (United States)

    Ishihara, K; Medina, K; Hayashi, S; Pietrangeli, C; Namen, A E; Miyake, K; Kincade, P W

    1991-01-01

    Five stromal-cell-dependent lymphocyte clones are described that correspond to late pre-B or early B-cell stages of differentiation. They are useful for determining the molecular requirements for pre-B replication, for studying the stromal cells that supply those factors, and for delineating the final sequence of differentiation events as newly formed lymphocytes prepare to exit the bone marrow. The efficiency of lymphocyte growth at limiting dilution varied substantially on different stromal-cell clones and may reflect functional heterogeneity of stromal cells. Most lymphocyte clones were similar to uncloned lymphocytes from Whitlock-Witte cultures in that they responded only transiently to interleukin-7 (IL-7) and then died, unless maintained on a stromal-cell clone. One unusual lymphocyte clone (2E8) was propagated for more than 1 year in IL-7 alone and was selectively responsive to that cytokine. Most of the lymphocyte clones were not tumorigenic in immunodeficient mice. However, one pre-B clone (1A9) grew autonomously in culture when held at high density, responded to conditioned medium from a number of cell lines, and was tumorigenic. Tumors derived from this clone were infiltrated by stromal cells and lymphocytes taken from the tumors' retained characteristics of the original clone. Ly-6 antigens were inducible on 2E8 and 1A9 cells, but the lymphocytes were otherwise arrested in differentiation. The 2E8 cells had rearranged and expressed kappa light-chain genes but displayed them on the surface along with surrogate light chains and mu heavy chains. Thus, expression of authentic light chain need not coincide with termination of surrogate light-chain utilization in newly formed B cells. Several glycoproteins have recently been demonstrated to be associated with surface immunoglobulin (Ig) on mature B-lineage cells and plasma-cell tumors. We now show that one member of this family (approximately 33 kD) was associated with the mu+surrogate light-chain complex on

  10. Self DNA from lymphocytes that have undergone activation-induced cell death enhances murine B cell proliferation and antibody production.

    Directory of Open Access Journals (Sweden)

    Qing Lu

    Full Text Available Systemic lupus erythematosus (SLE is characterized by prominent autoinflammatory tissue damage associated with impaired removal of dying cells and DNA. Self DNA-containing immune complexes are able to activate both innate and adaptive immune responses and play an important role in the maintenance and exacerbation of autoimmunity in SLE. In this study, we used DNA from lymphocytes that have undergone activation-induced cell death (ALD-DNA and analyzed its role on the activation and differentiation of B cells from normal BALB/c mice as well as lupus-prone MRL+/+ and MRL/lpr mice. We found that ALD-DNA directly increased the expression of costimulatory molecules and the survival of naïve B cells in vitro. Although ALD-DNA alone had little effect on the proliferation of naïve B cells, it enhanced LPS-activated B cell proliferation in vitro and in vivo. In addition, ALD-DNA increased plasma cell numbers and IgG production in LPS-stimulated cultures of naïve B cells, in part via enhancing IL-6 production. Importantly, B cells from lupus mice were hyperresponsive to ALD-DNA and/or LPS relative to normal control B cells in terminal plasma cell differentiation, as evidenced by increases in CD138+ cell numbers, IgM production, and mRNA levels of B lymphocyte-induced maturation protein-1 (Blimp-1 and the X-box binding protein 1 (XBP1. Furthermore, ALD-DNA enhanced CD40-activated naïve B cell proliferation. Collectively, these data indicate that self DNA can serve as a DAMP (damage-associated molecular pattern that cooperates with signals from both innate and adaptive immunity to promote polyclonal B cell activation, a common characteristic of autoimmune diseases.

  11. Chronic lymphocytic leukaemia: could immunological tolerance mechanisms be the origin of lymphoid neoplasms?

    Science.gov (United States)

    García-Muñoz, Ricardo; Llorente, Luis

    2014-08-01

    Immunological tolerance theory in chronic lymphocytic leukaemia (CLL): we suggest that B cells that express B-cell receptors (BCR) that recognize their own BCR epitopes are viewed by immune system as 'dangerous cells'. BCR autonomous signalling may induce constant receptor editing and mistakes in allelic exclusion. The fact that whole BCR recognizes a self-antigen or foreing antigen may be irrelevant in early B cell development. In early B cells, autonomous signalling induced by recognition of the BCR's own epitopes simulates an antigen-antibody engagement. In the bone marrow this interaction is viewed as recognition of self-molecules and induces receptor editing. In mature B cells autonomous signalling by the BCR may promote 'reversible anergy' and also may correct self-reactivity induced by the somatic hypermutation mechanisms in mutated CLL B cells. However, in unmutated CLL B cells, BCR autonomous signalling in addition to self-antigen recognition augments B cell activation, proliferation and genomic instability. We suggest that CLL originates from a coordinated normal immunologic tolerance mechanism to destroy self-reactive B cells. Additional genetic damage induced by tolerance mechanisms may immortalize self-reactive B cells and transform them into a leukemia. PMID:24645778

  12. Ibrutinib or Idelalisib in Treating Patients With Persistent or Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma After Donor Stem Cell Transplant

    Science.gov (United States)

    2016-04-08

    Chronic Lymphocytic Leukemia; Non-Hodgkin Lymphoma; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Small Lymphocytic Lymphoma

  13. Beetroot-Carrot Juice Intake either Alone or in Combination with Antileukemic Drug 'Chlorambucil' As A Potential Treatment for Chronic Lymphocytic Leukemia

    OpenAIRE

    Marie-Christine R. Shakib; Shreef G. N. Gabrial; Gamal N. Gabrial

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes. Patients with leukemia often seek unconventional treatments not prescribed by hematologist in order to improve their cancer treatment outcome or to manage symptoms. In the present report, a 76-year-old patient was diagnosed with B-cell chronic lymphocytic leukemia (B-CLL). Beetroot-carrot juice i...

  14. Natural Killer-like B Cells Prime Innate Lymphocytes against Microbial Infection.

    Science.gov (United States)

    Wang, Shuo; Xia, Pengyan; Chen, Yi; Huang, Guanling; Xiong, Zhen; Liu, Jing; Li, Chong; Ye, Buqing; Du, Ying; Fan, Zusen

    2016-07-19

    Natural killer (NK) cells and non-cytotoxic interferon-γ (IFN-γ)-producing group I innate lymphoid cells (ILC1s) produce large amounts of IFN-γ and cause activation of innate and adaptive immunity. However, how NKs and ILC1s are primed during infection remains elusive. Here we have shown that a lymphocyte subpopulation natural killer-like B (NKB) cells existed in spleen and mesenteric lymph nodes (MLNs). NKBs had unique features that differed from T and B cells, and produced interleukin-18 (IL-18) and IL-12 at an early phase of infection. NKB cells played a critical role in eradication of microbial infection via secretion of IL-18 and IL-12. Moreover, IL-18 deficiency abrogated the antibacterial effect of NKBs. Upon bacterial challenge, NKB precursors (NKBPs) rapidly differentiated to NKBs that activated NKs and ILC1s against microbial infection. Our findings suggest that NKBs might be exploited to develop effective therapies for treatment of infectious diseases. PMID:27421702

  15. Triple cancer: chronic lymphocytic leukemia with bladder and prostate carcinoma.

    Science.gov (United States)

    Gajendra, Smeeta; Sharma, Rashi; Sahoo, Manas Kumar

    2015-08-01

    B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common lymphoproliferative disorder with an increased risk of developing subsequent neoplasms of epithelial and mesenchymal origin. The decreased immunity and B-cell dysfunction in CLL probably accounts for this emergence of second malignancies. We report a case of synchronous bladder transitional cell carcinoma (TCC) and prostatic carcinoma with CLL. A 74-year-old male who underwent transurethral resection of the prostate (TURP) for benign prostatic hyperplasia 2 years before, presented with recurrent urinary tract infection. Peripheral blood smear revealed leukocytosis with absolute lymphocytosis (absolute lymphocyte count: 37870 cells/mm³). Flow cytometric immunophenotyping revealed 75% abnormal lymphoid cells which were positive for CD 19, CD5, CD23, CD22, CD200, CD20 (moderate) with lambda light chain restriction and negative for CD3, CD10, FMC7, CD38, CD138, IgM, CD103, CD123. F Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) showed increased metabolic activity of the left lateral wall of the urinary bladder extending to the left UV junction, adjacent part of trigone and bladder neck region along with multiple heterogeneous enhancing areas with increased FDG avidity within the prostate. Transurethral resection of the bladder tumour by cystoscopy was performed. Histopathology showed high grade, muscle invasive urothelial carcinoma. Due to presence of uptake in the prostate, transurethral resection of the prostate was done and histopathology revealed adenocarcinoma of prostate (prostate specific antigen- positive), Gleason grade III+III and Gleason score 6. A high index of suspicion is required to detect synchronous and metachronous malignancies. Ancillary studies such as immunohistochemistry, flow cytometry and PET/CT are often essential for detection and an accurate diagnosis. PMID:26277675

  16. Chronic lymphocytic leukemia (CLL)-Then and now.

    Science.gov (United States)

    Rai, Kanti R; Jain, Preetesh

    2016-03-01

    The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO-1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo-immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kδ inhibitor) and novel anti-CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT-199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL. Am. J. Hematol. 91:330-340, 2016. © 2015 Wiley Periodicals, Inc. PMID:26690614

  17. Children with chronic renal failure have reduced numbers of memory B cells.

    NARCIS (Netherlands)

    Bouts, A.H.M.; Davin, J.C.; Krediet, R.T.; Monnens, L.A.H.; Nauta, J.; Schröder, C.H.; Lier, R.A.W. van; Out, T.A.

    2004-01-01

    Reduced serum IgG and subclass levels have been demonstrated in children with chronic renal failure. To study possible causes of this reduction, we analysed B cell subset composition, T helper cell frequencies and immunoglobulin (Ig) production capacity in vitro in children with chronic renal failur

  18. B cell receptor-mediated apoptosis of human lymphocytes is associated with a new regulatory pathway of Bim isoform expression.

    Science.gov (United States)

    Mouhamad, Shahul; Besnault, Laurence; Auffredou, Marie Thérèse; Leprince, Corinne; Bourgeade, Marie Françoise; Leca, Gérald; Vazquez, Aimé

    2004-02-15

    Studies in Bim-deficient mice have shown that the proapoptotic molecule Bim plays a key role in the control of B cell homeostasis and activation. However, the role of Bim in human B lymphocyte apoptosis is unknown. We show in this study that, depending on the degree of cross-linking, B cell receptors can mediate both Bim-dependent and apparent Bim-independent apoptotic pathways. Cross-linked anti-mu Ab-mediated activation induces an original pathway governing the expression of the various Bim isoforms. This new pathway involves the following three sequential steps: 1) extracellular signal-regulated kinase-dependent phosphorylation of the BimEL isoform, which is produced in large amounts in healthy B cells; 2) proteasome-mediated degradation of phosphorylated BimEL; and 3) increased expression of the shorter apoptotic isoforms BimL and BimS. PMID:14764673

  19. Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2016-08-31

    Anemia; Fever, Sweat, and Hot Flashes; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma; Weight Change

  20. The lymph node in chronic lymphocytic leukemia.

    Science.gov (United States)

    Dick, F R; Maca, R D

    1978-01-01

    Lymph nodes were examined from 41 cases of typical chronic lymphocytic leukemia (CLL). Degree of immaturity was graded as absent to minimal (Grade I), moderate (Grade II) and marked (Grade III). A moderate degree of immaturity was found in the lymph node in 14 of 41 cases even though the cells seen on the initial bone marrow and peripheral blood smears obtained from these patients were essentially all mature. The morphology of these nodes could be confused with poorly differentiated lymphocytic or mixed lymphocytic-histiocytic lymphoma in terms of the degree of immaturity present. A marked degree of immaturity present. A marked degree of immaturity was found in 5 cases; the morphology of these cases resembled histiocytic lymphoma. In the remaining 22 cases immaturity was essentially absent. The morphology of these cases was similar to that of diffuse well differentiated lymphocytic lymphoma. Our studies suggest that a moderate degree of immaturity in the lymph node of patients with CLL does not indicate that these patients will have a marked shortening of their survival. PMID:580071

  1. BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia

    OpenAIRE

    Falchi, Lorenzo; Baron, Jessica M.; Orlikowski, Carrie Anne; Ferrajoli, Alessandra

    2016-01-01

    The B-cell receptor (BCR) signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in treatmen...

  2. BCR SIGNALING INHIBITORS: AN OVERVIEW OF TOXICITIES ASSOCIATED WITH IBRUTINIB AND IDELALISIB IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA

    OpenAIRE

    Lorenzo Falchi; Baron, Jessica M.; Carrie Anne Orlikowski; Alessandra Ferrajoli

    2016-01-01

    The B-cell receptor signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment landscape of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in trea...

  3. Chronic lymphocytic leukemia: a clinical review including Korean cohorts

    Science.gov (United States)

    Jeon, Young-Woo; Cho, Seok-Goo

    2016-01-01

    Only 5th decade ago, chronic lymphocytic leukemia (CLL) was only recognized as disease group of presenting features like peripheral lymphocytosis, organomegaly including of splenomegaly. As understanding of disease biology and molecular diagnostic tools are getting improved gradually, characterization of variation in CLL’s clinical courses was facilitated, resulting in better risk stratification and targeted treatments. Consequently multiple new targeted agents have been used in treatment of CLL, it makes improved clinical outcome. Rituximab containing chemoimmunotherapy (combination of rituximab, fludarabine, and cyclophosphamide) have shown better overall response rate and progression-free survival on fit patients’ group in front-line setting, result in standard first-line therapeutic option for CLL. Furthermore, after introducing that the B-cell receptor is crucial for the evolution and progression of CLL, emerging treatments targeting highly activated surface antigens and oncogenic signaling pathways have been associated with several successes in recent decades. These include new anti-CD 20 monoclonal antibody (obinutuzumab), the bruton tyrosine kinase inhibitor (ibrutinib), the phosphatidylinositol 3-kinase inhibitor (idelalisib), and B-cell CLL/lymphoma 2 inhibitor (ABT-199 and ABT-263). So, we discuss not only general pathophysiology of CLL, but also rapidly advancing treatment strategies that are being studied or approved for treatment of CLL. PMID:27044858

  4. Chronic lymphocytic leukemia: a clinical review including Korean cohorts.

    Science.gov (United States)

    Jeon, Young-Woo; Cho, Seok-Goo

    2016-05-01

    Only 5th decade ago, chronic lymphocytic leukemia (CLL) was only recognized as disease group of presenting features like peripheral lymphocytosis, organomegaly including of splenomegaly. As understanding of disease biology and molecular diagnostic tools are getting improved gradually, characterization of variation in CLL's clinical courses was facilitated, resulting in better risk stratification and targeted treatments. Consequently multiple new targeted agents have been used in treatment of CLL, it makes improved clinical outcome. Rituximab containing chemoimmunotherapy (combination of rituximab, fludarabine, and cyclophosphamide) have shown better overall response rate and progression-free survival on fit patients' group in front-line setting, result in standard first-line therapeutic option for CLL. Furthermore, after introducing that the B-cell receptor is crucial for the evolution and progression of CLL, emerging treatments targeting highly activated surface antigens and oncogenic signaling pathways have been associated with several successes in recent decades. These include new anti-CD 20 monoclonal antibody (obinutuzumab), the bruton tyrosine kinase inhibitor (ibrutinib), the phosphatidylinositol 3-kinase inhibitor (idelalisib), and B-cell CLL/lymphoma 2 inhibitor (ABT-199 and ABT-263). So, we discuss not only general pathophysiology of CLL, but also rapidly advancing treatment strategies that are being studied or approved for treatment of CLL. PMID:27044858

  5. Early stem cell transplantation for chronic lymphocytic leukaemia: a chance for cure?

    OpenAIRE

    Dreger, P; von Neuhoff, N.; Kuse, R.; Sonnen, R.; GLASS, B.; Uharek, L.; Schoch, R.; Löffler, H.; Schmitz, N.

    1998-01-01

    B-cell chronic lymphocytic leukaemia (CLL) cannot be cured by conventional therapy. To improve the prognosis of patients with CLL, we have designed a sequential treatment strategy that comprises intensive chemotherapy for mobilization of peripheral blood progenitor cells (PBPCs) and induction of minimal disease, followed by high-dose radiochemotherapy with stem cell reinfusion and post-transplant molecular monitoring by polymerase chain reaction (PCR) amplification of the complementary determ...

  6. Fungal natural products targeting chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Bladt, Tanja Thorskov; Kildgaard, Sara; Knudsen, Peter Boldsen;

    2012-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults from the western world. No curative treatments of CLL are presently known so the treatment strategy today is primarily to prolong patient survival,1 why we have initiated new activities towards discovery of novel compounds....../compounds.2,3 This includes analysis of the spectroscopic data generated from LC-DAD-MS to reveal whether the active principles are either structurally known compounds or are likely to be novel compounds. This paper will illustrate our integrated discovery approaches and recent findings of anti-leukemia...

  7. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study

    OpenAIRE

    Herman, Sarah E. M.; Niemann, Carsten U.; Farooqui, Mohammed; Jones, Jade; Mustafa, Rashida Z.; Lipsky, Andrew; Saba, Nakhle; Martyr, Sabrina; Soto, Susan; Valdez, Janet; Gyamfi, Jennifer A.; Maric, Irina; Calvo, Katherine R.; Pedersen, Lone B; Geisler, Christian H.

    2014-01-01

    Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further investigation. We here report correlative studies in 64 patients with CLL treated with ibrutinib. We quantified tumor burden in blood, lymph nodes, spleen, and bone marrow, assessed phenotypic change...

  8. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo

    OpenAIRE

    Ponader, Sabine; Chen, Shih-Shih; Buggy, Joseph J.; Balakrishnan, Kumudha; Gandhi, Varsha; William G Wierda; Michael J Keating; O'Brien, Susan; Chiorazzi, Nicholas; Burger, Jan A.

    2012-01-01

    B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in ...

  9. B-Cell Activating Factor (BAFF) is elevated in Chronic Granulomatous Disease

    OpenAIRE

    Matharu, Kabir; Zarember, Kol A.; Marciano, Beatriz E.; Kuhns, Douglas B; Spalding, Christine; Garofalo, Mary; DiMaggio, Thomas; Estwick, Tyra; Huang, Chiung-yu; Fink, Danielle; Priel, Debra L.; Fleisher, Thomas A.; Holland, Steven M.; Malech, Harry L.; Gallin, John I.

    2013-01-01

    Chronic Granulomatous Disease (CGD) is an inherited defect in superoxide production leading to life-threatening infections, granulomas, and, possibly, abnormal immunoglobulin concentrations. We investigated whether factors controlling antibody production, such as B-cell activating factor (BAFF), were altered in CGD. CGD subjects had significantly increased mean (2.3-fold, p

  10. Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy

    OpenAIRE

    Tackenberg, Björn; Jelčić, Ilijas; Baerenwaldt, Anne; Wolfgang H Oertel; Sommer, Norbert; Nimmerjahn, Falk; Lünemann, Jan D.

    2009-01-01

    The inhibitory Fc-γ receptor FcγRIIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and autoimmunity, and is required for the antiinflammatory activity of intravenous Ig (IVIG) in various murine disease models. However, the function of FcγRIIB and its regulation by IVIG in human autoimmune diseases are less well understood. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common treatable acquired chronic polyneuropathy, and IVIG is wide...

  11. SPECIFIC UPTAKE OF MONOCLONAL ANTIBODY-CONJUGATED METHOTREXATE BY HUMAN LYMPHOCYTIC LEUKEMIC B CELLS

    Institute of Scientific and Technical Information of China (English)

    Zhu Zhenping; Yang Chunzheng; Tarunendu Ghose; Jaroslav Kralovec

    1998-01-01

    Objective: To analysis the uptake of free MTX and MTX conjugated to tumor specific monoclonal antibody by target and non-target cells. Methods: The folate antagonist methotrexate (MTX) was conjugated to two monoclonal antibodies (Mab) directed against human chronic lymphocytic leukemia (CLL), Dal B01 and Dal B02, by an active ester method. Both conjugates were more cytotoxic toward the target tumor cell line D10-1than to the non-target cell line MOLT-3, and Dal B02-MTX conjugate was more inhibitory to D10-1 cells than free MTX in a 6 h pulse exposure assay. Results: Drug uptake studies revealed that D10-1 cells took up much more Dal B01 and Dal B02-conjugated MTX than free MTX. The amounts of drug taken up by D10-1 cells incubated with Dal B01 and Dal B02-conjugated MTX were always 3 to 5-fold higher than that taken up by MOLT-3 cells, although the latter took up more drug when incubated with free MTX. Furthermore, tumor cells incubated with Dal B01 or Dal B02-conjugated MTX retained much larger amounts of drug for a prolonged period of time than those incubated with free MTX.Conclusion: The enhanced specific cytotoxicity of Dal B01 and Dal B02-MTX conjugates toward target tumor cells is therefore likely due to (Ⅰ) delivery of larger amounts of MTX to target cells when the drug is conjugated to Mab;(ii) longer retention of Mab-conjugated MTX by target cells; and (iii) slow, prolonged release of MTX from the surface-bound or endocytosed conjugates, rendering them into a sustained release dosage form.

  12. Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease.

    Science.gov (United States)

    Flynn, Ryan; Allen, Jessica L; Luznik, Leo; MacDonald, Kelli P; Paz, Katelyn; Alexander, Kylie A; Vulic, Ante; Du, Jing; Panoskaltsis-Mortari, Angela; Taylor, Patricia A; Poe, Jonathan C; Serody, Jonathan S; Murphy, William J; Hill, Geoffrey R; Maillard, Ivan; Koreth, John; Cutler, Corey S; Soiffer, Robert J; Antin, Joseph H; Ritz, Jerome; Chao, Nelson J; Clynes, Raphael A; Sarantopoulos, Stefanie; Blazar, Bruce R

    2015-06-25

    Novel therapies for chronic graft-versus-host disease (cGVHD) are needed. Aberrant B-cell activation has been demonstrated in mice and humans with cGVHD. Having previously found that human cGVHD B cells are activated and primed for survival, we sought to further evaluate the role of the spleen tyrosine kinase (Syk) in cGVHD in multiple murine models and human peripheral blood cells. In a murine model of multiorgan system, nonsclerodermatous disease with bronchiolitis obliterans where cGVHD is dependent on antibody and germinal center (GC) B cells, we found that activation of Syk was necessary in donor B cells, but not T cells, for disease progression. Bone marrow-specific Syk deletion in vivo was effective in treating established cGVHD, as was a small-molecule inhibitor of Syk, fostamatinib, which normalized GC formation and decreased activated CD80/86(+) dendritic cells. In multiple distinct models of sclerodermatous cGVHD, clinical and pathological disease manifestations were not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these scleroderma models. We further demonstrated that Syk inhibition was effective at inducing apoptosis of human cGVHD B cells. Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD. PMID:25852057

  13. Autologous Peripheral Blood Stem Cell Transplant Followed by Donor Bone Marrow Transplant in Treating Patients With High-Risk Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

    Science.gov (United States)

    2016-06-17

    B-Cell Prolymphocytic Leukemia; Plasma Cell Leukemia; Progression of Multiple Myeloma or Plasma Cell Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Non-Hodgkin Lymphoma; Refractory Plasma Cell Myeloma; Refractory Small Lymphocytic Lymphoma; T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia

  14. The molecular basis of familial chronic lymphocytic leukemia

    OpenAIRE

    Crowther-Swanepoel, Dalemari; Houlston, Richard S.

    2009-01-01

    Our understanding of the genetic basis of chronic lymphocytic leukemia is only just starting to be recognized. This perspective article by Drs. Crowther-Swanepoel and Houlston provides an up-to-date review the molecular epidemiology of chronic lymphocytic leukemia, with emphasis on the integration of biology and genomics. See related paper on page 647.

  15. Altered pattern of Naïve and memory B cells and B1 cells in patients with chronic granulomatous disease.

    Science.gov (United States)

    Mohsenzadegan, Monireh; Fattahi, Fahimeh; Fattahi, Fatemeh; Mirshafiey, Abbas; Fazlollahi, Mohammad Reza; Naderi Beni, Fariba; Movahedi, Masoud; Pourpak, Zahra

    2014-06-01

    Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder characterized by a greatly increased susceptibility to severe fungal and bacterial infections caused by defects in NADPH oxidase of phagocytic cells. We aimed to investigate immunophenotype alterations of naïve and memory B cells and B1a cells in peripheral whole blood from Iranian patients with CGD. Flow cytometric analysis was performed on peripheral blood samples from 31 CGD patients and 23 healthy controls (HC) to study naïve (IgD+/CD27-), memory (CD27+) B and B1a (CD5+) cells. Soluble CD27 (sCD27) and immunoglobulins were also measured by ELISA and the nephelometric method, respectively. We found significantly higher levels of naïve B cells and B1a cells but lower levels of memory B cells in CGD patients compared to HC.. There was no significant difference in soluble CD27 (sCD27) alteration between CGD patients and HC. Our findings suggested a role for NADPH oxidase in process of B cell differentiation and impairing conversion of naïve B cells to memory B cells and altered B1a cells in CGD patients. Increased susceptibility of CGD patients to opportunistic infections and autoimmune disorders could be partly explained by the altered phenotype of B lymphocytes in these patients. PMID:24659119

  16. Altered pattern of Naïve and memory B cells and B1 cells in patients with chronic granulomatous disease.

    Directory of Open Access Journals (Sweden)

    Monireh Mohsenzadegan

    2014-06-01

    Full Text Available Chronic granulomatous disease (CGD is a rare primary immunodeficiency disorder characterized by a greatly increased susceptibility to severe fungal and bacterial infections caused by defects in NADPH oxidase of phagocytic cells. We aimed to investigate immunophenotype alterations of naïve and memory B cells and B1a cells in peripheral whole blood from Iranian patients with CGD. Flow cytometric analysis was performed on peripheral blood samples from 31 CGD patients and 23 healthy controls (HC to study naïve (IgD+/CD27-, memory (CD27+ B and B1a (CD5+ cells. Soluble CD27 (sCD27 and immunoglobulins were also measured by ELISA and the nephelometric method, respectively. We found significantly higher levels of naïve B cells and B1a cells but lower levels of memory B cells in CGD patients compared to HC.. There was no significant difference in soluble CD27 (sCD27 alteration between CGD patients and HC. Our findings suggested a role for NADPH oxidase in process of B cell differentiation and impairing conversion of naïve B cells to memory B cells and altered B1a cells in CGD patients. Increased susceptibility of CGD patients to opportunistic infections and autoimmune disorders could be partly explained by the altered phenotype of B lymphocytes in these patients.

  17. Initial therapy of chronic lymphocytic leukemia.

    Science.gov (United States)

    Eichhorst, Barbara; Cramer, Paula; Hallek, Michael

    2016-04-01

    Only chronic lymphocytic leukemia (CLL) patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. Prognostic risk factor profile and comorbidity burden are most relevant for the choice of treatment. For physically fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab remains the current standard therapy. For unfit patients, treatment with an anti-CD20 antibody (obinutuzumab or rituximab or ofatumumab) plus milder chemotherapy (chlorambucil) may be applied. Patients with a del(17p) or TP53 mutation should be treated with the kinase inhibitors ibrutinib or a combination of idelalisib and rituximab. Clinical trials over the next several years will determine, whether kinase inhibitors, other small molecules, immunotherapeutics, or combinations thereof will further improve outcomes for patients with CLL. PMID:27040702

  18. Fungal natural products targeting chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Bladt, Tanja Thorskov; Kildgaard, Sara; Knudsen, Peter Boldsen; Gotfredsen, Charlotte Held; Duerr, C.; Seiffert, M.; Larsen, Thomas Ostenfeld

    2012-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults from the western world. No curative treatments of CLL are presently known so the treatment strategy today is primarily to prolong patient survival,1 why we have initiated new activities towards discovery of novel compounds...... with potential tumor specificity. Our starting point is a diverse fungal collection of thousands of Penicillium and Aspergillus species. These fungi have proven to be a very rich source of various bioactive compounds and yet our dereplication investigations have demonstrated that there are still...... numerous unknown compounds to be identified within these species. Until now we have found that 11 out of 289 fungal extracts are active against CLL cells. Using our established chemotaxonomic discovery approach we have dereplicated and fractionated these extracts to track the activity into single fractions/compounds...

  19. Corruption of Human Follicular B-Lymphocyte Trafficking by a B-Cell Superantigen

    Science.gov (United States)

    Borhis, Gwenoline; Viau, Muriel; Badr, Gamal; Richard, Yolande; Zouali, Moncef

    2012-01-01

    Protein A (SpA) of Staphylococcus aureus is known to target the paratope of immunoglobulins expressing VH3 genes, and to delete marginal zone B cells and B-1a in vivo. We have discovered that SpA endows S. aureus with the potential to subvert B-cell trafficking in the host. We found that SpA, whose Fc-binding site has been inactivated, binds essentially to naïve B cells and induces a long-lasting decrease in CXCR4 expression and in B-cell chemotaxis to CXCL12. Competition experiments indicated that SpA does not interfere with binding of CXCR4 ligands and does not directly bind to CXCR4. This conclusion is strongly supported by the inability of SpA to modulate clathrin-mediated CXCR4 internalization, which contrasts with the potent effect of anti-immunoglobin M (IgM) antibodies. Microscopy and biochemical experiments confirmed that SpA binds to the surface IgM/IgD complex and induces its clathrin-dependent internalization. Concomitantly, the SpA-induced signaling leads to protein kinase C–dependent CXCR4 downmodulation, suggesting that SpA impairs the recycling of CXCR4, a postclathrin process that leads to either degradation into lysozomes or de novo expression at the cell surface. In addition to providing novel insight into disruption of B-cell trafficking by an infectious agent, our findings may have therapeutic implications. Because CXCR4 has been associated with cancer metastasis and with certain autoimmune diseases, SpA behaves as an evolutionary tailored highly specific, chemokine receptor inhibitor that may have value in addition to conventional cytotoxic therapy in patients with various malignancies and immune-mediated diseases. PMID:22367177

  20. Cutaneous lymphocyte antigen expression on human effector B cells depends on the site and on the nature of antigen encounter.

    Science.gov (United States)

    Kantele, Anu; Savilahti, Erkki; Tiimonen, Heidi; Iikkanen, Katja; Autio, Soile; Kantele, Jussi M

    2003-12-01

    In contrast to T cells, information on skin-homing B cells expressing the cutaneous lymphocyte antigen (CLA) is sparse. CLA expression on human B cells was investigated among circulating immunoglobulin-secreting cells (ISC) and among antigen-specific antibody-secreting cells (ASC) elicited by parenteral, oral or rectal primary immunization, or by parenteral or oral secondary immunization with Salmonella typhi Ty21a. CLA expression was examined by combining cell sorting with an enzyme-linked immunospot assay. Among all ISC, the proportion of CLA(+) cells was 13-21%. Parenteral immunization induced antigen-specific ASC of which 13% were CLA(+), while oral and rectal immunizations were followed by only 1% of CLA(+) ASC (p<0.001). Oral re-immunization was followed by an up-regulation of CLA (34-48%) regardless of the route of priming. Parenteral re-immunization elicited ASC of which 9-14% were CLA(+). In conclusion, the expression of CLA on human effector B cells depends on the site of antigen encounter: intestinal stimulation elicits cells with no CLA, while parenteral encounter elicits significant numbers of CLA(+) cells. Even though primary antigen encounter in the intestine failed to stimulate CLA expression, up-regulation of CLA was found upon intestinal antigen re-encounter. These findings may be of relevance in the pathogenesis of some cutaneous disorders. PMID:14635035

  1. p53 mutations in human lymphoid malignancies: Association with Burkitt lymphoma and chronic lymphocytic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Gaidano, G.; Ballerini, P.; Gong, J.Z.; Inghirami, G.; Knowles, D.M.; Dalla-Favera, R. (Columbia Univ., New York, NY (United States)); Neri, A, (Columbia Univ., New York, NY (United States) Centro Malattie del Sangue G. Marcora, Milan (Italy)); Newcomb, E.W. (New York Univ. School of Medicine, New York (United States)); Magrath, I.T. (National Cancer Institute, Bethesda, MD (United States))

    1991-06-15

    The authors have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies, including acute lymphoblastic leukemia, the major subtypes of non-Hodgkin lymphoma, and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direst sequencing of PCR-amplified fragments. Mutations were found associated with (i) Burkitt lymphoma (9/27 biopsoes; 17/27 cell lines) and its leukemic counterpart L{sub 3}-type B-cell acute lymphoblastic leukemia (5/9), both of which also carry activated c-myc oncogenes, and (ii) B-cell chronic lymphocytic leukemia (6/40) and, in particular, its stage of progression known as Richter's transformation (3/7). Mutations were not found at any significant frequency in other types of non-Hodgkin lymphoma or acute lymphoblastic leukemia. In many cases, only the mutated allele was detectable, implying loss of the normal allele. These results suggest that (1) significant differences in the frequency of p53 mutations are present among subtypes of neoplasms derived from the same tissue; (2) p53 may play a role in tumor progression in B-cell chronic lymphocytic leukemia; (3) the presence of both p53 loss/inactivation and c-myc oncogene activation may be important in the pathogenesis of Burkitt lymphoma and its leukemia form L{sub 3}-type B-cell acute lymphoblastic leukemia.

  2. Synthesis of antibodies to hepatitis B virus by cultured lymphocytes from chronic hepatitis B surface antigen carriers

    International Nuclear Information System (INIS)

    It has been postulated that host immune defects are responsible for the development and persistence of the hepatitis B surface antigen (HBsAg) carrier state. The synthesis of both anti-HBs and antibody to hepatitis B core antigen (anti-HBc) in cultures containing peripheral blood mononuclear cells from chronic HBsAg carriers and from control (antibody-positive) patients was measured in the presence of pokeweed mitogen. Similar amounts of polyclonal IgG and IgM were synthesized by cultures containing lymphocytes from chronic carriers and controls. Anti-HBc was detectable in lymphocyte supernatants from 2 of 20 controls and from 21 of 29 carriers. The presence of anti-HBc synthesis in vitro correlated with high serum titers of anti-HBc. In contrast, anti-HBs was detected in lymphocyte supernatants from 6 of 20 controls (predominantly in those who had high serum titers of anti-HBs) but in none of the supernatants from 29 HBsAg carriers. Co-culture experiments were performed using T and B lymphocyte fractions that had been purified by affinity chromatography. B lymphocytes from carriers co-cultured with allogeneic irradiated (''helper'') T lymphocytes from controls synthesized normal amounts of IgG, IgM, and anti-HBc but still did not synthesize detectable amounts of anti-HBs. In the converse experiments, B lymphocytes from controls were co-cultured with irradiated T lymphocytes from carriers. The T lymphocytes from 16 of 24 carriers augmented anti-HBs production by control B cells normally, the remaining eight did not. Finally, mixtures of control B cells and control irradiated T lymphocytes were co-cultured with T lymphocytes from chronic HBsAg carriers. 5 of 12 carriers demonstrated active suppression of anti-HBs production, and in three this suppression was specific, as IgG and IgM production remained normal

  3. Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells

    OpenAIRE

    Moir, Susan; De Ravin, Suk See; Santich, Brian H.; Kim, Jin Young; Posada, Jacqueline G.; Ho, Jason; Buckner, Clarisa M.; Wang, Wei; Kardava, Lela; Garofalo, Mary; Marciano, Beatriz E.; Manischewitz, Jody; King, Lisa R.; Khurana, Surender; Chun, Tae-Wook

    2012-01-01

    CD27+ memory B cells are reduced in the blood of patients with chronic granulomatous disease (CGD) for reasons and consequences that remain unclear. Here we confirm not only decreased CD27+ but also IgG+ B cells in the blood of CGD patients compared with healthy donors (HDs). However, among IgG+ B cells, the ratio of CD27− to CD27+ was significantly higher in CGD patients compared with HDs. Similar to conventional memory B cells, CD27−IgG+ B cells of CGD patients expressed activation markers ...

  4. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    AnnaMaria Nosari

    2012-11-01

    Full Text Available Infectious complications have been known to be a major cause of morbidity and mortality in CLL patients who are predisposed to infections because of both the humoral immunodepression inherent to hematologic disease, which is related to stage and duration of CLL, and to further immunosuppression related to therapy. The majority of infections in CLL patients treated with alkilating agents is of bacterial origin. The immunodeficiency and natural infectious history of alkylator-resistant, corticosteroid-treated patients appears to have changed with the administration of purine analogs, which has been complicated by very severe and unusual infections and also more viral infections due to sustained reduction of CD4-positive T lymphocytes. The following introduction of monoclonal antibody therapies, in particular alemtuzumab, further increased the immunodepression, increasing also infections which appeared more often in patients with recurrent neutropenia due to chemotherapy cycles. Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. Italian SEIFEM group in a retrospective multicentre study regarding CLL patients reported an incidence of mycoses 0.5%; however, chronic lymphoproliferative disorders emerged as second haematological underlying disease after acute leukemia in a French study on aspergillosis; in particular CLL with aspergillosis accounted for a third of these chronic lymphoproliferative diseases presenting mould infection.

  5. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    AnnaMaria Nosari

    2012-01-01

    Full Text Available

    Infectious complications have been known to be a major cause of morbidity and mortality in CLL patients who are predisposed to infections because of both the humoral immunodepression inherent to hematologic disease, which is related to stage and duration of CLL, and to further immunosuppression related to therapy. The majority of infections in CLL patients treated with alkilating agents is of bacterial origin. The immunodeficiency and natural infectious history of alkylator-resistant, corticosteroid-treated patients appears to have changed with the administration of purine analogs, which has been complicated by very severe and unusual infections and also more viral infections due to sustained reduction of CD4-positive T lymphocytes. The following introduction of monoclonal antibody therapies, in particular alemtuzumab, further increased the immunodepression, increasing also infections which appeared more often in patients with recurrent neutropenia due to chemotherapy cycles.

    Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. Italian SEIFEM group in a retrospective multicentre study regarding CLL patients reported an incidence of mycoses 0.5%; however, chronic lymphoproliferative disorders emerged as second haematological underlying disease after acute leukemia in a French study on aspergillosis; in particular CLL with aspergillosis accounted for a third of these chronic lymphoproliferative diseases presenting mould infection.

  6. Therapeutic activity of two xanthones in a xenograft murine model of human chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Berthou Christian

    2010-12-01

    Full Text Available Abstract Background We previously reported that allanxanthone C and macluraxanthone, two xanthones purified from Guttiferae trees, display in vitro antiproliferative and proapoptotic activities in leukemic cells from chronic lymphocytic leukemia (CLL and leukemia B cell lines. Results Here, we investigated the in vivo therapeutic effects of the two xanthones in a xenograft murine model of human CLL, developed by engrafting CD5-transfected chronic leukemia B cells into SCID mice. Treatment of the animals with five daily injections of either allanxanthone C or macluraxanthone resulted in a significant prolongation of their survival as compared to control animals injected with the solvent alone (p = 0.0006 and p = 0.0141, respectively. The same treatment of mice which were not xenografted induced no mortality. Conclusion These data show for the first time the in vivo antileukemic activities of two plant-derived xanthones, and confirm their potential interest for CLL therapy.

  7. ALLOGENEIC TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Patrizia Chiusolo

    2010-05-01

    Full Text Available

    Even if Chronic lymphocytic leukemia (CLL often has an indolent behavior with good responsiveness to cytoreductive treatment, about 20% of the patients, so called "poor-risk" patients, show an aggressive course and die within a few years despite early intensive therapies. Criteria for poor-risk disease according to the European Bone Marrow Transplantation (EBMT CLL Transplant Consensus are: purine analogue refractoriness, early relapse after purine analogue combination therapy, CLL with p53 lesion requiring treatment.

    Allogeneic transplant has potential curative role in CLL, however burden with very  high transplant related mortality (TRM rates of 38-50%:

    A major advance in reducing the short-term morbidity and mortality of allogeneic stem cell transplantation (SCT has been the introduction of non-myeloablative or reduced intensity conditioning (RIC regimens to allow engraftment of allogeneic stem cells. There is no doubt that the crucial therapeutic principle of allo-SCT in CLL is graft versus leukemia (GVL activity.

    The major complications of allogeneic SCT in CLL are: chronic graft-versus-host-disease (GVHD affecting quality of life, high graft rejection and infection rates rates correlated with preexisting immunosuppression. Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients.

    Sensitive minimal residual disease (MRD quantification has strong prognostic impact after transplant.

     

  8. Targeted treatment for chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Masood A

    2011-11-01

    Full Text Available Aisha Masood1, Taimur Sher2, Aneel Paulus2, Kena C Miller2, Kasyapa S Chitta3, Asher Chanan-Khan4 1The Tisch Cancer Institute, Bone Marrow Transplant Unit, Mount Sinai School of Medicine, 2Department of Medicine, Roswell Park Cancer Institute, 3Department of Molecular Targets and Experimental Therapeutics, Roswell Park Cancer Institute, New York, NY, 4Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA Abstract: The treatment of chronic lymphocytic leukemia (CLL has evolved over the last few decades. Recognition has increased of several key components of CLL biology currently manipulated for therapeutics. A milestone in the treatment of CLL was reached with the incorporation of immunotherapy with conventional chemotherapy. The fludarabine/cyclophosphamide/rituximab combination has demonstrated survival advantage for the first time in the treatment of CLL. Several other biological compounds are being explored with the hope of improving responses, impacting survival, and ultimately curing CLL. Important agents being tested are targeted on CLL surface molecules and their ligands, signal transduction protein and oncogenes. This review provides a brief summary of the recent advances made in preclinical and clinical investigation of selected promising therapeutic agents, which lead the target-directed therapeutic approach. Keywords: CLL, Akt inhibitors, Bcl-2 inhibitors, cyclin d kinase inhibitors, heat shock protein inhibitors, immunomodulatory drugs, monoclonal antibodies

  9. Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL)

    Science.gov (United States)

    2016-07-04

    Non-Hodgkin Lymphoma; Burkitt's Lymphoma; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Lymphoma, Marginal Zone; Waldenstrom Macroglobulinemia

  10. Prognostic significance of serum immunoglobulin pareprotein in chronic lymphocytic leukemia

    Institute of Scientific and Technical Information of China (English)

    杨舒

    2012-01-01

    Objective To investigate the incidence of serum immunoglobulin (Ig) paraprotein in chronic lymphocytic leukemia(CLL) ,and to explore its clinical associated laboratory features and prognostic implication. Methods Serum protein electrophoresis and immunofixation

  11. Improving the treatment outcome of patients with chronic lymphocytic leukemia through targeted antibody therapy.

    Science.gov (United States)

    Stephens, Deborah M; Byrd, John C

    2013-04-01

    Therapy for chronic lymphocytic leukemia (CLL) has evolved dramatically throughout the years. In 1997, rituximab (Rituxan), a CD20 monoclonal antibody (mAb), became the first mAb approved by the Food and Drug Administration for marketing in the treatment of cancer, specifically targeting B-cell malignancies. Over the last 10 years, rituximab or other mAbs including alemtuzumab and ofatumumab have become an integral part of the standard of care for CLL patients as single agents or in combination with chemotherapy or other immunotherapy. This review discusses the currently approved and novel mAbs for the treatment of CLL. PMID:23561475

  12. An Urologic Face of Chronic Lymphocytic Leukemia:Sequential Prostatic and Penis Localization

    Directory of Open Access Journals (Sweden)

    Giovanni D'Arena

    2013-01-01

    Full Text Available We report a patient with chronic lymphocytic leukemia (CLL in whom a leukemic involvement of prostate and penis occurred in the advanced phase of his disease. Obstructive urinary symptoms were indicative of prostatic CLL infiltration, followed by the occurrence of an ulcerative lesion on the glans. Histologic examination confirmed  the  neoplastic B-cell infiltration. Both localizations responded to conventional treatments. A review of the literature confirms that leukemic involvement of the genito-urinary system is   uncommon in CLL patients. However, such an involvement should be considered in CLL patients with urologic symptoms and a long history of the disease.

  13. AR-42 in Treating Patients With Advanced or Relapsed Multiple Myeloma, Chronic Lymphocytic Leukemia, or Lymphoma

    Science.gov (United States)

    2016-03-16

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large

  14. Sweet Syndrome in a Patient with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Curious Lymphocyte/Neutrophil Fluctuations

    OpenAIRE

    Çiğdem Usul Afşar; Semra Paydaş; Meral Günaldı; Berna Bozkurt Duman; Vehbi Erçolak; Suzan Zorludemir; Arbil Açıkalın

    2013-01-01

    Sweet syndrome, also referred to as acute febrile neutrophilic dermatosis, is characterized by tender, red inflammatory nodules or papules that occur in association with infection, malignancy, connective tissue disease, or following exposure to certain drugs. Here, we present Sweet syndrome in a case with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) which is a relatively rare co-occurrence. Conflict of interest:None declared.

  15. Sweet Syndrome in a Patient with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Curious Lymphocyte/Neutrophil Fluctuations

    Directory of Open Access Journals (Sweden)

    Çiğdem Usul Afşar

    2013-12-01

    Full Text Available Sweet syndrome, also referred to as acute febrile neutrophilic dermatosis, is characterized by tender, red inflammatory nodules or papules that occur in association with infection, malignancy, connective tissue disease, or following exposure to certain drugs. Here, we present Sweet syndrome in a case with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL which is a relatively rare co-occurrence.

  16. The microenvironment differentially impairs passive and active immunotherapy in Chronic lymphocytic leukemia - Potential therapeutic synergism of CXCR4 antagonists

    OpenAIRE

    Buchner, Maike; Brantner, Philipp; Prinz, Gabriele; Burger, Meike; Baer, Constance; Dierks, Christine; Pfeifer, Dietmar; Mertelsmann, Roland; Gribben, John G.; Veelken, Hendrik; Zirlik, Katja

    2010-01-01

    Abstract Direct contact with stromal cells protects chronic lymphocytic leukemia (CLL) B cells from chemotherapy-induced apoptosis in vitro. Blockade of CXCR4 signaling antagonizes stroma-mediated interactions and restores CLL chemosensitivity. In vivo, administration of CXCR4 antagonists may also effect efficient mobilization of hematopoetic progenitor cells. Therefore, combinations of CXCR4 blockade with cytoreductive treatment with selective activity on CLL cells may avoid poten...

  17. Ibrutinib: A New Frontier in the Treatment of Chronic Lymphocytic Leukemia by Bruton’s Tyrosine Kinase Inhibition

    OpenAIRE

    Dias, Ajoy Lawrence; Jain, Dharamvir

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of nonfunctional mature B cells in blood, bone marrow and lymphoid tissues. In the last decade, our understanding of CLL and consequently our diagnostic and therapeutic approaches have changed dramatically. Conventional fludarabine based chemotherapy has led to improved disease response and longer survival in young patients with CLL. However its application in elderly patients has been restricted by substantial my...

  18. Three newly approved drugs for chronic lymphocytic leukemia (CLL): Incorporating ibrutinib, idelalisib and obinutuzumab into clinical practice

    OpenAIRE

    Sanford, David; Wierda, William G.; Burger, Jan A.; Keating, Michael J.; O’Brien, Susan M.

    2015-01-01

    Three agents have received FDA approval for treatment of chronic lymphocytic leukemia (CLL) within the last year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of BTK and PI3Kδ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in in the relapsed setting and is currently approved for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline...

  19. Detection of Hodgkin Transformation in a Case of Chronic Lymphocytic Leukemia by PET/CT

    Directory of Open Access Journals (Sweden)

    Sabire Yılmaz

    2014-06-01

    Full Text Available Richter’s transformation (RT represents the development of high grade lymphoma, most commonly diffuse large B-cell lymphoma, in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL. CLL/SLL may convert also to Hodgkin’s lymphoma, the so-called Hodgkin’s variant of Richter transformation. Histopathological proof is needed to confirm a definitive diagnosis. Patients with RT generally have a poor prognosis, with prompt recognition optimise clinical management. Whole-body PET scan with 18F-FDG can be used for detection of RT of CLL/SLL. We describe the case of 64-year-old woman with CLL/SLL who developed Hodgkin lymphoma detected with PET/CT.

  20. Improving therapy of chronic lymphocytic leukemia with chimeric antigen receptor T cells.

    Science.gov (United States)

    Fraietta, Joseph A; Schwab, Robert D; Maus, Marcela V

    2016-04-01

    Adoptive cell immunotherapy for the treatment of chronic lymphocytic leukemia (CLL) has heralded a new era of synthetic biology. The infusion of genetically engineered, autologous chimeric antigen receptor (CAR) T cells directed against CD19 expressed by normal and malignant B cells represents a novel approach to cancer therapy. The results of recent clinical trials of CAR T cells in relapsed and refractory CLL have demonstrated long-term disease-free remissions, underscoring the power of harnessing and redirecting the immune system against cancer. This review will briefly summarize T-cell therapies in development for CLL disease. We discuss the role of T-cell function and phenotype, T-cell culture optimization, CAR design, and approaches to potentiate the survival and anti-tumor effects of infused lymphocytes. Future efforts will focus on improving the efficacy of CAR T cells for the treatment of CLL and incorporating adoptive cell immunotherapy into standard medical management of CLL. PMID:27040708

  1. Hodgkin lymphoma transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

    OpenAIRE

    Krause, John R.; Drinkard, Lee C.; Keglovits, Latoya C.

    2013-01-01

    Transformation to a large cell lymphoma may occur during the course of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in approximately 5% of the cases. This is known as Richter's transformation. A much less frequent transformation to Hodgkin lymphoma may occur. We report a case of CLL/SLL in which a transformation to Hodgkin lymphoma occurred, and we review previously published reports of this transformation. Transformation to Hodgkin lymphoma in CLL/SLL has a poor outcome ...

  2. Research progress of B cell receptor pathway inhibitors in the treatment of chronic lymphocytic leukemia:reports from the 57th American Society of Hematology annual meeting%B细胞受体通路抑制剂在慢性淋巴细胞白血病治疗中的研究进展:第57届美国血液学会年会报道

    Institute of Scientific and Technical Information of China (English)

    孙倩; 徐卫; 李建勇

    2016-01-01

    随着Bruton酪氨酸激酶(BTK)抑制剂依鲁替尼(ibrutinib)及磷脂酰肌醇-3-激酶(PI3K)抑制剂idelalisib在复发/难治非霍奇金淋巴瘤(NHL)治疗中的成功,一系列新的B细胞受体(BCR)通路抑制剂也逐步进入临床试验。第57届美国血液学会(ASH)年会继续对依鲁替尼和idelalisib单药或联合用药治疗慢性淋巴细胞白血病(CLL)的探索保持了高度热情。另外脾酪氨酸激酶(SYK)抑制剂及新的BTK和PI3K抑制剂也崭露头角,为改善依鲁替尼和idelalisib耐药患者的疗效提供了新的选择。文章就第57届ASH年会中关于BCR通路抑制剂治疗CLL的进展进行介绍。%With the recent success of the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, and the phosphoinositide-3-kinase (PI3K) inhibitor idelalisib in the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL), a number of new agents targeting the B cell receptor (BCR) pathway are in clinical development. In the 57th American Society of Hematology (ASH) annual meeting, great interests are still focused on these two drugs, either monotherapy or combination in the treatment of CLL. On the other hand, SYK inhibitors, new BTK and PI3K antagonists are also coming to the forefront, casting a new light on the treatment of ibrutinib/idelalisb-resistant patients. The progresses of BCR pathway inhibitors in CLL will be summarized in this paper based on the reports in the 57th ASH annual meeting.

  3. Protein profiles distinguish stable and progressive chronic lymphocytic leukemia.

    Science.gov (United States)

    Huang, Pauline Y; Mactier, Swetlana; Armacki, Natalie; Giles Best, O; Belov, Larissa; Kaufman, Kimberley L; Pascovici, Dana; Mulligan, Stephen P; Christopherson, Richard I

    2016-05-01

    Patients with a stable chronic lymphocytic leukemia (CLL) double their blood lymphocyte count in >5 years, but may develop progressive disease with lymphocytes doubling in selected reaction monitoring) using extracts of purified CD19(+) CLL cells from patients (n = 50). Hierarchical clustering of these protein profiles showed two clusters of patients that correlated with progressive and stable CLL, providing signatures that should be useful for triaging patients. Some of the proteins in the progressive cluster have not been linked with CLL, for example, glutamate dehydrogenase 1 and transcription intermediary factor 1-beta. PMID:26422656

  4. Cutaneous diffuse large B-cell lymphoma of the leg associated with chronic lymphedema.

    Science.gov (United States)

    González-Vela, M Carmen; González-López, Marcos A; Val-Bernal, J Fernando; Fernández-Llaca, Héctor

    2008-02-01

    Development of malignant tumors is a rare but well known complication in chronic lymphedema (CL). We report herein a cutaneous diffuse large B-cell lymphoma of the leg associated with CL. An 89-year-old man presented with multiple cutaneous lesions on his right limb that showed a CL. Dermatological examination disclosed multiple violaceous, firm, slightly infiltrated nodules on the anterior aspect of the leg and the dorsum and sole of the foot. A biopsy of one nodule of the leg disclosed a diffuse large B-cell lymphoma, type of the legs. There was no evidence of lymphadenopathy on computed tomography (CT) scans of the chest, abdomen, and pelvis. A bone marrow aspiration and biopsy showed normal results. The patient was treated with local radiotherapy at a dose of 40 Gy, obtaining a highly significant, almost complete, clinical remission. A literature search identified 11 additional cases of primary cutaneous lymphoma associated with CL. An inadequate lymphatic drainage may make the lymphedematous region an immunologically vulnerable area, predisposing to neoplasia. PMID:18211492

  5. The clinical significance of 8q24/MYC rearrangement in chronic lymphocytic leukemia.

    Science.gov (United States)

    Li, Yan; Hu, Shimin; Wang, Sa A; Li, Shaoying; Huh, Yang O; Tang, Zhenya; Medeiros, L Jeffrey; Tang, Guilin

    2016-05-01

    Chromosome 8q24/MYC rearrangement is associated with Burkitt lymphoma and some aggressive B-cell lymphomas, but is rare in chronic lymphocytic leukemia. We here report a cohort of 20 chronic lymphocytic leukemia patients with 8q24/MYC rearrangement, 3 detected at time of initial diagnosis and 17 acquired after a median interval of 48 months. At the time when 8q24/MYC arrangement was detected, 18 patients had B-symptoms, 17 had lymphadenopathy, and 17 had splenomegaly. Histologically, typical chronic lymphocytic leukemia morphology was seen in six patients, increased prolymphocytes in nine and Richter's transformation in five patients. Eighteen patients had karyotypic information available that showed t(8;v) in a complex karyotype in 12 patients and in a non-complex karyotype in 6 patients. Fluorescence in situ hybridization confirmed MYC rearrangement in 17/17 patients. All patients required therapy after 8q24/MYC rearrangement was detected. At last follow-up, five of six patients with a non-complex karyotype were alive after a median of 74 months (10~143 months) from the detection of 8q24/MYC rearrangement. In contrast, 10 of 12 patients with a complex karyotype died with a median survival of 5.5 months. We conclude that 8q24/MYC rearrangement in chronic lymphocytic leukemia is rare and often acquired during the course of disease. If it is presented in a complex karyotype, it is often associated with Richter's transformation, refractory to therapy and an aggressive clinical course; on the other hand, if it is present in a non-complex karyotype, patients often respond to risk-adapted therapies and achieve remission. PMID:26916070

  6. Ibrutinib: an evidence-based review of its potential in the treatment of advanced chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Chavez JC

    2013-05-01

    Full Text Available Julio C Chavez, Eva Sahakian, Javier Pinilla-IbarzH Lee Moffitt Cancer and Research Institute, Division of Malignant Hematology, and University of South Florida, Tampa, FL, USAAbstract: Chronic lymphocytic leukemia (CLL is a heterogeneous disease with a variable course, and remains an incurable disease. Frequent relapses and eventual resistance to fludarabine characterize symptomatic CLL and portends a dismal prognosis for patients. Growing evidence has shown that signaling pathways such as the B cell receptor and NFkB are implicated in the survival and proliferation of the CLL cells which are ultimately associated with persistence of the disease. The Bruton’s tyrosine kinase pathway regulates downstream activation of the B cell receptor and has emerged as an attractive target. Ibrutinib inhibits the Bruton’s tyrosine kinase pathway, and consequently induces apoptosis of B cells. Phase I and II studies have shown impressive response rates with an excellent safety profile in patients with refractory/relapsed CLL and elderly treatment-naïve CLL patients. This paper reviews the preclinical and clinical data for ibrutinib when used in the treatment of CLL. Recent studies showing the benefit of combination therapy using ibrutinib, monoclonal antibodies, and chemoimmunotherapy are also discussed.Keywords: ibrutinib, B-cell receptor, chronic lymphocytic leukemia, Bruton’s tyrosine kinase

  7. Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

    OpenAIRE

    Komarova, Natalia L.; Burger, Jan A.; Wodarz, Dominik

    2014-01-01

    Chronic ymphocytic leukemia is the most common leukemia, mostly arising in patients over the age of 50. The disease has been treated with chemo-immunotherapies with varying outcomes, depending on the genetic make-up of the tumor cells. Recently, a promising new tyrosine kinase inhibitor, ibrutinib, has been developed, which resulted in successful responses in clinical trials, even for the most aggressive chronic lymphocytic leukemia types. The crucial current questions include how long diseas...

  8. The role of idelalisib in the treatment of relapsed and refractory chronic lymphocytic leukemia.

    Science.gov (United States)

    Nair, Kruti Sheth; Cheson, Bruce

    2016-04-01

    Idelalisib is a first in class, delta isoform specific, PI3-kinase inhibitor. Based on its high level of efficacy and acceptable safety profile, this oral drug has been approved by the US Food and Drug Administration as a single agent for the treatment of relapsed or refractory small lymphocytic lymphoma, and follicular non-Hodgkin lymphoma, and in combination with rituximab for patients with chronic lymphocytic leukemia. Adverse effects of particular concern include diarrhea, pneumonitis, and transient elevations of hepatic transaminase levels. Efforts to improve on the activity of this drug have included combinations with standard chemotherapy agents, such as bendamustine, and other targeted therapies, including checkpoint inhibitors. However, other combinations have been associated with life-threatening and fatal toxicities. Thus, the development of such regimens should be conducted carefully in the context of a clinical research study. Idelalisib has a vital role as second-line therapy for chronic lymphocytic leukemia, especially for patients with high-risk disease and multiple comorbidities, and studies are exploring the use of this agent as front-line therapy to improve the outcome of patients with indolent B-cell malignancies. PMID:27054023

  9. miRNA expression profiles in chronic lymphocytic and acute lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    D.L. Zanette

    2007-11-01

    Full Text Available MicroRNAs (miRNAs are a class of small endogenous RNAs that play important regulatory roles by targeting mRNAs for cleavage or translational repression. miRNAs act in diverse biological processes including development, cell growth, apoptosis, and hematopoiesis, suggesting their association with cancer. We determined the miRNA expression profile of chronic and acute lymphocytic leukemias (CLL and ALL using the TaqMan® MicroRNA Assays Human Panel (Applied Biosystems. Pooled leukemia samples were compared to pooled CD19+ samples from healthy individuals (calibrator by the 2-DDCt method. Total RNA input was normalized based on the Ct values obtained for hsa-miR-30b. The five most highly expressed miRNAs were miR-128b, miR-204, miR-218, miR-331, and miR-181b-1 in ALL, and miR-331, miR-29a, miR-195, miR-34a, and miR-29c in CLL. To our knowledge, this is the first report associating miR-128b, miR-204 and miR-331 to hematological malignancies. The miR-17-92 cluster was also found to be up-regulated in ALL, as previously reported for some types of lymphomas. The differences observed in gene expression levels were validated for miR-331 and miR-128b in ALL and CD19+ samples. These miRNAs were up-regulated in ALL, in agreement with our initial results. A brief target analysis was performed for miR-331. One of its putative targets, SOCS1, promotes STAT activation, which is a known mediator of cell proliferation and survival, suggesting the possibility of an association between miR-331 and these processes. This initial screening provided information on miRNA differentially expressed in normal and malignant B-cells that could suggest the potential roles of these miRNAs in hematopoiesis and leukemogenesis.

  10. Rituximab for the treatment of patients with chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    M Gentile

    2010-03-01

    Full Text Available M Gentile, E Vigna, C Mazzone, E Lucia, AG Recchia, L Morabito2, MG Bisconte, C Gentile, F Morabito1UOC di Ematologia, Azienda Ospedaliera di Cosenza, Italy; 2Servicio de Hematología y Hemoterapia, Hospital Universitario de Canarias, La Laguna, Tenerife, SpainAbstract: Chronic lymphocytic leukemia (CLL is a lymphoproliferative disorder that originates from antigen-experienced B lymphocytes that do not die and hence accumulate due to external survival signals or undergo apoptosis and are replenished by proliferating precursors. These neoplastic lymphocytes exhibit a characteristic immunophenotype of CD5+/CD19+/CD20+/HLA-DR+/CD23+/sIgdim. Thus, the CD20 antigen has been an appealing target for therapy. The introduction of the monoclonal antibody rituximab (anti-CD20 enabled an outstanding advance in CLL treatment. The introduction of this monoclonal antibody into chemotherapy regimens has dramatically improved complete response rates and progression-free survival in patients with both untreated and relapsed CLL. Although only preliminary data from phase III confirmatory trials have been reported, the FCR regimen, which combines fludarabine and cyclophosphamide with rituximab, is currently the most effective treatment regimen for CLL patients, and has also been demonstrated to significantly improve overall survival . The success of rituximab and the identification of other CLL lymphocyte surface antigens have spurred the development of a multitude of monoclonal antibodies targeting distinct proteins and epitopes in an attempt to target CLL cells more effectively.Keywords: rituximab, chronic lymphocytic leukemia, chemotherapy

  11. Interleukin 5, a T-cell-derived B-cell differentiation factor also induces cytotoxic T lymphocytes.

    OpenAIRE

    Takatsu, K; Kikuchi, Y; Takahashi, T.; Honjo, T; Matsumoto, M.; Harada, N.; Yamaguchi, N.; Tominaga, A

    1987-01-01

    We describe an interleukin, termed interleukin 5, that is the recombinant product previously referred to as T-cell-replacing factor (TRF), B-cell growth factor II (BCGF II), or killer-helper factor (KHF). TRF has been defined as a T-cell-derived lymphokine that acts on activated B cells as a B-cell differentiation factor. We have previously demonstrated that TRF is identical to BCGF II and induces expression of receptors for interleukin 2 (IL-2) on activated B cells. We also have reported tha...

  12. Differential expression and function of CD27 in chronic lymphocytic leukemia cells expressing ZAP-70.

    Science.gov (United States)

    Lafarge, Sandrine T; Hou, Sen; Pauls, Samantha D; Johnston, James B; Gibson, Spencer B; Marshall, Aaron J

    2015-07-01

    Chronic lymphocytic leukemia is a malignancy driven by abberant B cell signaling and survival. Leukemic B cells accumulate in the peripheral blood and the lymphoid organs where contact with stromal cells and T cells provide critical survival signals. Clinical severity of CLL is associated with several prognostic markers including expression of the kinase ZAP-70. ZAP-70 expression enhances signaling via the B cell antigen receptor and is associated with increased cell adhesion and migration capacity. Here we report that ZAP-70-positive CLL patients display significantly higher expression of the TNF superfamily receptor and memory marker CD27 than do ZAP-70 negative patients. CD27 expression by CLL was acutely elevated upon BCR cross-linking, or upon ectopic expression of ZAP-70. CD27 expression correlated with functional capacity to adhere to stromal cells and antibody blockade of CD27 impaired CLL binding to stroma. These results provide the first evidence for differential expression of CD27 among CLL prognostic groups, suggest a role for ZAP-70 dependent signaling in CD27 induction and implicate CD27 in cell-cell interactions with the lymphoid tissue microenvironment. PMID:26002513

  13. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with everolimus (RAD001) and alemtuzumab: a Phase I/II study.

    Science.gov (United States)

    Zent, Clive S; Bowen, Deborah A; Conte, Michael J; LaPlant, Betsy R; Call, Timothy G

    2016-07-01

    Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL), and especially those with purine analogue refractory disease or TP53 deletion/mutation, had a poor prognosis prior to the introduction of therapy targeting B cell receptor signaling. The mammalian target of rapamycin (mTOR) inhibitor everolimus has biological activity in CLL and can mobilize CLL cells from the lymphoid tissues into the circulation. In this clinical trial we determined the maximum tolerated dose (MTD) of everolimus together with eight weeks of standard dose subcutaneous alemtuzumab (Phase I) and then evaluated the tolerability and efficacy of therapy of relapsed/refractory CLL with the combination of everolimus and alemtuzumab (Phase II). The maximum tolerated dose of oral everolimus was 2.5 mg three times/week. Therapy with everolimus and alemtuzumab was tolerable, but not sufficiently efficacious (33% partial responses, no complete responses) to recommend further development of the regimen. PMID:26699397

  14. Cutting Edge: B Cell-Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection.

    Science.gov (United States)

    Barnett, Burton E; Staupe, Ryan P; Odorizzi, Pamela M; Palko, Olesya; Tomov, Vesselin T; Mahan, Alison E; Gunn, Bronwyn; Chen, Diana; Paley, Michael A; Alter, Galit; Reiner, Steven L; Lauer, Georg M; Teijaro, John R; Wherry, E John

    2016-08-15

    The role of Ab and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections, and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. We demonstrate that B cell-specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells controlled IgG2a production, as well as mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a because T-bet in B cells was important, even in the presence of virus-specific IgG2a. Our data support a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages. PMID:27430722

  15. Acquisition of an anti-idiotypic cytotoxic T lymphocyte repertoire in B cell-transferred or tetraparental bone marrow chimeric mice

    International Nuclear Information System (INIS)

    In previous studies we showed that major histocompatibility complex-restricted cytotoxic T lymphocytes (CTL) specific for the cross-reactive idiotype (CRI) of MOPC-104E myeloma protein could only be induced in BALB/c or BAB-14 mice which have the ability to produce the CRI, but not in C.AL-20 or C.B-20 mice which have no ability to produce the CRI. The strong correlation between CRI-specific CTL responder strains and CRI producers supports the idea that the VH gene products are intrinsic primary antigenic stimuli for the generation of the anti-idiotypic CTL. To investigate the role of B lymphocytes in the selection of T lymphocyte repertoire, the purified B cells of CRI producer strains were repeatedly injected into anti-CRI CTL nonresponder neonatal mice. CRI-specific CTL activity was successfully induced in the CRI nonproducer mice only when they were exposed to CRI producer strain B lymphocytes from neonatal life. When the CTL nonresponder adult mice received CRI producer B lymphocytes, the nonresponder phenotype was not changed into the responder phenotype. Inducibility of CRI-specific CTL was also analyzed in tetraparental bone marrow chimeras. When CRI nonproducer bone marrow cells repopulated along with CRI producer bone marrow cells, the anti-CRI CTL of CRI nonproducer origin were generated. Adaptive differentiation of haplotype preference was also observed. When these observations are taken collectively, we see that the anti-idiotypic T lymphocyte repertoire is not a genetically determined one, but rather that the repertoire of T lymphocytes strongly depends on the postnatal selection process through the intrinsic idiotypic repertoire of B lymphocytes, i.e., internal images

  16. Chromosomal study for prognostic grouping in chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    To determine the frequency of various cytogenetic aberrations in newly diagnosed chronic lymphocytic leukemia (CLL) patients, and their detection rate by cytogenetic and fluorescent In situ hybridization (FISH) technique separately. Analysis was made on 100 diagnosed chronic lymphocytic leukemia patients. Cytogenetics and FISH technique were performed on blood or bone marrow samples. Nineteen out of 100 cases (19%) showed karyotype abnormalities; whereas 55 showed abnormalities using the CLL - specific FISH probes. The most frequent abnormality detected by standard cytogenetics was trisomy 12. The most common abnormality detected by FISH was a deletion of 13q14 (40 out of 55 cases; 72% of the abnormal). For prognostic grouping of CLL patients, FISH must always be requested which may even replace standard karyotyping. These chromosomal markers help in choosing the therapeutic options. (author)

  17. Lenalidomide in the treatment of chronic lymphocytic leukemia

    OpenAIRE

    Agostino Cortelezzi; Mariarita Sciumè; Gianluigi Reda

    2012-01-01

    The application of nucleoside analogue-based chemotherapy and immunotherapy with rituximab or alemtuzumab has increased both response rate and survival in patients with Chronic Lymphocytic Leukemia (CLL). However, because none of these therapies is curative, sequential therapeutic regimens are required. The majority of patients with relapsed or refractory CLL carry poor prognostic factors and show shorter overall survival and resistance to standard treatment. Numerous drugs have recently be...

  18. Aureobasidium pullulans infection in a patient with chronic lymphocytic leukemia

    OpenAIRE

    Leonardo Rodrigues de Oliveira; Helio Moraes-Souza; Andre Luiz Maltos; Keila Cristina dos Santos; Rodrigo Juliano Molina; Cristina Hueb Barata

    2013-01-01

    Saprophytic fungi are being increasingly recognized as etiologic agents of mycoses in immunosuppressed patients. We report a case of subcutaneous infiltration by Aureobasidium pullulans, likely due to traumatic inoculation, in a neutropenic patient during chemotherapy for chronic lymphocytic leukemia. The patient was treated with amphotericin B deoxycholate but was subsequently switched to itraconazole, which improved the lesion. This case highlights the importance of considering unusual fung...

  19. Small intestinal bacterial overgrowth in patients with chronic lymphocytic leukaemia.

    OpenAIRE

    Smith, G M; Chesner, I M; Asquith, P; Leyland, M. J.

    1990-01-01

    As part of a study to assess the possible contribution of lymphoid infiltration of the gastrointestinal mucosa to occult blood loss or malabsorption 20 patients with chronic lymphocytic leukaemia (CLL) had a lactulose hydrogen breath test. In 10 cases (50%) a small intestinal peak was detected, suggesting small bowel bacterial overgrowth, and this was confirmed in seven patients by the positive culture of jejunal aspirate. Of the patients with a positive hydrogen breath test, radiological exa...

  20. No evidence of transmission of chronic lymphocytic leukemia through blood transfusion

    DEFF Research Database (Denmark)

    Hjalgrim, Henrik; Rostgaard, Klaus; Vasan, Senthil K;

    2015-01-01

    occurrence among 7413 recipients of blood from 796 donors diagnosed with CLL after donation cessation, and among 80 431 recipients of blood from 7477 matched CLL-free donors. During follow-up, 12 and 107 cases of CLL occurred among the exposed and unexposed recipients, respectively, yielding a relative risk......Monoclonal B-cell lymphocytosis (MBL) is a precursor of chronic lymphocytic leukemia (CLL). Observations of MBL in blood donors raise concern that transmitted MBL may cause recipient CLL. Using a database with health information on 1.5 million donors and 2.1 million recipients, we compared CLL...... of 0.94 (95% confidence interval, 0.52-1.71). Analyses using the entire database showed no evidence of CLL clustering among recipients of blood from individual donors. In conclusion, when donor MBL was approximated by subsequent donor CLL diagnosis, data from 2 countries' entire computerized...

  1. Novel agents in the treatment of chronic lymphocytic leukemia: a review about the future.

    Science.gov (United States)

    Desai, Anjali Varma; El-Bakkar, Hassan; Abdul-Hay, Maher

    2015-06-01

    Half of a century ago, physicians managing chronic lymphocytic leukemia (CLL) recognized some of its presenting features such as lymphocytosis, lymphadenopathy, and splenomegaly. Subsequently, an enhanced understanding of the disease mechanisms involved in CLL led to new, more targeted treatments. There is now a plethora of treatments available for CLL. In this review article we discuss in detail several of the novel agents that are being studied or approved for the treatment of CLL including: phosphatidylinositol 3-kinase inhibitors (idelalisib and IPI-145), Bruton tyrosine kinase inhibitors (ibrutinib), B cell lymphoma 2 inhibitors (ABT-263 and ABT-199), new anti-CD20 monoclonal antibodies (obinutuzumab), cyclin-dependent kinase inhibitors (flavopiridol and dinaciclib), immunomodulators (lenalidomide) and chimeric antigen receptor T-cell therapy. PMID:25445466

  2. Clinical significance of B cell dysfunction in patients with chronic HIV-1 infection%HIV-1慢性感染者B细胞功能受损的临床意义

    Institute of Scientific and Technical Information of China (English)

    张学秀; 徐向升; 张政; 王福生

    2013-01-01

    HIV慢性感染是全球性的问题和大家关注的热点,其主要标志是CD4+ T淋巴细胞计数的减少和免疫系统的功能失调.关于其发病机制方面的研究很多,但是关于B细胞方面的研究较少,而且关于其在HIV慢性感染中的功能和意义尚不清楚.本文对HIV-1慢性感染者B细胞功能受损的临床意义进行综述,以期为HIV感染的研究工作提供参考.%Chronic HIV infection is a global question and an issue focused on by many researchers.The major characteristics of chronic HIV infection are the decrease in CD4+ T lymphocyte counts and the dysfunction of immune system.Many studies have been carried out on the pathogenesis of HIV infection,but only a few studies on B cells in patients with chronic HIV infection.Moreover,the function and significance of B cells in chronic HIV infection remain unknown.The authors summarize the clinical significance of B cell dysfunction in patients with chronic HIV-1 infection,intending to provide a reference for the studies on HIV infection.

  3. Occurrence of chronic lymphocytic leukemia in patients with chronic myelogenous leukemia

    OpenAIRE

    Bhattacharyya, Pritish K

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in the western world and constitutes about 33% of all leukemia′s. The incidence of CLL increases with age and are more common in older population. Chronic myeloid leukemia (CML) on the contrary occurs in both young adults and elderly and is a chronic myeloproliferative disease that originates from abnormal pluripotent stem cells and results in involvement of multiple hematopoietic lineages, but predominantly myeloid and ...

  4. Peripheral blood lymphocytes DNA in patients with chronic liver diseases

    Institute of Scientific and Technical Information of China (English)

    Vasiliy I Reshetnyak; Tatyana I Sharafanova; Ludmila U Ilchenko; Elena V Golovanova; Gennadiy G Poroshenko

    2001-01-01

    BACKGROUND Viral replication in blood cells with nucleuses may lead to the damage of lymphocytes genetic apparatus and the beginning of immunopathological reactions.AIM Of this investigation is to reveal the damage to peripheral blood lymphocytes (PBL)DNA in the patients with chronic liver diseases.MATERIALS AND METHODS Sixteen-ninepatients with chronic liver diseases (37 patients with chronic viral hepatitis, 2 patients with liver cirrhosis of mixed etiology (alcohol + virus G),30 women with primary biliary cirrhosis-PBC)were examined. The condition of DNA structure of PBL-was measured by the fluorescenceanalysis of DNA unwinding (FADU) technique with modification. Changes of fluorescence (in %) reflected the DNA distractions degree (thepresence of DNA single-stranded breaks and alkalinelabile sights).RESULTS AND CONCLUSION . The quantity of DNA single-stranded breaks and alkalinelabile sightsin DNA in all patients with chronic viral hepatitis .didnt differ from the control group,excluding the patients with chronic hepatitis (CH) C + G. Patients with HGV and TTV monoinfection had demonstrated the increase of the DNA single-stranded breaks PBL quantity.This fact may be connected with hypothesisabout the viruses replication in white blood cells discussed in the literature. Tendency to increase quantity of DNA PBL damages in the patients with primary biliary cirrhosis (PBC) accordingly to the alkaline phosphatase activity increase was revealed. Significant decrease of the DNA single-stranded breaks and alkalinelabile sights in the PBC patients that were treated with prednison was demonstrated. Probably, the tendency to increase the quantity of DNA singlestranded breaks and alkalinelabile sights in lymphocytes of the PBC patients was depended on the surplus of the blood bile acid content.

  5. Ibrutinib Improves Survival in Patients with Previously Treated Chronic Lymphocytic Leukemia

    Science.gov (United States)

    A summary of results from an international phase III trial that compared ibrutinib (Imbruvica®) and ofatumumab (Arzerra®) for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

  6. Chronic Inflammation-Related Diffuse Large B-Cell Lymphoma Around the Area of Thoracotomy After Decortication

    Directory of Open Access Journals (Sweden)

    Bayram Metin

    2014-06-01

    Full Text Available Chest wall tumors consist 5% of all tumors in the thorax. Lymphomas compose of less than 5% of all primary chest wall malignancy.Sixty three years old patient who had an operation for pleural thickness two years ago admitted with complaint of left-sided chest pain.Following the detection of mass lesion radiologically at the place of previous operation area, the patient was operated based on needle biopsy result suggesting Ewing /PNET or pulmonary originated tumor. After the operation, pathological examination confirmed chronic inflammation-related diffuse large B-cell lymphoma. Since it has been rarely reported in the literature, we aimed to present the case of chronic inflammation-related diffuse large B-cell lymphoma developed within such a short time as two years on the ground of surgical incision scar tissue together with our radiologic, surgical, and pathological findings.

  7. Characterization and functional studies of forkhead box protein 3(-) lymphocyte activation gene 3(+) CD4(+) regulatory T cells induced by mucosal B cells.

    Science.gov (United States)

    Chu, K-H; Chiang, B-L

    2015-05-01

    The induction of mucosal tolerance has been demonstrated to be an effective therapeutic approach for the treatment of allergic diseases. Our previous study demonstrated that Peyer's patch B cells could convert naive T cells into regulatory T cells (so-called Treg -of-B(P) cells); however, it is important to characterize this particular subset of Treg -of-B cells for future applications. This study aimed to investigate the role of lymphocyte activating gene 3 (LAG3) in mediating the regulatory function of Treg -of-B(P) cells induced by mucosal follicular B (FOB) cells. Microarray analysis and real-time polymerase chain reaction (PCR) were used to assess the gene expression pattern of Treg -of-B(P) cells. To evaluate the role of LAG3, the in-vitro suppressive function and the alleviation of airway inflammation in a murine model of asthma was assessed. Our data indicated that FOB cells isolated from Peyer's patches had the ability to generate more suppressive Treg -of-B cells with LAG3 expression, compared with CD23(lo) CD21(lo) B cells. LAG3 is not only a marker for Treg -of-B(P) cells, but also participate in the suppressive ability. Moreover, CCR4 and CCR6 could be detected on the LAG3(+) , not LAG3(-) , Treg -of-B(P) cells and would help cells homing to allergic lung. In the murine model of asthma, the adoptive transfer of LAG3(+) Treg -of-B(P) cells was able to sufficiently suppress T helper type 2 (Th2) cytokine production, eosinophil infiltration and alleviate asthmatic symptoms. LAG3 was expressed in Treg -of-B(P) cells and was also involved in the function of Treg -of-B(P) cells. In the future, this particular subset of Treg -of-B cells might be used to alleviate allergic symptoms. PMID:25581421

  8. Monosomy 12 and deletion of 13q34 in a case of chronic lymphocytic leukemia with concomitant lung cancer

    Directory of Open Access Journals (Sweden)

    Antić Darko

    2010-01-01

    Full Text Available Background. We described a patient with chronic lymphocytic leukemia (CLL and lung cancer and unusual chromosomal aberrations. Case report. At the same time with the diagnosis of B-cell CLL, squamocellular lung carcinoma diagnosis was established. Using interphase fluoresecence in situ hybridization technique (FISH we detected monosomy 12 and deletion of 13q34 occured in the same clone. One month after the beginning of examination the patient died unexpectedly during sleep immediately before we applied a specific treatment for CLL or lung carcinoma. Conclusion. Simultaneous occurrence of monosomy 12 and deletion of 13q34 in a patient with B-cell CLL has been described only once before, but as a part of a complex karyotype. The prognostic significance of these abnormalities remains uncertain.

  9. Aureobasidium pullulans infection in a patient with chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Leonardo Rodrigues de Oliveira

    2013-09-01

    Full Text Available Saprophytic fungi are being increasingly recognized as etiologic agents of mycoses in immunosuppressed patients. We report a case of subcutaneous infiltration by Aureobasidium pullulans, likely due to traumatic inoculation, in a neutropenic patient during chemotherapy for chronic lymphocytic leukemia. The patient was treated with amphotericin B deoxycholate but was subsequently switched to itraconazole, which improved the lesion. This case highlights the importance of considering unusual fungal infections in critically ill patients such as those who are immunosuppressed due to chemotherapy. Diagnostic techniques and effective antifungal therapy have improved the prognosis of these cases.

  10. Reverse Pseudohyperkalemia: An Important Clinical Entity in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Sahar Mansoor

    2015-01-01

    Full Text Available Hyperkalemia is a potentially lethal electrolyte derangement commonly seen in patients with hematologic neoplasms with or without renal failure. Pseudohyperkalemia and reverse pseudohyperkalemia also can be seen in this patient population and early recognition and diagnosis of these conditions are vital. Here, we report a case of reverse pseudohyperkalemia in a patient with chronic lymphocytic leukemia (CLL and provide recommendations regarding diagnostic and therapeutic strategies for management of such patients. Further, we discuss the pathogenesis of this condition and its potential role as a surrogate of favorable prognostic features in patients with CLL.

  11. PARP1-Driven Apoptosis in Chronic Lymphocytic Leukemia

    OpenAIRE

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is considered a malignancy resulting from defects in apoptosis. For this reason, targeting apoptotic pathways in CLL may be valuable for its management. Poly [ADP-ribose] polymerase 1 (PARP1) is the main member of a family of nuclear enzymes that act as DNA damage sensors. Through binding on DNA damaged structures, PARP1 recruits repair enzymes and serves as a survival factor, but if the damage is severe enough, its action may lead the cell to apoptosis thro...

  12. IL-10-producing regulatory B-cells suppressed effector T-cells but enhanced regulatory T-cells in chronic HBV infection.

    Science.gov (United States)

    Liu, Yun; Cheng, Li-Sha; Wu, Sheng-di; Wang, Si-Qi; Li, Lei; She, Wei-Min; Li, Jing; Wang, Ji-Yao; Jiang, Wei

    2016-06-01

    Non-specific immune responses to antigens have been demonstrated as being enhanced during chronic hepatitis B virus (HBV) infection. Here, we evaluated the role of interleukin-10 (IL-10)-producing regulatory B-cells (Bregs) in the pathogenesis of HBV-related liver fibrosis (HBV-LF) and assessed their immunoregulatory effects. Sixty-seven patients diagnosed with chronic hepatitis B (CHB) were enrolled in this study. Numbers and frequencies of peripheral B-cells (memory CD19(+)CD24(hi)CD27(+) cells, immature/transitional CD19(+)CD24(hi)CD38(hi) cells, mature CD19(+)CD24(int)CD38(int) cells) were tested and analysed. Flow cytometry-sorted CD4(+)T cells were cultured with autologous Bregs to elucidate the effects of Bregs on CD4(+)T cells, including effector T and regulatory T-cells (Tregs). The potential immunoregulatory mechanism of Bregs was also investigated. The numbers of total B-cells and Bregs were enriched in CHB patients. The frequency of Bregs was negatively correlated with elevated alanine aminotransferase (ALT) and histological inflammation grades (G), but positively correlated with advanced histological fibrosis stages (S) and enhanced HBV replication. The phenotype of Bregs was predominantly characterized as CD19(+)CD24(hi)CD38(hi) In co-culture with Bregs, CD4(+)CD25(-)T cells from CHB patients produced less interferon-γ (IFN-γ) and IL-17 but more IL-4 than CD4(+)CD25(-)T cells alone, whereas their conversions into Tregs and IL-10(+)T cells were enhanced. In addition, Breg depletion in CHB samples dramatically decreased Treg numbers and expression of cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), IL-10 and transforming growth factor-β (TGF-β). Moreover, the observed regulatory effect was partly dependent on IL-10 release and cell-to-cell contact. Elevated Bregs can suppress effector T but enhance Treg functions, which might influence immune tolerance in chronic HBV infection. PMID:26980345

  13. Chronic lymphocytic leukaemia induces an exhausted T cell phenotype in the TCL1 transgenic mouse model.

    Science.gov (United States)

    Gassner, Franz J; Zaborsky, Nadja; Catakovic, Kemal; Rebhandl, Stefan; Huemer, Michael; Egle, Alexander; Hartmann, Tanja N; Greil, Richard; Geisberger, Roland

    2015-08-01

    Although chronic lymphocytic leukaemia (CLL) is a B cell malignancy, earlier studies have indicated a role of T cells in tumour growth and disease progression. In particular, the functional silencing of antigen-experienced T cells, called T cell exhaustion, has become implicated in immune evasion in CLL. In this study, we tested whether T cell exhaustion is recapitulated in the TCL1(tg) mouse model for CLL. We show that T cells express high levels of the inhibitory exhaustion markers programmed cell death 1 (PDCD1, also termed PD-1) and lymphocyte-activation gene 3 (LAG3), whereas CLL cells express high levels of CD274 (also termed PD-ligand 1). In addition, the fraction of exhausted T cells increases with CLL progression. Finally, we demonstrate that exhausted T cells are reinvigorated towards CLL cytotoxicity by inhibition of PDCD1/CD274 interaction in vivo. These results suggest that T cell exhaustion contributes to CLL pathogenesis and that interference with PDCD1/CD274 signalling holds high potential for therapeutic approaches. PMID:25940792

  14. Targeting PI3Kδ: emerging therapy for chronic lymphocytic leukemia and beyond.

    Science.gov (United States)

    Wei, Manman; Wang, Xiang; Song, Zilan; Jiao, Mingkun; Ding, Jian; Meng, Ling-Hua; Zhang, Ao

    2015-07-01

    Chronic lymphocytic leukemia (CLL) remains the most incurable leukemia. Early chemotherapeutic treatments, including alkylating agents, purine nucleoside derivatives, and immunotherapeutic antibodies, only show limited benefits for patients but severe off-target related side effects. Recent advances in understanding of the critical molecular pathways of regulating proliferation and survival of B-CLL cells have spurred a new therapeutical strategy by selectively targeting phosphoinositide 3-kinase delta (PI3Kδ). Idelalisib, a first-in-class PI3Kδ-selective small molecule has received the FDA's fast-track approval in July of 2014 as a new treatment of CLL, indolent B-cell non-Hodgkin's lymphoma, and relapsed small lymphocytic lymphoma. Undoubtedly, the success of idelalisib has provided a solid support in the development of PI3Kδ-specific inhibitors and reformed the concept of treating CLL. However, the number of reported selective inhibitors of PI3Kδ is very limited and very few have advanced into clinical trials. The mechanism of their actions remains elusive. More profound understanding on the modes of action of new PI3Kδ inhibitors will further validate the PI3Kδ-targeting strategy, and help to identify biomarkers capable of stratifying patients who will most likely benefit from the therapy. PMID:25763934

  15. Interleukin 2-induced proliferation of leukemic human B cells

    OpenAIRE

    1985-01-01

    The proliferative responses of purified leukemic human B cells from nine B cell chronic lymphocytic leukemias to recombinant interleukin 2 (IL-2), spontaneously, and after preactivation by Staphylococcus aureus Cowan I (SAC) or anti-mu antibodies were studied. Three patterns of response were observed: (a) no response (three cases); (b) a moderate spontaneous response enhanced by anti-mu (one case); (c) a high proliferative response after preactivation by anti-mu and/or SAC (five cases). IL-2 ...

  16. Trisomy 12 in a Case of Multiple Cutaneous Squamous Cell Carcinoma in Association with Chronic Lymphocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    XU Zhou-min; CHEN Yan; GAO Wei-ran

    2007-01-01

    Chronic lymphocytic leukaemia (CLL), which shares clinical and morphological overlap with small lymphocytic lyjmphoma (SLL), is a low-grade clonal B-cell lymphoproliferative disorder that accounts for 25% of all cases of leukaemia in Western countries, while it is considered rare in Oriental patients and is thought to constitute only 2% of all leukemias in these patients[1]. CLL is associated with an increased incidence of secondary malignant neoplasms, such as brain tumors, melanomas, and gastrointestinal-tract carcinomas[2]. However, the simulataneous occurrence of CLL and cutaneous squamous cell carcinoma (SCC) is rarely reported. We present here a case of CLL with multiple SCC on the face. Subsequent studies demonstrated the patient to have a trisomy 12 identified in bone marrow specimen.

  17. A case of chronic lymphocytic leukemia with massive ascites

    Science.gov (United States)

    Yonal, Ipek; Nazlıgul, Esra; Tas, Gulsum; Agan, Mehmet Ramazan; Yenerel, Mustafa Nuri; Nalcaci, Meliha

    2012-01-01

    An 81-year old woman with a history of chronic lymphocytic leukemia (CLL) was admitted with night sweats and abdominal distension. A complete blood count showed hemoglobin 5 g/dL, white blood cell (WBC) count 28.5×109/L and platelets 38.4×109/L. Peripheral blood smear examination showed a large number of smudge cells and lymphocytosis composed of mature-looking lymphocytes with clumped nuclear chromatin. Computed tomography scan demonstrated enlarged cervical, axillary, paraaortic, retroperitoneal and mesenteric lymph nodes with concomitant omental thickening and ascites. Also, the liver and the spleen were enlarged in the presence of multiple ill-defined hypoechoic areas in the latter. Histopathological analysis of the cervical lymph node biopsy was consistent with CLL. Bone marrow examination showed diffuse infiltration of the marrow with small lymphocytes. Analysis of the ascitic fluid revealed an exudate with WBC 1220 cells/mL. Cytocentrifuge preparation of the ascitic fluid showed small mature lymphoid cells containing hyperchromatic nuclei with coarsely granular chromatin. On flow cytometric analysis of the ascitic fluid, expression of CD5, CD19, CD20, CD22, CD23, CD45 and HLA-DR was compatible with a diagnosis of CLL, in accordance with the results of the peripheral blood analysis. The patient was treated with chemotherapy consisting of cyclophosphamide, vincristine and prednisolone but died within one month after development of non-chylous ascites. PMID:23372915

  18. A case of chronic lymphocytic leukemia with massive ascites

    Directory of Open Access Journals (Sweden)

    Meliha Nalcaci

    2012-10-01

    Full Text Available An 81-year old woman with a history of chronic lymphocytic leukemia (CLL was admitted with night sweats and abdominal distension. A complete blood count showed hemoglobin 5 g/dL, white blood cell (WBC count 28.5x109/L and platelets 38.4x109/L. Peripheral blood smear examination showed a large number of smudge cells and lymphocytosis composed of mature-looking lymphocytes with clumped nuclear chromatin. Computed tomography scan demonstrated enlarged cervical, axillary, paraaortic, retroperitoneal and mesenteric lymph nodes with concomitant omental thickening and ascites. Also, the liver and the spleen were enlarged in the presence of multiple ill-defined hypoechoic areas in the latter. Histopathological analysis of the cervical lymph node biopsy was consistent with CLL. Bone marrow examination showed diffuse infiltration of the marrow with small lymphocytes. Analysis of the ascitic fluid revealed an exudate with WBC 1220 cells/mL. Cytocentrifuge preparation of the ascitic fluid showed small mature lymphoid cells containing hyperchromatic nuclei with coarsely gran- ular chromatin. On flow cytometric analysis of the ascitic fluid, expression of CD5, CD19, CD20, CD22, CD23, CD45 and HLA-DR was compatible with a diagnosis of CLL, in accordance with the results of the peripheral blood analysis. The patient was treated with chemotherapy consisting of cyclophosphamide, vincristine and prednisolone but died within one month after development of non-chylous ascites.

  19. Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells

    International Nuclear Information System (INIS)

    Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34+ cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor γ-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML

  20. Chronic Lymphocytic Inflammation Specifies the Organ Tropism of Prions

    Science.gov (United States)

    Heikenwalder, Mathias; Zeller, Nicolas; Seeger, Harald; Prinz, Marco; Klöhn, Peter-Christian; Schwarz, Petra; Ruddle, Nancy H.; Weissmann, Charles; Aguzzi, Adriano

    2005-02-01

    Prions typically accumulate in nervous and lymphoid tissues. Because proinflammatory cytokines and immune cells are required for lymphoid prion replication, we tested whether inflammatory conditions affect prion pathogenesis. We administered prions to mice with five inflammatory diseases of the kidney, pancreas, or liver. In all cases, chronic lymphocytic inflammation enabled prion accumulation in otherwise prion-free organs. Inflammatory foci consistently correlated with lymphotoxin up-regulation and ectopic induction of FDC-M1+ cells expressing the normal cellular prion protein PrPC. By contrast, inflamed organs of mice lacking lymphotoxin-α or its receptor did not accumulate the abnormal isoform PrPSc, nor did they display infectivity upon prion inoculation. By expanding the tissue distribution of prions, chronic inflammatory conditions may act as modifiers of natural and iatrogenic prion transmission.

  1. Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab

    Directory of Open Access Journals (Sweden)

    Smolej L

    2014-12-01

    Full Text Available Lukáš Smolej 4th Department of Internal Medicine – Hematology, University Hospital Hradec Králové and Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic Abstract: Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101 is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL. Keywords: chronic lymphocytic leukemia, anti-CD20 antibodies, chlorambucil, rituximab, ofatumumab, obinutuzumab, overall survival

  2. The role of antigen in the development of B-cell chronic lymphocytic leukemia

    OpenAIRE

    Hoogeboom, R.

    2013-01-01

    These studies strongly suggest that MALT-lymphomas and M-CLL in majority are highly selected for single extrinsic antigens and that these antigens can be both self-antigens and exo-antigens. Our finding that primary CLL cells are responsive to stimulation with their cognate antigen suggests that antigen-dependent BCR signaling may drive CLL expansion in vivo.

  3. Memory B cells and CD8⁺ lymphocytes do not control seasonal influenza A virus replication after homologous re-challenge of rhesus macaques.

    Directory of Open Access Journals (Sweden)

    Timothy D Carroll

    Full Text Available This study sought to define the role of memory lymphocytes in the protection from homologous influenza A virus re-challenge in rhesus macaques. Depleting monoclonal antibodies (mAb were administered to the animals prior to their second experimental inoculation with a human seasonal influenza A virus strain. Treatment with either anti-CD8α or anti-CD20 mAbs prior to re-challenge had minimal effect on influenza A virus replication. Thus, in non-human primates with pre-existing anti-influenza A antibodies, memory B cells and CD8α⁺ T cells do not contribute to the control of virus replication after re-challenge with a homologous strain of influenza A virus.

  4. A critical appraisal of ibrutinib in the treatment of mantle cell lymphoma and chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Tucker DL

    2015-06-01

    Full Text Available David L Tucker, Simon A Rule Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, UK Abstract: Although chemo-immunotherapy remains at the forefront of first-line treatment for mantle cell lymphoma (MCL and chronic lymphocytic leukemia (CLL, small molecules, such as ibrutinib, are beginning to play a significant role, particularly in patients with multiply relapsed or chemotherapy-refractory disease and where toxicity is an overriding concern. Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase, which functions by irreversible inhibition of the downstream signaling pathway of the B-cell receptor, which normally promotes cell survival and proliferation. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile even in elderly and multiply pretreated patient cohorts. Although the majority of disease responses tend to be partial, efficacy data have also been encouraging with more than two-thirds of patients with CLL and MCL demonstrating a durable response, even in the high-risk disease setting. Resistance mechanisms are only partially understood and appear to be multifactorial, including the binding site mutation C481S, and escape through other common cell-signaling pathways. This article appraises the currently available data on safety and efficacy from clinical trials of ibrutinib in the management of MCL and CLL, both as a single agent and in combination with other therapies, and considers how this drug is likely to be used in future clinical practice. Keywords: ibrutinib, mantle cell lymphoma, chronic lymphocytic leukemia, Bruton’s tyrosine kinase, lymphoproliferative disorders

  5. [Linear and adhesive phenotype of tumor lymphocytes and clinical course of chronic leucosis].

    Science.gov (United States)

    Golenkov, A K; Baryshnikov, A Iu; Mitina, T A; Novikov, V V

    2005-01-01

    Determination of chronic lymphatic leukemia immunological phenotype, performed by the authors, was based upon the study of quantitative expression of membrane differentiation antigens on peripheral blood lymphocytes. The research included study of co-expression of adhesion molecules, belonging to the following families: beta 2 integrins (CD 11 beta, CD 18), immunoglobulins (CD 50), and CD 38 on tumor blood B-lymphocytes of various CD-types and T-lymphocytes in chronic leucosis. The authors developed a functional model of trans-endothelial migration of peripheral blood lymphocytes in chronic chronic lymphatic leukemia, taking into account their membrane adhesive characteristics and serum level of CD 50. The researchers determined clinical importance of the expression of linear and adhesive antigens on peripheral blood lymphocytes, and soluble HLA-1 (sHLA-1) serum levels in patients with chronic lymphatic leukemia. PMID:15960204

  6. Rituximab plus Ifosfamide, Carboplatin and Etoposide for T-Cell/Histiocyte-Rich B-Cell Lymphoma Arising in Nodular Lymphocyte-Predominant Hodgkin’s Lymphoma

    Directory of Open Access Journals (Sweden)

    Hyung-Chul Park

    2012-08-01

    Full Text Available A small subset of patients with nodular lymphocyte-predominant Hodgkin’s lymphoma (NLPHLs develop a non-Hodgkin lymphoma either concurrently or subsequently, usuallyT-cell/histiocyte-rich B-cell lymphomas (T/HRBCL, which are subtypes of diffuse large B-cell lymphomas (DLBCL. The standard treatment of DLBCL patients is rituximab-based chemotherapy with cyclophosphamide, adriamycin, vincristine and prednisolone. However, the administration of this chemotherapy regimen to patients with DLBCL arising in NLPHL brings concern about the cardiac toxicity of anthracycline because the majority of these patients had already received anthracycline-based chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine at the time of NLPHL. Herein, we report 2 patients with sequential transformation of NLPHL to T/HRBCL. They initially presented with limited-stage NLPHL and subsequently developed T/HRBCL after 16 and 8 months, respectively. At the time of T/HRBCL, they were treated with rituximab, ifosfamide, carboplatin and etoposide, and complete responses were obtained.

  7. DNA repair initiated in chronic lymphocytic leukemia lymphocytes by 4-hydroperoxycyclophosphamide is inhibited by fludarabine and clofarabine.

    OpenAIRE

    Yamauchi, Takahiro; Nowak, Billie J.; Michael J Keating; Plunkett, William

    2001-01-01

    PURPOSE: Chronic lymphocytic leukemia (CLL) lymphocytes respond to DNA alkylation by excision repair, with the extent of repair increasing as the cells acquire resistance to alkylating agents. Because incorporation of nucleotide analogues into the repair patches elicits death signals in quiescent cells, the increased capacity for excision repair in alkylator-resistant cells could facilitate incorporation of nucleotide analogues. We hypothesized that the mechanism-based interaction of nucleosi...

  8. Analysis of chromatin pattern in blood lymphocytes of healthy donors and in lymphoid cells of patients with chronic lymphocytic leukaemia.

    OpenAIRE

    Rozycka, M; Sawicki, W; Traczyk, Z; Bem, W; Strojny, P

    1988-01-01

    The optical Fourier transformation was used to analyse the chromatin/interchromatin pattern of lymphocytes of healthy subjects and lymphoid cells of patients with chronic lymphocytic leukaemia (CLL, type B, stage O). Peripheral blood smears were prepared routinely, fixed, and stained by the Feulgen method, and the photographic images of the nuclei were quantitatively analysed. From the radial distribution of light intensity of diffractograms, several Feulgen chromatin (F-chromatin/interchroma...

  9. Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma.

    Science.gov (United States)

    Nasr, Samih H; Shanafelt, Tait D; Hanson, Curtis A; Fidler, Mary E; Cornell, Lynn D; Sethi, Sanjeev; Chaffee, Kari G; Morris, Joseph; Leung, Nelson

    2015-06-01

    Granulomatous interstitial nephritis (GIN) is an uncommon pathologic lesion encountered in 0.5% to 5.9% of renal biopsies. Drugs, sarcoidosis, and infections are responsible for most cases of GIN. Malignancy is not an established cause of GIN. Here, we report a series of 5 patients with GIN secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients were mostly elderly white males with an established history of CLL/SLL who presented with severe renal impairment (median peak serum creatinine, 7.3 mg/dL), leukocyturia, and mild proteinuria. One had nephromegaly. In 2 patients, the development and relapse of renal insufficiency closely paralleled the level of lymphocytosis. Kidney biopsy in all patients showed GIN concomitant with CLL/SLL leukemic interstitial infiltration. Granulomas were nonnecrotizing and epithelioid and were associated with giant cells. One biopsy showed granulomatous arteritis. One patient had a granulomatous reaction in lymph nodes and skin. Steroids with/without CLL/SLL-directed chemotherapy led to partial improvement of kidney function in all patients except 1 who had advanced cortical scarring on biopsy. In conclusion, we report an association between CLL/SLL and GIN. Patients typically present with severe renal failure due to both GIN and leukemic interstitial infiltration, which tends to respond to steroids with/without CLL/SLL-directed chemotherapy. The pathogenesis of GIN in this clinical setting is unknown but may represent a local hypersensitivity reaction to the CLL/SLL tumor cells. PMID:25795422

  10. B cells and platelets harbor prion infectivity in the blood of deer infected with chronic wasting disease.

    Science.gov (United States)

    Mathiason, Candace K; Hayes-Klug, Jeanette; Hays, Sheila A; Powers, Jenny; Osborn, David A; Dahmes, Sallie J; Miller, Karl V; Warren, Robert J; Mason, Gary L; Telling, Glenn C; Young, Alan J; Hoover, Edward A

    2010-05-01

    Substantial evidence for prion transmission via blood transfusion exists for many transmissible spongiform encephalopathy (TSE) diseases. Determining which cell phenotype(s) is responsible for trafficking infectivity has important implications for our understanding of the dissemination of prions, as well as their detection and elimination from blood products. We used bioassay studies of native white-tailed deer and transgenic cervidized mice to determine (i) if chronic wasting disease (CWD) blood infectivity is associated with the cellular versus the cell-free/plasma fraction of blood and (ii) in particular if B-cell (MAb 2-104(+)), platelet (CD41/61(+)), or CD14(+) monocyte blood cell phenotypes harbor infectious prions. All four deer transfused with the blood mononuclear cell fraction from CWD(+) donor deer became PrP(CWD) positive by 19 months postinoculation, whereas none of the four deer inoculated with cell-free plasma from the same source developed prion infection. All four of the deer injected with B cells and three of four deer receiving platelets from CWD(+) donor deer became PrP(CWD) positive in as little as 6 months postinoculation, whereas none of the four deer receiving blood CD14(+) monocytes developed evidence of CWD infection (immunohistochemistry and Western blot analysis) after 19 months of observation. Results of the Tg(CerPrP) mouse bioassays mirrored those of the native cervid host. These results indicate that CWD blood infectivity is cell associated and suggest a significant role for B cells and platelets in trafficking CWD infectivity in vivo and support earlier tissue-based studies associating putative follicular B cells with PrP(CWD). Localization of CWD infectivity with leukocyte subpopulations may aid in enhancing the sensitivity of blood-based diagnostic assays for CWD and other TSEs. PMID:20219916

  11. Practical approach to management of chronic lymphocytic leukemia.

    Science.gov (United States)

    Smolej, Lukáš; Šimkovič, Martin

    2016-04-01

    Revolutionary progress has recently changed the landscape of chronic lymphocytic leukemia (CLL). Powerful prognostic factors, especially p53 mutation and/or deletion and IGHV mutation status, have refined individual patient prognosis. Purine analogs and monoclonal antibodies paved the way from palliative treatment to chemoimmunotherapy capable of eradication of minimal residual disease and prolongation of survival. Obinutuzumab (GA-101) and ofatumumab have been recently approved for the treatment of comorbid patients. Bendamustine is available for first-line treatment of patients ineligible for fludarabine, cyclophosphamide, and rituximab (FCR). High-dose glucocorticoids combined with rituximab represent a promising option for refractory CLL; ofatumumab is approved for fludarabine- and alemtuzumab-refractory patients. Allogeneic stem cell transplantation is the only curative option but is feasible in a highly selected group of patients only. The novel small molecule inhibitors ibrutinib and idelalisib have been recently approved for relapsed/refractory CLL. This review provides practical advice for diagnosis, prognostication and treatment of CLL. PMID:27186193

  12. Novel Therapies for Chronic Lymphocytic Leukemia: A Canadian Perspective.

    Science.gov (United States)

    Owen, Carolyn; Assouline, Sarit; Kuruvilla, John; Uchida, Cassandra; Bellingham, Catherine; Sehn, Laurie

    2015-11-01

    Chronic lymphocytic leukemia (CLL) is the most common adult lymphoproliferative disorder in Western countries. The current standard of care for CLL is chemoimmunotherapy, typically with fludarabine, cyclophosphamide, and rituximab (FCR). However, most patients with CLL are elderly with comorbidities and are unable to tolerate FCR. In order to choose the best treatment for each individual patient, physicians must balance efficacy with toxicity. In addition, most currently available treatments are ineffective in CLL patients with loss of TP53. Two groups of novel therapeutic agents-anti-CD20 monoclonal antibodies and small molecule inhibitors-are attempting to address these issues, and 5 of these agents have progressed to phase 3 trials: obinutuzumab, idelalisib, ibrutinib, venetoclax (ABT-199), and duvelisib (IPI-145). We present the current evidence for these novel agents in the treatment of CLL, along with the perspectives of 4 Canadian oncology experts. PMID:26416145

  13. Dynamic changes of B-cell compartments in kidney transplantation: lack of transitional B cells is associated with allograft rejection.

    Science.gov (United States)

    Svachova, Veronika; Sekerkova, Alena; Hruba, Petra; Tycova, Irena; Rodova, Marketa; Cecrdlova, Eva; Slatinska, Janka; Honsova, Eva; Striz, Ilja; Viklicky, Ondrej

    2016-05-01

    B cells play an important role in the immune responses which affect the outcomes of kidney allografts. Dynamic changes of B-cell compartments in clinical kidney transplantation are still poorly understood. B-cell subsets were prospectively monitored using flow cytometry for 1 year in 98 kidney transplant recipients. Data were correlated with immunosuppression and clinical outcomes. An increase in the total population of B lymphocytes was observed during the first week after transplantation. The level of IgM(high) CD38(high) CD24(high) transitional B cells reduced significantly up until the third month, with partial repopulation in the first year. Lower numbers of transitional B cells in the third month were associated with higher risk of graft rejection. IgM(+) IgD(+) CD27(-) naive B cells did not change within follow-up. IgM(+) CD27(+) nonswitched memory B cells and IgM(-) CD27(+) switched memory B cells increased on post-operative day 7. IgM(-) CD38(high) CD27(high) plasmablasts showed similar kinetics during the first post-transplant year, similar to transitional B cells. In conclusion, sensitized kidney transplant recipients as well as those with either acute or chronic rejection within the first post-transplant year exhibited lower levels of transitional B cells. Therefore, these data further support the hypothesis that transitional B cells have a protective role in kidney transplantation. PMID:26839984

  14. An in vitro study of liposomal curcumin: stability, toxicity and biological activity in human lymphocytes and Epstein-Barr virus-transformed human B-cells.

    Science.gov (United States)

    Chen, Changguo; Johnston, Thomas D; Jeon, Hoonbae; Gedaly, Roberto; McHugh, Patrick P; Burke, Thomas G; Ranjan, Dinesh

    2009-01-21

    Curcumin is a multi-functional and pharmacologically safe natural agent. Used as a food additive for centuries, it also has anti-inflammatory, anti-virus and anti-tumor properties. We previously found that it is a potent inhibitor of cyclosporin A (CsA)-resistant T-cell co-stimulation pathway. It inhibits mitogen-stimulated lymphocyte proliferation, NFkappaB activation and IL-2 signaling. In spite of its safety and efficacy, the in vivo bioavailability of curcumin is poor, and this may be a major obstacle to its utility as a therapeutic agent. Liposomes are known to be excellent carriers for drug delivery. In this in vitro study, we report the effects of different liposome formulations on curcumin stability in phosphate buffered saline (PBS), human blood, plasma and culture medium RPMI-1640+10% FBS (pH 7.4, 37 degrees C). Liposomal curcumin had higher stability than free curcumin in PBS. Liposomal and free curcumin had similar stability in human blood, plasma and RPMI-1640+10% FBS. We looked at the toxicity of non-drug-containing liposomes on (3)H-thymidine incorporation by concanavalin A (Con A)-stimulated human lymphocytes, splenocytes and Epstein-Barr virus (EBV)-transformed human B-cell lymphoblastoid cell line (LCL). We found that dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) were toxic to the tested cells. However, addition of cholesterol to the lipids at DMPC:DMPG:cholesterol=7:1:8 (molar ratio) almost completely eliminated the lipid toxicity to these cells. Liposomal curcumin had similar or even stronger inhibitory effects on Con A-stimulated human lymphocyte, splenocyte and LCL proliferation. We conclude that liposomal curcumin may be useful for intravenous administration to improve the bioavailability and efficacy, facilitating in vivo studies that could ultimately lead to clinical application of curcumin. PMID:18840516

  15. Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia.

    Science.gov (United States)

    Kern, D; Regl, G; Hofbauer, S W; Altenhofer, P; Achatz, G; Dlugosz, A; Schnidar, H; Greil, R; Hartmann, T N; Aberger, F

    2015-10-16

    The initiation and maintenance of a malignant phenotype requires complex and synergistic interactions of multiple oncogenic signals. The Hedgehog (HH)/GLI pathway has been implicated in a variety of cancer entities and targeted pathway inhibition is of therapeutic relevance. Signal cross-talk with other cancer pathways including PI3K/AKT modulates HH/GLI signal strength and its oncogenicity. In this study, we addressed the role of HH/GLI and its putative interaction with the PI3K/AKT cascade in the initiation and maintenance of chronic lymphocytic leukemia (CLL). Using transgenic mouse models, we show that B-cell-specific constitutive activation of HH/GLI signaling either at the level of the HH effector and drug target Smoothened or at the level of the GLI transcription factors does not suffice to initiate a CLL-like phenotype characterized by the accumulation of CD5(+) B cells in the lymphatic system and peripheral blood. Furthermore, Hh/Gli activation in Pten-deficient B cells with activated Pi3K/Akt signaling failed to enhance the expansion of leukemic CD5(+) B cells, suggesting that genetic or epigenetic alterations leading to aberrant HH/GLI signaling in B cells do not suffice to elicit a CLL-like phenotype in mice. By contrast, we identify a critical role of GLI and PI3K signaling for the survival of human primary CLL cells. We show that combined targeting of GLI and PI3K/AKT/mTOR signaling can have a synergistic therapeutic effect in cells from a subgroup of CLL patients, thereby providing a basis for the evaluation of future combination therapies targeting HH/GLI and PI3K signaling in this common hematopoietic malignancy. PMID:25639866

  16. Detection of chromosomal changes in chronic lymphocytic leukemia using classical cytogenetic methods and FISH: application of rich mitogen mixtures for lymphocyte cultures.

    Science.gov (United States)

    Koczkodaj, Dorota; Popek, Sylwia; Zmorzyński, Szymon; Wąsik-Szczepanek, Ewa; Filip, Agata A

    2016-04-01

    One of the research methods of prognostic value in chronic lymphocytic leukemia (CLL) is cytogenetic analysis. This method requires the presence of appropriate B-cell mitogens in cultures in order to obtain a high mitotic index. The aim of our research was to determine the most effective methods of in vitro B-cell stimulation to maximize the number of metaphases from peripheral blood cells of patients with CLL for classical cytogenetic examination, and then to correlate the results with those obtained using fluorescence in situ hybridization (FISH). The study group involved 50 consecutive patients with CLL. Cell cultures were maintained with the basic composition of culture medium and addition of respective stimulators. We used the following stimulators: Pokeweed Mitogen (PWM), 12-O-tetradecanoylphorbol 13-acetate (TPA), ionophore, lipopolysaccharide (LPS), and CpG-oligonucleotide DSP30. We received the highest mitotic index when using the mixture of PWM+TPA+I+DSP30. With classical cytogenetic tests using banding techniques, numerical and structural aberrations of chromosomes were detected in 46 patients, and no change was found in only four patients. Test results clearly confirmed the legitimacy of using cell cultures enriched with the mixture of cell stimulators and combining classical cytogenetic techniques with the FISH technique in later patient diagnosing. PMID:26956786

  17. Biclonal Gammopathy in Chronic Lymphocytic Leukemia: Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Nafila Al-Riyami

    2015-05-01

    Full Text Available Monoclonal gammopathies are frequently seen in B-cell malignancies. Monoclonal proteins are seen in a significant proportion of patients with chronic lymphocytic leukemia (CLL, which is a clonal disorder of mature B cells. The use of more sensitive laboratory methods has enabled the detection of monoclonal proteins or light chains in the serum and/or urine in the majority of these patients. The presence of some of these monoclonal proteins may explain the different autoimmune phenomena that are associated with this disease. Some reports indicate that the finding of monoclonal proteins has a negative impact on patients’ survival. The presence of two different monoclonal proteins (i.e. biclonal gammopathy is on the other hand rare. Most of the reported cases in the literature are of patients with plasma cell disorders. In this report, we describe a rare occurrence of biclonal gammopathy in a patient with CLL. Serum protein electrophoresis and immunofixation, which were negative at the time of initial diagnosis, showed biclonal immunoglobin A (IgA kappa and IgA lambda during the course of the disease. The patient’s disease showed steady progression, despite multiple treatments. Although this could just be the result of using more sensitive laboratory techniques, biclonal gammopathy in this patient likely reflects the evolution of another clone, which would explain the encountered resistance to therapy. Because of paucity of reports, the impact of biclonal gammopathies in such patients is not known and an effort to collectively report the presentation and outcome of these patients is needed to further understand the pathophysiology and clinical significance of such a finding.

  18. CPI-613, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

    Science.gov (United States)

    2016-07-26

    B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  19. B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues.

    Science.gov (United States)

    Frank, D A; Mahajan, S; Ritz, J

    1997-12-15

    To explore the pathogenesis of chronic lymphocytic leukemia (CLL), we examined whether phosphorylation of one or more signal transducer and activator of transcription (STAT) factors was abnormal in cells from CLL patients. No constitutive tyrosine phosphorylation was detected on any STAT in CLL cells. To assess the phosphorylation of serine residues of STAT1 and STAT3 in CLL cells, we raised antibodies that specifically recognize the form of STAT1 phosphorylated on ser-727 and the form of STAT3 phosphorylated on ser-727. We found that in 100% of patients with CLL (n = 32), STAT1 and STAT3 were constitutively phosphorylated on serine. This was in contrast to normal peripheral blood B lymphocytes or CD5+) B cells isolated from tonsils, in which this phosphorylation was absent. Serine phosphorylation of STAT1 and STAT3 was seen occasionally in other leukemias, but it was a universal finding only in CLL. The serine phosphorylation of these STATs was a continuous process, as incubation of CLL cells with the kinase inhibitor H7 led to the dephosphorylation of these serine residues. The STAT serine kinase in CLL cells has not been identified, and appears to be neither mitogen-activated protein kinase nor pp70(s6k). In summary, the constitutive serine phosphorylation of STAT1 and STAT3 is present in all CLL samples tested to date, although the physiologic significance of this modification remains to be determined. PMID:9399961

  20. Down modulation of MHC surface molecules on B cells by suppressive immune complexes obtained from chronic intestinal schistosomiasis patients.

    Science.gov (United States)

    Rezende, S A; Gollob, K J; Correa-Oliveira, R; Goes, A M

    1998-06-01

    Granulomatous inflammation around parasite eggs is the prominent lesion in human schistosomiasis. Studies have suggested the involvement of a series of suppressive mechanisms in the control of this reaction, such as macrophages, cytokines, idiotypic interactions and immune complexes (IC). The studies examine the role of IC obtained from chronic intestinal schistosomiasis patients (ISP) in the reactivity of peripheral blood mononuclear cells (PBMC). The results have shown that these immune complexes are able to suppress cell reactivity by inducing an increase in the production of soluble mediators such as prostaglandins and IL-10. To gain a better understanding of how this suppression occurs the present study examines the phenotypic pattern of PBMC after immune complex treatment in cell proliferation assays. These data show that cultures including immune complex present a higher percentage of B lymphocytes in which a lower expression of a MHC-class II gene product, HLA-DR was detected. This altered expression of the HLA-DR molecule on B lymphocytes after IC treatment suggests a novel mechanism for the suppression observed, that is, IC might decrease the antigen-presenting function of B lymphocytes. PMID:9698100

  1. Development of fludarabine formulations in the treatment of chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Ann Janssens

    2009-10-01

    Full Text Available Ann Janssens, Marc Boogaerts, Gregor VerhoefDepartment of Hematology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, BelgiumAbstract: Fludarabine is an antineoplastic agent used in the treatment of hematological malignancies, particularly chronic lymphocytic leukemia (CLL and indolent B-cell lymphoma. Because of its immunosuppressive effects, fludarabine has been added to reduced intensity conditioning regimens. The oral formulation of fludarabine has become widely available. Pharmacokinetic studies have shown that an oral dose of 40 mg/m2/d would provide systemic drug exposure similar to the standard intravenous (IV dose of 25 mg/m2/d. The oral dose can be taken once daily without any dietary restrictions. Dose adjustments are mandatory in patients with renal impairment to avoid increased toxicity. Several noncomparative trials in previously untreated and treated patients with CLL have shown that treatment with the oral formulation demonstrates similar efficacy compared to historical control groups treated with the IV formulation. The tolerability profile of oral fludarabine seems similar to that of the IV formulation. Myelosuppression and infectious complications are the most frequently reported adverse events. Gastrointestinal toxicity is more frequent with the oral formulation, but is usually of mild or moderate severity. Although oral fludarabine makes treatment more convenient, health care workers must be aware of the compliance behavior of each patient. Keywords: CLL, treatment, oral fludarabine, intravenous fludarabine

  2. GENOMIC PROFILING BY MULTIPLEX LIGATION - DEPENDENT PROBE AMPLIFICATION IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS

    Directory of Open Access Journals (Sweden)

    Georgiana-Emilia Grigore

    2013-11-01

    Full Text Available The clinical management of severe pathological conditions, such as B-cell chronic lymphocytic leukemia (B-CLL, is subject to continuous optimization and re-evaluation. Patients may fully benefit from rapid, standardized laboratory tools designed to facilitate their early stratification according to disease risk, stage and prognosis. Such technologies may also aid the clinician in selecting the therapeutic option with the greatest chances of success. The presence of specific genetic abnormalities are frequently associated with the clinical outcome of oncologic patients in general, and B-CLL patients in particular. In the current study, a group of 58 B-CLL patients were evaluated for the detection of gene copy number alterations (deletions or duplication/ amplifications within 45 distinct genetic targets, by means of a novel molecular methodology, Multiplex Ligation - Dependent Probe Amplification (MLPA. Simple or complex genetic defects were identified in 67% of cases, and the most common aberrations observed were: deletion of the short arm of chromosome 13 in 33% of cases, deletion of the long arm of chromosome 11 in 16% of cases, trisomy 12 in 16% of cases, and deletion of the short arm of chromosome 17 in 7% of cases. The main conclusion of the study presented here points towards MLPA as a potential key step of clinical management protocols in B-CLL, providing that it will be fully standardised for routine diagnosis.

  3. Antibody therapy alone and in combination with targeted drugs in chronic lymphocytic leukemia.

    Science.gov (United States)

    Robak, Tadeusz; Blonski, Jerzy Z; Robak, Pawel

    2016-04-01

    The development of non-chemotherapeutic agents, including monoclonal antibodies (mAbs) and other targeted drugs, makes chemotherapy-free treatment an attractive option for chronic lymphocytic leukemia (CLL). The classical mAb, rituximab, has been authorized for use in both first-line and second-line therapy for CLL. New mAbs directed against CD20, ofatumumab, and obinutuzumab (GA-101) have also been approved for the treatment of this disease. Recently, several new mAbs with potential benefits over the approved anti-CD20 antibodies have been developed for use in CLL. Anti-CD37, anti-CD19, and anti-CD40 mAbs are in early clinical trials and show promise in treating CLL. In addition, the combination of mAbs with B-cell receptor signaling pathway inhibitors and immunomodulatory drugs makes the chemotherapy-free option a reality today. Combinations of antibodies with targeted drugs like ibrutinib, idelalisib, or lenalidomide are expected to replace chemotherapy-based combinations for treating CLL in the near future. However, phase III trials should confirm the benefit of these new treatment strategies and establish their exact place in the therapeutic armamentarium for CLL. PMID:27040707

  4. New developments in the management of chronic lymphocytic leukemia: role of ofatumumab.

    Science.gov (United States)

    Laurenti, Luca; Innocenti, Idanna; Autore, Francesco; Sica, Simona; Efremov, Dimitar G

    2016-01-01

    Ofatumumab is one of the three anti-CD20 monoclonal antibodies currently available for the treatment of chronic lymphocytic leukemia (CLL). The US Food and Drug Administration (FDA) approved the use of ofatumumab in patients with CLL refractory to fludarabine and alemtuzumab in 2009, and the European Medicines Agency (EMA) granted approval for the same indication in 2010. Subsequent positive results of ofatumumab in combination with chlorambucil in treatment-naïve patients led the FDA in April 2014 to approve the use of this combination for first-line treatment of patients with CLL for whom fludarabine-based therapy is considered inappropriate. Later that year, the EMA approved the use of ofatumumab in combination with chlorambucil or bendamustine for the same indication. Ofatumumab has also shown potential as maintenance therapy for patients with relapsed CLL; an application to broaden the label for ofatumumab as maintenance therapy was submitted earlier this year to the EMA and FDA. Finally, ofatumumab has shown promising activity in combination with ibrutinib or idelalisib in relapsed/refractory CLL patients; combinations of ofatumumab with B-cell-receptor pathway inhibitors could represent another potential use of this antibody in the near future. PMID:26855591

  5. The PI3K pathway: clinical inhibition in chronic lymphocytic leukemia.

    Science.gov (United States)

    Brown, Jennifer R

    2016-04-01

    Constitutive or mutational activation of the phosphatidylinositol 3 kinase, or PI3K, has been implicated in many cancers, including chronic lymphocytic leukemia (CLL). The δ isoform of the p110 catalytic subunit of PI3K has its primary physiologic function in B cells and appears to be the predominant mediator of most PI3K signals in CLL cells. Idelalisib is a first-in-class inhibitor of the PI3K delta isoform that shows near complete inhibition of AKT phosphorylation in CLL cells in vitro and in vivo. Idelalisib shows the classic pattern of response to BCR inhibition in CLL, with rapid nodal response and transient increase in lymphocytosis. The phase I study established the recommended dose as 150 mg twice per day. Subsequent registration trials have focused predominantly on antibody combinations, leading to the US Food and Drug Administration (FDA) approval of idelalisib with rituximab for relapsed CLL patients for whom rituximab is appropriate therapy in summer 2014. The median progression-free survival (PFS) of idelalisib-rituximab in this heavily pretreated CLL population with multiple comorbidities and frequent 17p deletion was an impressive 19.4 months. The success of idelalisib has paved the way for the development of other PI3K inhibitors in CLL, including duvelisib and TGR-1202, which are in or moving toward registration trials. PMID:27040704

  6. New developments in the management of chronic lymphocytic leukemia: role of ofatumumab

    Directory of Open Access Journals (Sweden)

    Laurenti L

    2016-01-01

    Full Text Available Luca Laurenti,1 Idanna Innocenti,1 Francesco Autore,1 Simona Sica,1 Dimitar G Efremov2 1Department of Hematology, Catholic University of the Sacred Heart, Rome, 2Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Monterotondo, Italy Abstract: Ofatumumab is one of the three anti-CD20 monoclonal antibodies currently available for the treatment of chronic lymphocytic leukemia (CLL. The US Food and Drug Administration (FDA approved the use of ofatumumab in patients with CLL refractory to fludarabine and alemtuzumab in 2009, and the European Medicines Agency (EMA granted approval for the same indication in 2010. Subsequent positive results of ofatumumab in combination with chlorambucil in treatment-naïve patients led the FDA in April 2014 to approve the use of this combination for first-line treatment of patients with CLL for whom fludarabine-based therapy is considered inappropriate. Later that year, the EMA approved the use of ofatumumab in combination with chlorambucil or bendamustine for the same indication. Ofatumumab has also shown potential as maintenance therapy for patients with relapsed CLL; an application to broaden the label for ofatumumab as maintenance therapy was submitted earlier this year to the EMA and FDA. Finally, ofatumumab has shown promising activity in combination with ibrutinib or idelalisib in relapsed/refractory CLL patients; combinations of ofatumumab with B-cell-receptor pathway inhibitors could represent another potential use of this antibody in the near future. Keywords: CLL, ofatumumab, monoclonal antibodies, immunotherapy

  7. Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells.

    Science.gov (United States)

    Daneshmanesh, A H; Hojjat-Farsangi, M; Khan, A S; Jeddi-Tehrani, M; Akhondi, M M; Bayat, A A; Ghods, R; Mahmoudi, A-R; Hadavi, R; Österborg, A; Shokri, F; Rabbani, H; Mellstedt, H

    2012-06-01

    ROR1 is a receptor tyrosine kinase (RTK) recently identified to be overexpressed at the gene and protein levels in chronic lymphocytic leukemia (CLL). Monoclonal antibodies (MAbs) against RTKs have been successfully applied for therapy of solid tumors. We generated five MAbs against the Ig (n = 1), cysteine-rich (CRD) (n = 2) and kringle (KNG) (n = 2) domains, respectively, of the extracellular part of ROR1. All CLL patients (n = 20) expressed ROR1 on the surface of the leukemic cells. A significantly higher frequency of ROR1 expression was found in patients with progressive versus non-progressive disease, and in those with unmutated versus mutated IgVH genes. All five MAbs alone induced apoptosis in the absence of complement or added effector cells (Annexin-V and MTT, as well as cleavage of poly-(ADP ribose)-polymerase, caspase-8 and caspase-9) of CLL cells but not of normal B cells. Most effective were MAbs against CRD and KNG, significantly superior to rituximab (P < 0.005). Cross-linking of anti-ROR1 MAbs using the F(ab')(2) fragments of anti-Fc antibodies significantly augmented apoptosis. Two of the MAbs induced complement-dependent cytotoxicity (CDC) similar to that of rituximab and one anti-ROR1 MAb (KNG) (IgG1) showed killing activity by antibody-dependent cellular cytotoxicity. The identified ROR1 epitopes may provide a basis for generating human ROR1 MAbs for therapy. PMID:22289919

  8. Attenuation of the cytotoxic T lymphocyte response to lymphocytic choriomeningitis virus in mice subjected to chronic social stress

    OpenAIRE

    Sommershof, Annette; Basler, Michael; Riether, Carsten; Engler, Harald; Gröttrup, Marcus

    2011-01-01

    Chronic stress is suspected to increase the susceptibility to infections but experimental evidence from physiological stress models is scarce. We examined the effects of chronic social stress on virus-specific CTL responses in mice after infection with lymphocytic choriomeningitis virus (LCMV). Mice subjected to social stress on six consecutive days prior to infection showed a significant reduction of IFN-γ producing TCD8+ splenocytes and markedly lowered plasma concentrations of IFN-γ. In co...

  9. Chronic lymphocytic leukemia cells diversify and differentiate in vivo via a nonclassical Th1-dependent, Bcl-6–deficient process

    Science.gov (United States)

    Patten, Piers E.M.; Ferrer, Gerardo; Chen, Shih-Shih; Simone, Rita; Marsilio, Sonia; Yan, Xiao-Jie; Gitto, Zachary; Yuan, Chaohui; Kolitz, Jonathan E.; Barrientos, Jacqueline; Allen, Steven L.; Rai, Kanti R.; MacCarthy, Thomas; Chu, Charles C.; Chiorazzi, Nicholas

    2016-01-01

    Xenografting primary tumor cells allows modeling of the heterogeneous natures of malignant diseases and the influences of the tissue microenvironment. Here, we demonstrate that xenografting primary chronic lymphocytic leukemia (CLL) B lymphocytes with activated autologous T cells into alymphoid mice results in considerable CLL B cell division and sizable T cell expansion. Nevertheless, most/all CD5+CD19+ cells are eventually lost, due in part to differentiation into antibody-secreting plasmablasts/plasma cells. CLL B cell differentiation is associated with isotype class switching and development of new IGHV-D-J mutations and occurs via an activation-induced deaminase-dependent pathway that upregulates IRF4 and Blimp-1 without appreciable levels of the expected Bcl-6. These processes were induced in IGHV-unmutated and IGHV-mutated clones by Th1-polarized T-bet+ T cells, not classical T follicular helper (Tfh) cells. Thus, the block in B cell maturation, defects in T cell action, and absence of antigen-receptor diversification, which are often cardinal characteristics of CLL, are not inherent but imposed by external signals and the microenvironment. Although these activities are not dominant features in human CLL, each occurs in tissue proliferation centers where the mechanisms responsible for clonal evolution operate. Thus, in this setting, CLL B cell diversification and differentiation develop by a nonclassical germinal center–like reaction that might reflect the cell of origin of this leukemia.

  10. A combination of an anti-SLAMF6 antibody and ibrutinib efficiently abrogates expansion of chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Yigit, Burcu; Halibozek, Peter J; Chen, Shih-Shih; O'Keeffe, Michael S; Arnason, Jon; Avigan, David; Gattei, Valter; Bhan, Atul; Cen, Osman; Longnecker, Richard; Chiorazzi, Nicholas; Wang, Ninghai; Engel, Pablo; Terhorst, Cox

    2016-05-01

    The signaling lymphocyte activation molecule family [SLAMF] of cell surface receptors partakes in both the development of several immunocyte lineages and innate and adaptive immune responses in humans and mice. For instance, the homophilic molecule SLAMF6 (CD352) is in part involved in natural killer T cell development, but also modulates T follicular helper cell and germinal B cell interactions. Here we report that upon transplantation of a well-defined aggressive murine B220+CD5+ Chronic Lymphocytic Leukemia (CLL) cell clone, TCL1-192, into SCID mice one injection of a monoclonal antibody directed against SLAMF6 (αSlamf6) abrogates tumor progression in the spleen, bone marrow and blood. Similarly, progression of a murine B cell lymphoma, LMP2A/λMyc, was also eliminated by αSlamf6. But, surprisingly, αSLAMF6 neither eliminated TCL1-192 nor LMP2A/λMyc cells, which resided in the peritoneal cavity or omentum. This appeared to be dependent upon the tumor environment, which affected the frequency of sub-populations of the TCL1-192 clone or the inability of peritoneal macrophages to induce Antibody Dependent Cellular Cytotoxicity (ADCC). However, co-administering αSlamf6 with the Bruton tyrosine kinase (Btk) inhibitor, ibrutinib, synergized to efficiently eliminate the tumor cells in the spleen, bone marrow, liver and the peritoneal cavity. Because an anti-human SLAMF6 mAb efficiently killed human CLL cells in vitro and in vivo, we propose that a combination of αSlamf6 with ibrutinib should be considered as a novel therapeutic approach for CLL and other B cell tumors. PMID:27029059

  11. Occurrence of chronic lymphocytic leukemia in patients with chronic myelogenous leukemia

    Directory of Open Access Journals (Sweden)

    Pritish K Bhattacharyya

    2013-01-01

    Full Text Available Chronic lymphocytic leukemia (CLL is the most common leukemia of adults in the western world and constitutes about 33% of all leukemia′s. The incidence of CLL increases with age and are more common in older population. Chronic myeloid leukemia (CML on the contrary occurs in both young adults and elderly and is a chronic myeloproliferative disease that originates from abnormal pluripotent stem cells and results in involvement of multiple hematopoietic lineages, but predominantly myeloid and less commonly lymphoid. Association between CLL and myeloid malignancies (CML, acute myeloid leukemia and MDS, myelodysplastic syndrome is rare. In literature documenting CLL and CML in same patients, occur either simultaneously or CML is preceded by CLL.

  12. Metabolic control and B cell function in patients with insulin-dependent diabetes mellitus secondary to chronic pancreatitis

    DEFF Research Database (Denmark)

    Larsen, S; Hilsted, J; Tronier, B;

    1987-01-01

    Among 88 unselected patients with chronic pancreatitis 35% (95% confidence limits 25 to 46) had insulin-dependent diabetes, 31% (21% to 41%) had non-insulin-dependent diabetes or impaired glucose tolerance (by intravenous glucose tolerance test), and 34% (24% to 45%) had normal glucose tolerance. B...... less than .01 to .05) in the 31 patients with pancreatogenic diabetes than than in 35 otherwise comparable patients with type I (insulin-dependent) diabetes, yet daily insulin dose was similar in the two groups. Glucagon stimulated C-peptide was inversely correlated to glycosylated hemoglobin in...... insulin-dependent patients with pancreatogenic diabetes and in type I diabetes. Since body mass indices were identical in the two groups, better glucoregulation was not due to reduced food intake or malabsorption in pancreatogenic diabetes. Rather residual B cell function and/or different secretion of...

  13. L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo.

    Science.gov (United States)

    Lafouresse, Fanny; Bellard, Elisabeth; Laurent, Camille; Moussion, Christine; Fournié, Jean-Jacques; Ysebaert, Loïc; Girard, Jean-Philippe

    2015-09-10

    B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Lymph nodes (LNs) are sites of malignant proliferation and LN enlargement is associated with poor prognosis in the clinics. The LN microenvironment is believed to favor disease progression by promoting CLL cell growth and drug resistance. A better understanding of the mechanisms regulating trafficking of CLL cells to LNs is thus urgently needed. Here, we studied the first step of CLL cell migration to LNs, their interaction with high endothelial venules (HEVs), specialized blood vessels for lymphocyte extravasation in lymphoid organs. We observed that the density of HEV blood vessels was increased in CLL LNs and that CD20(+) CLL cells accumulated within HEV pockets, suggesting intense trafficking. We used intravital imaging to visualize the behavior of human CLL cells within the mouse LN microcirculation, and discovered that CLL cells bind to HEVs in vivo via a multistep adhesion cascade, which involves rolling, sticking, and crawling of the leukemic cells on the endothelium. Functional analyses revealed that the lymphocyte homing receptor L-selectin (CD62L) is the key factor controlling the binding of CLL cells to HEV walls in vivo. Interestingly, L-selectin expression was decreased on CLL cells from patients treated with idelalisib, a phosphoinositide-3-kinase δ inhibitor recently approved for CLL therapy. Interference with L-selectin-mediated trafficking in HEVs could represent a novel strategy to block dissemination of CLL cells to LNs and increase the efficacy of conventional therapy. PMID:26162407

  14. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia

    OpenAIRE

    Brown, Jennifer R; Barrientos, Jacqueline C.; Barr, Paul M.; Flinn, Ian W.; Burger, Jan A.; Tran, Anh; Clow, Fong; James, Danelle F; Graef, Thorsten; Friedberg, Jonathan W.; Rai, Kanti; O’Brien, Susan

    2015-01-01

    Ibrutinib was well tolerated when administered with BR CIT in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma.Ibrutinib added to CIT was associated with a high degree of clinical activity that compares favorably to historical reports of CIT alone.

  15. Lenalidomide in the Treatment of Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Agostino Cortelezzi

    2012-01-01

    Full Text Available The application of nucleoside analogue-based chemotherapy and immunotherapy with rituximab or alemtuzumab has increased both response rate and survival in patients with Chronic Lymphocytic Leukemia (CLL. However, because none of these therapies is curative, sequential therapeutic regimens are required. The majority of patients with relapsed or refractory CLL carry poor prognostic factors and show shorter overall survival and resistance to standard treatment. Numerous drugs have recently been approved for CLL therapy and many novel agents are under clinical investigation. The role of the tumor microenvironment and of immune dysfunction in CLL have allowed to enlarge the therapeutic armamentarium for CLL patients. This article will provide a comprehensive summary regarding mechanism of action, efficacy and safety of lenalidomide in CLL patients. Relevant clinical trials using lenalidomide alone or in combinations are discussed. Lenalidomide shows good activity also in relapsed/refractory or treatment-naive CLL patients. Definitive data from ongoing studies are needed to validate overall and progression-free survival. The toxicity profile might limit lenalidomide use because it can result in serious side effects, but largely controlled by gradual dose escalation. Further understanding of the exact mechanism of action in CLL will allow more efficacious use of lenalidomide alone or in combination regimens.

  16. Flavopiridol in chronic lymphocytic leukemia: a concise review.

    Science.gov (United States)

    Christian, Beth A; Grever, Michael R; Byrd, John C; Lin, Thomas S

    2009-01-01

    Patients with chronic lymphocytic leukemia (CLL) with high-risk cytogenetic features such as del(17p13) have limited treatment options and decreased overall survival. Dysfunction of p53 leads to resistance to fludarabine-based therapies. Cyclin-dependent kinase inhibitors (CDKi) are a novel class of agents that induce apoptosis in CLL cells independent of p53 mutational status. The synthetic flavone flavopiridol demonstrated promising in vitro activity in CLL. In initial phase I studies using a continuous infusion dosing schedule in a variety of malignancies, no clinical activity was observed. Detailed pharmacokinetic modeling led to the development of a novel dosing schedule designed to achieve target drug concentrations in vivo. In phase I testing, this dosing schedule resulted in acute tumor lysis syndrome (TLS) as the dose-limiting toxicity. With the implementation of a standardized protocol to prevent severe TLS, flavopiridol was administered safely, and responses were observed in heavily pretreated, fludarabine-refractory patients, cytogenetically high-risk patients, and patients with bulky lymphadenopathy. In a pharmacokinetic analysis, flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome. Phase II studies are under way with encouraging preliminary results. Flavopiridol is currently under active investigation in combination with other agents and as a means to eradicate minimal residual disease in patients following cytoreductive chemotherapy. Several other investigational CDKi in preclinical and early clinical development are briefly discussed in this review. PMID:19778838

  17. The clinical implications of gene mutations in chronic lymphocytic leukaemia.

    Science.gov (United States)

    Rossi, Davide; Gaidano, Gianluca

    2016-04-12

    Chronic lymphocytic leukaemia (CLL) is a molecularly heterogeneous disease as revealed by recent genomic studies. Among genetic lesions that are recurrent in CLL, few clinically validated prognostic markers, such as TP53 mutations and 17p deletion, are available for the use in clinical practice to guide treatment decisions. Recently, several novel molecular markers have been identified in CLL. Though these mutations have not yet gained the qualification of predictive factors for treatment tailoring, they have shown to be promising to refine the prognostic stratification of patients. The introduction of targeted drugs is changing the genetics of CLL, and has disclosed the acquisition of previously unexpected drug resistant mutations in signalling pathway genes. Ultra-deep next generation sequencing has allowed to reach deep levels of resolution of the genetic portrait of CLL providing a precise definition of its subclonal genetic architecture. This approach has shown that small subclones harbouring drug resistant mutations anticipate the development of a chemorefractory phenotype. Here we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterise the clinical implications of old and new molecular lesions in the setting of both conventional chemo-immunotherapy and targeted drugs. PMID:27031852

  18. PARP1-Driven Apoptosis in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Panagiotis T. Diamantopoulos

    2014-01-01

    Full Text Available Chronic lymphocytic leukemia (CLL is considered a malignancy resulting from defects in apoptosis. For this reason, targeting apoptotic pathways in CLL may be valuable for its management. Poly [ADP-ribose] polymerase 1 (PARP1 is the main member of a family of nuclear enzymes that act as DNA damage sensors. Through binding on DNA damaged structures, PARP1 recruits repair enzymes and serves as a survival factor, but if the damage is severe enough, its action may lead the cell to apoptosis through caspase activation, or necrosis. We measured the PARP1 mRNA and protein pretreatment levels in 26 patients with CLL and the corresponding posttreatment levels in 15 patients after 3 cycles of immunochemotherapy, as well as in 15 healthy blood donors. No difference was found between the pre- and posttreatment levels of PARP1, but we found a statistically significant relative increase of the 89 kDa fragment of PARP1 that is cleaved by caspases in the posttreatment samples, indicating PARP1-related apoptosis in CLL patients after treatment. Our findings constitute an important step in the field, especially in the era of PARP1 inhibitors, and may serve as a base for future clinical trials with these agents in CLL.

  19. A role for oleoylethanolamide in chronic lymphocytic leukemia.

    Science.gov (United States)

    Masoodi, M; Lee, E; Eiden, M; Bahlo, A; Shi, Y; Ceddia, R B; Baccei, C; Prasit, P; Spaner, D E

    2014-07-01

    Oleoylethanolamide (OEA) is a bioactive lipid that stimulates nuclear and G protein-coupled receptors and regulates appetite and fat metabolism. It has not previously been shown to have a role in cancer. However, a mass spectrometry-based lipidomics platform revealed the presence of high amounts of OEA in the plasma of chronic lymphocytic leukemia (CLL) patients compared with normal donors. CLL cells produced OEA and the magnitude of plasma OEA levels was related directly to the circulating leukemic cell number. OEA from CLL cells was increased by URB-597, an inhibitor of fatty acid amide hydrolase (FAAH), and decreased by inflammatory mediators that downregulate expression of N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD). These enzymes degrade and synthesize OEA, respectively. Nonphysiologic doses of OEA prevented spontaneous apoptosis of CLL cells in a receptor-independent manner that was mimicked by its free fatty acid (FFA) derivative oleate. However, OEA-containing supernatants from CLL cells induced lipolysis in adipocytes, lipid products from adipocytes protected CLL cells from cytotoxic chemotherapy, and increased levels of FFAs were found in CLL plasma that correlated with OEA. We suggest OEA is a lipolytic factor produced by CLL cells to fuel their growth with a potential role in drug resistance and cancer cachexia. PMID:24413323

  20. Gastrointestinal bleeding due to large bowel infiltration by chronic lymphocytic leukaemia.

    OpenAIRE

    Tucker, J.; Cachia, P. G.

    1986-01-01

    A 66 year old woman with a 9 year history of chronic lymphocytic leukaemia developed intermittent rectal bleeding for 9 months; sigmoidoscopic biopsy proved that this was due to large bowel infiltration by leukaemia. This is a very rare occurrence.

  1. CD19-Chimeric Antigen Receptor T Cells for Treatment of Chronic Lymphocytic Leukaemia and Acute Lymphoblastic Leukaemia

    DEFF Research Database (Denmark)

    Lorentzen, C L; thor Straten, Per

    2015-01-01

    Adoptive cell therapy (ACT) for cancer represents a promising new treatment modality. ACT based on the administration of cytotoxic T cells genetically engineered to express a chimeric antigen receptor (CAR) recognizing CD19 expressed by B cell malignancies has been shown to induce complete lasting...... responses in patients with chronic lymphocytic leukaemia (CLL) and acute lymphoblastic leukaemia (ALL). So far, eleven clinical trials including 99 CLL and ALL patients treated with CAR T cells targeting CD19 have been published, and the results from these trials are promising with impressive clinical...... responses in heavily pretreated patients. Thus, CAR T cell therapy has induced complete responses in both CLL and ALL, and surprisingly, current results indicate that patients with ALL are more prone to respond than are CLL patients. Importantly, the majority of CAR cell studies have observed severe therapy...

  2. Low-Dose Total Body Irradiation and Donor Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Patients With Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Multiple Myeloma

    Science.gov (United States)

    2015-10-30

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Testicular Lymphoma; Waldenström Macroglobulinemia

  3. The HELIOS trial protocol: a phase III study of ibrutinib in combination with bendamustine and rituximab in relapsed/refractory chronic lymphocytic leukemia.

    Science.gov (United States)

    Hallek, Michael; Kay, Neil E; Osterborg, Anders; Chanan-Khan, Asher A; Mahler, Michelle; Salman, Mariya; Wan, Ying; Sun, Steven; Zhuang, Sen Hong; Howes, Angela

    2015-01-01

    Ibrutinib is an orally administered, covalent inhibitor of Bruton's tyrosine kinase with activity in B-cell malignancies based on Phase I/II studies. We describe the design and rationale for the Phase III HELIOS trial (trial registration: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745) investigating whether ibrutinib added to bendamustine and rituximab (BR) provides benefits over BR alone in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Eligible patients must have relapsed/refractory disease measurable on CT scan and meet ≥ 1 International Workshop on Chronic Lymphocytic Leukemia criterion for requiring treatment; patients with del(17p) are excluded. All patients receive BR (maximum six cycles) as background therapy and are randomized 1:1 to placebo or ibrutinib 420 mg/day. Treatment with ibrutinib or placebo will start concomitantly with BR and continue until disease progression or unacceptable toxicity. The primary end point is progression-free survival. Secondary end points include safety, objective response rate, overall survival, rate of minimal residual disease-negative remissions, and patient-reported outcomes. Tumor response will be assessed using the International Workshop on Chronic Lymphocytic Leukemia guidelines. PMID:24901734

  4. Beetroot-Carrot Juice Intake either Alone or in Combination with Antileukemic Drug 'Chlorambucil' As A Potential Treatment for Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Shakib, Marie-Christine R; Gabrial, Shreef G N; Gabrial, Gamal N

    2015-06-15

    Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes. Patients with leukemia often seek unconventional treatments not prescribed by hematologist in order to improve their cancer treatment outcome or to manage symptoms. In the present report, a 76-year-old patient was diagnosed with B-cell chronic lymphocytic leukemia (B-CLL). Beetroot-carrot juice is used as a complementary and or/alternative therapy used in conjunction with conventional leukemic treatment (chlorambucil) that has been a standard first-line chemotherapeutic agent for patients with CLL and known to have serious and undesirable side-effects. After one month and 15 days of administration of beetroot-carrot juice therapy, the patient had improved appetite, a sense of general well-being and increased vigor daily activities. Furthermore, beetroot-carrot juice was used as an adjuvant to chlorambucil resulted in a substantial reduction in leukocytes and lymphocytes count in peripheral blood and improvement in the relevant biochemical parameters. Beetroot-carrot juice can be used as an effective treatment for CLL alone or in combination with chlorambucil when taken orally with regular diet on daily basis. PMID:27275246

  5. Beetroot-Carrot Juice Intake either Alone or in Combination with Antileukemic Drug ‘Chlorambucil’ As A Potential Treatment for Chronic Lymphocytic Leukemia

    Science.gov (United States)

    Shakib, Marie-Christine R.; Gabrial, Shreef G. N.; Gabrial, Gamal N.

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes. Patients with leukemia often seek unconventional treatments not prescribed by hematologist in order to improve their cancer treatment outcome or to manage symptoms. In the present report, a 76-year-old patient was diagnosed with B-cell chronic lymphocytic leukemia (B-CLL). Beetroot-carrot juice is used as a complementary and or/alternative therapy used in conjunction with conventional leukemic treatment (chlorambucil) that has been a standard first-line chemotherapeutic agent for patients with CLL and known to have serious and undesirable side-effects. After one month and 15 days of administration of beetroot-carrot juice therapy, the patient had improved appetite, a sense of general well-being and increased vigor daily activities. Furthermore, beetroot-carrot juice was used as an adjuvant to chlorambucil resulted in a substantial reduction in leukocytes and lymphocytes count in peripheral blood and improvement in the relevant biochemical parameters. Beetroot-carrot juice can be used as an effective treatment for CLL alone or in combination with chlorambucil when taken orally with regular diet on daily basis. PMID:27275246

  6. Beetroot-Carrot Juice Intake either Alone or in Combination with Antileukemic Drug 'Chlorambucil' As A Potential Treatment for Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Marie-Christine R. Shakib

    2015-06-01

    Full Text Available Chronic lymphocytic leukemia (CLL is one of the chronic lymphoproliferative disorders (lymphoid neoplasms. It is characterized by a progressive accumulation of functionally incompetent lymphocytes. Patients with leukemia often seek unconventional treatments not prescribed by hematologist in order to improve their cancer treatment outcome or to manage symptoms. In the present report, a 76-year-old patient was diagnosed with B-cell chronic lymphocytic leukemia (B-CLL. Beetroot-carrot juice is used as a complementary and or/ alternative therapy used in conjunction with conventional leukemic treatment (chlorambucil that has been a standard first-line chemotherapeutic agent for patients with CLL and known to have serious and undesirable side-effects. After one month and 15 days of administration of beetroot-carrot juice therapy, the patient had improved appetite, a sense of general well-being and increased vigor daily activities. Furthermore, beetroot-carrot juice was used as an adjuvant to chlorambucil resulted in a substantial reduction in leukocytes and lymphocytes count in peripheral blood and improvement in the relevant biochemical parameters.  Beetroot-carrot juice can be used as an effective treatment for CLL alone or in combination with chlorambucil when taken orally with regular diet on daily basis.

  7. Effect of chronic low level radiation on lectin-induced lymphocyte transformation

    International Nuclear Information System (INIS)

    As part of a comprehensive study of the effect of chronic irradiation on leukemogenesis, we have assessed the immune status of dogs subjected to such irradiation. For this purpose, we found that the whole blood lymphocyte stimulation test (WB/LST) was a more sensitive test and required much less blood. Radioresistant populations were observed. PHA-stimulated lymphocytes showed a profound reduction in response whereas the con-A-stimulated lymphocytes did not exhibit any changes. In dogs showing severe aplastic anemia, the con-A-stimulated lymphocytes were also affected. This dichotomy of immunologic response provides a radionale to explain radiation survival of specific individuals

  8. Ibrutinib for B cell malignancies

    OpenAIRE

    Novero, Aileen; Ravella, Pavan M; Chen, Yamei; Dous, George; Liu, Delong

    2014-01-01

    Research over the role of Bruton’s agammaglobulinemia tyrosine kinase (BTK) in B-lymphocyte development, differentiation, signaling and survival has led to better understanding of the pathogenesis of B-cell malignancies. Down-regulation of BTK activity is an attractive novel strategy for treating patients with B-cell malignancies. Ibrutinib (PCI-32765), a potent inhibitor of BTK induces impressive responses in B-cell malignancies through irreversible bond with cysteine-481 in the active site ...

  9. Modern concepts in the treatment of chronic lymphocytic leukemia.

    Science.gov (United States)

    Smolej, Lukas

    2009-10-01

    There has been considerable progress in the treatment of chronic lymphocytic leukemia (CLL) during last 10 years. Purine analogs and monoclonal antibodies have enabled the shift from purely palliative treatment to intensive regimens aiming at complete remissions and possible prolongation of survival. Many patients have now been shown to achieve molecular responses in addition to their hematological remission. Despite this success, virtually all patients with CLL will eventually relapse and will become refractory to treatment. Allogeneic stem cell transplantation offers a chance of definite cure but is feasible in a minority of patients only. Therefore, considerable effort has been devoted to the further development of more conventional CLL management that is applicable to patient population generally affected by the disease. Emerging treatment concepts include novel combination of well-know agents such as rituximab and chlorambucil, fludarabine, cyclophosphamide and alemtuzumab, FCR with mitoxantrone amongst many. Consolidation regimens using mainly alemtuzumab are also increasingly used but are associated with a major increase in severe infections. High-dose steroids in combination with rituximab or alemtuzumab represent a promising option for refractory patients. Modern chemoimmunotherapy with the FCR regimen has also been tested in early stage patients with unfavourable prognostic factors. Finally, a there are a wide variety of novel drugs including bendamustine, a unique cytostatic with combined properties of an alkylating agent and purine analog, the monoclonal antibodies anti-CD20 ofatumumab and the anti-CD23 lumiliximab, thalidomide and its analog lenalidomide, the semi-synthetic flavonoid flavopiridol and other agents which are currently undergoing clinical trials with promising results. This article reviews the recent advances and future possibilities in the treatment of CLL. PMID:19843378

  10. Paranasal Manifestations of Early Stage Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Ceren Günel

    2015-04-01

    Full Text Available OBJECTIVE: Chronic lymphocytic leukemia (CLL is the most common adult leukemia. A few studies have been reported about the relationship between CLL and paranasal sinuses. We aimed to investigate the paranasal manifestations of CLL and to determine the expression of nuclear factor-ĸB (NF-kB and tumor necrosis factor (TNF-α in the nasal mucosa in patients with CLL. MATERIALS AND METHODS: This study was a clinical trial that involved 40 patients. Group CLL (n=20 consisted of patients with early-stage CLL who were followed-up at the hematology clinic and who did not receive any treatment. The control group (n=20 consisted of patients who had undergone concha surgery because of nasal obstruction. Paranasal sinus computer tomography scans of all patients were taken, they were scored on the basis of the Lund–Mackay system, and sinusitis findings were recorded. The biopsy material taken from the inferior concha head of all patients was immunohistochemically stained with primary antibodies against NF-kB and TNF-α. RESULTS: There were no statistically significant differences between the two groups with respect to NF-κB (p=0.716 and TNF-α staining scores (p=1.000. The Lund–Mackay scores were significantly higher in the CLL group than in the control group (p=0.004. Fourteen patients had sinusitis at different locations, while the most common diagnosis was maxillary sinusitis (n=8 in the CLL group. CONCLUSION: This study showed that patients with early-stage CLL tend to have rhinosinusitis. However, NF-kB and TNF-α may not have a role in the inflammatory process involving the paranasal sinuses in patients with CLL.

  11. BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Falchi, Lorenzo; Baron, Jessica M; Orlikowski, Carrie Anne; Ferrajoli, Alessandra

    2016-01-01

    The B-cell receptor (BCR) signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in treatment-naïve CLL patients. Both ibrutinib and idelalisib are well tolerated by most patients, including older, frailer individuals. Toxicities are usually mild and self-resolving. Clinicians must, however, be aware of a number of peculiar adverse events, the effects of which can be severe enough to limit the clinical use of these agents. In this review, we survey the salient aspects of the pharmacology and clinical experience with the use of BCR signaling inhibitors for the treatment of patients with CLL. We next focus on both the most common and the most clinically significant toxicities associated with these drugs. PMID:26977270

  12. BCR SIGNALING INHIBITORS: AN OVERVIEW OF TOXICITIES ASSOCIATED WITH IBRUTINIB AND IDELALISIB IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Lorenzo Falchi

    2016-02-01

    Full Text Available The B-cell receptor signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment landscape of chronic lymphocytic leukemia (CLL and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in treatment-naïve CLL patients. Both ibrutinib and idelalisib are well tolerated by most patients, including older, frailer individuals. Toxicities are usually mild and self-resolving. Clinicians must, however, be aware of a number of peculiar adverse events, the effects of which can be severe enough to limit the clinical use of these agents. In this review, we survey the salient aspects of the pharmacology of these agents, as well as clinical experience regarding their use for the treatment of patients with CLL. Our foci will be both the most common and the most clinically significant toxicities associated with these drugs.

  13. Three newly approved drugs for chronic lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice.

    Science.gov (United States)

    Sanford, David S; Wierda, William G; Burger, Jan A; Keating, Michael J; O'Brien, Susan M

    2015-07-01

    Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase δ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL. PMID:25817936

  14. Update in the management of chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Lin Thomas S

    2009-07-01

    Full Text Available Abstract Advances in the treatment of chronic lymphocytic leukemia (CLL have improved initial overall response (OR rates, complete response (CR rates and progression free survival (PFS. Despite these advances, CLL remains incurable with standard therapies. Thus, there remains a need for more effective therapies in both the upfront and relapsed setting, particularly for patients with high-risk cytogenetic abnormalities such as del(11q22 and del(17p13. The 2008 American Society of Hematology (ASH Annual Meeting featured several presentations which highlighted the ongoing clinical advances in CLL. The benefit of adding rituximab to purine analog therapy in the upfront setting was demonstrated by a large randomized study which showed that the addition of rituximab to fludarabine and cyclophosphamide (FCR significantly improved OR, CR and PFS. The improvement in PFS directly resulted from an improved ability to eliminate minimal residual disease (MRD in the peripheral blood, highlighting the importance of MRD eradication. However, a multi-center study suggested that the high CR rates to chemoimmunotherapy regimens such as FCR obtained in academic centers may not be reproducible when the same regimens are given in the community setting. The immunomodulatory drug lenalidomide is active in relapsed high-risk CLL, but two studies of lenalidomide in previously untreated CLL patients failed to achieve a CR and were associated with significant tumor lysis, tumor flare and hematologic toxicity. In the relapsed setting, a combination study of the bifunctional alkylator bendamustine and rituximab (BR demonstrated a high OR rate in patients with del(11q22 and del(17p13, indicating that further studies to define's bendamustine activity are warranted in high-risk CLL. Similarly, the CDK inhibitor flavopiridol demonstrated significant clinical activity and durable remissions in heavily treated, refractory CLL patients with high-risk cytogenetic features and bulky

  15. Use of immune-nanoparticles containig chemiotherapeutic agents for the treatment of B-cell malignancies

    OpenAIRE

    Capolla, Sara

    2015-01-01

    B-cell malignancies are a heterogeneous group of clinical conditions including indolent diseases such as Chronic Lymphocytic Leukemia (CLL) and highly aggressive lymphoproliferative disorders such as Burkitt’s lymphoma. B-cell malignancies treatments take advantage of dose-intensive chemotherapeutic regimens and immunotherapy via monoclonal antibodies. Unfortunately, they may lead to insufficient tumor distribution of therapeutic agents and cause several adverse effects. Thus, we propose a...

  16. Targeting neoplastic B cells and harnessing microenvironment: the “double face” of ibrutinib and idelalisib

    OpenAIRE

    Maffei, Rossana; Fiorcari, Stefania; Martinelli, Silvia; Potenza, Leonardo; Luppi, Mario; Marasca, Roberto

    2015-01-01

    Tyrosine kinase inhibitors (TKIs) targeting signaling molecules downstream B cell receptor (BCR) are powerfully spreading in the therapeutic landscape of B cell lymphoproliferative disease, due to a manageable toxicity profile and encouraging clinical effectiveness. In particular, ibrutinib, previously called PCI-32765, is a potent inhibitor of Bruton tyrosine kinase (Btk), recently approved for the treatment of relapsed mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Moreo...

  17. Effects of chronic metoprolol and sulphinpyrazone on human lymphocyte beta-adrenoceptors.

    OpenAIRE

    Blasi, A.; Cortellaro, M; Costantini, C.

    1984-01-01

    Multiple (100 mg twice daily for 21 days) but not single (100 mg) oral doses of metoprolol significantly reduced the number (Bmax) and the KD of beta-adrenoceptors on intact lymphocytes from nine healthy volunteers. Sulphinpyrazone (400 mg twice daily for 21 days) did not change lymphocyte beta-adrenoceptors and did not modify their reaction to chronic metoprolol. In vitro sulphinpyrazone (10-4M) increased [3H]-DHA specific binding on intact lymphocytes. This effect was not modified by metopr...

  18. Automated classification of patients with chronic lymphocytic leukemia and immunocytoma from flow cytometric three-color immunophenotypes.

    Science.gov (United States)

    Valet, G K; Höffkes, H G

    1997-12-15

    The goal of this study was the discrimination between chronic lymphocytic leukemia (B-CLL), clinically more aggressive lymphoplasmocytoid immunocytoma (LP-IC) and other low-grade non-Hodgkin's lymphomas (NHL) of the B-cell type by automated analysis of flow cytometric immunophenotypes CD45/14/20, CD4/8/3, kappa/CD19/5, lambda/CD19/5 and CD10/23/19 from peripheral blood and bone marrow aspirate leukocytes using the multiparameter classification program CLASSIF1. The immunophenotype list mode files were exhaustively evaluated by combined lymphocyte, monocyte, and granulocyte (LMG) analysis. The results were introduced into databases and automatically classified in a standardized way. The resulting triple matrix classifiers are laboratory and instrument independent, error tolerant, and robust in the classification of unknown test samples. Practically 100% correct individual patient classification was achievable, and most manually unclassifiable patients were unambiguously classified. It is of interest that the single lambda/CD19/5 antibody triplet provided practically the same information as the full set of the five antibody triplets. This demonstrates that standardized classification can be used to optimize immunophenotype panels. On-line classification of test samples is accessible on the Internet: http://www.biochem.mpg.de/valet/leukaem1.html Immunophenotype panels are usually devised for the detection of the frequency of abnormal cell populations. As shown by computer classification, most the highly discriminant information is, however, not contained in percentage frequency values of cell populations, but rather in total antibody binding, antibody binding ratios, and relative antibody surface density parameters of various lymphocyte, monocyte, and granulocyte cell populations. PMID:9440819

  19. Altered pattern of Naïve and memory B cells and B1 cells in patients with chronic granulomatous disease.

    OpenAIRE

    2014-01-01

    Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder characterized by a greatly increased susceptibility to severe fungal and bacterial infections caused by defects in NADPH oxidase of phagocytic cells. We aimed to investigate immunophenotype alterations of naïve and memory B cells and B1a cells in peripheral whole blood from Iranian patients with CGD. Flow cytometric analysis was performed on peripheral blood samples from 31 CGD patients and 23 healthy controls (HC...

  20. Protective Effects of Lentinan against T Lymphocytes Injury in Mice under Chronic Radiation Stress

    Institute of Scientific and Technical Information of China (English)

    WANG; Yong; LI; Ming-chun; FU; Qing-jie

    2013-01-01

    Objective To study the effects of lentinan (LTN) on mice exposed to chronic radiation. Methods Animals were divided into three groups (n = 10), they were animals exposed to radiation (Rad), normal control animals (Ctr), and irradiated animals treated with LTN (Rad + LTN). Animal model of chronic radiation stress injury was induced by irradiating mice with 60 Co γ-ray for 6 weeks from Monday to Friday consecutively. Before radiation, the mice in Rad + LTN group were ip injected with 0.5 mL LTN (0.01 mg/mL), whereas mice in other groups were injected with 0.9% physiological saline. The effects of LTN treatment on irradiated mice were examined by histological analysis on the spleen. The cell numbers and viability of T lymphocytes, which were isolated from the spleen, were determined by Trypan blue staining. Nitric oxide (NO) production and interleukin-2 (IL-2) secretion in T lymphocytes were also measured. Results Chronic radiation significantly reduced the body weights and the spleen and thymus indexes, associated with reduced T lymphocytes viability and functions, and elevated NO production. Treatment with LTN significantly normalized the elevated NO production, and attenuated the negative outcomes resulting from radiation mentioned above. Conclusion The results suggest that radioprotective effect of LTN may be contributed by improved T lymphocytes viability and functions via regulating the NO and IL-2 production in T lymphocytes.

  1. Protective Effects of Lentinan against T Lymphocytes Injury in Mice under Chronic Radiation Stress

    Institute of Scientific and Technical Information of China (English)

    WANG Yong; LI Ming-chun; FU Qing-jie

    2013-01-01

    Objective To study the effects of lentinan (LTN) on mice exposed to chronic radiation.Methods Animals were divided into three groups (n =10),they were animals exposed to radiation (Rad),normal control animals (Ctr),and irradiated animals treated with LTN (Rad + LTN).Animal model of chronic radiation stress injury was induced by irradiating mice with 60Co γ-ray for 6 weeks from Monday to Friday consecutively.Before radiation,the mice in Rad + LTN group were ip injected with 0.5 mL LTN (0.01 mg/mL),whereas mice in other groups were injected with 0.9% physiological saline.The effects of LTN treatment on irradiated mice were examined by histological analysis on the spleen.The cell numbers and viability of T lymphocytes,which were isolated from the spleen,were determined by Trypan blue staining.Nitric oxide (NO) production and interleukin-2 (IL-2) secretion in T lymphocytes were also measured.Results Chronic radiation significantly reduced the body weights and the spleen and thymus indexes,associated with reduced T lymphocytes viability and functions,and elevated NO production.Treatment with LTN significantly normalized the elevated NO production,and attenuated the negative outcomes resulting from radiation mentioned above.Conclusion The results suggest that radioprotective effect of LTN may be contributed by improved T lymphocytes viability and functions via regulating the NO and IL-2 production in T lymphocytes.

  2. Remodeling of B-Cell Subsets in Blood during Pegylated IFNα-2a Therapy in Patients with Chronic Hepatitis B Infection

    Science.gov (United States)

    Jacob, Marie-Christine; Dufeu-Duchesne, Tania; Bertucci, Inga; Pouget, Noelle; Brevot-Lutton, Ophelie; Zoulim, Fabien; Bourliere, Marc; Plumas, Joel; Leroy, Vincent

    2016-01-01

    The ultimate goal of pegylated interferon-alfa-2a (Peg-IFN-α) therapy in chronic hepatitis B (CHB) infection is HBsAg seroconversion. Even though B cells are major mediators of a positive clinical outcome, their modulation during Peg-IFN-α therapy has not yet been described. We investigated here the effects of Peg-IFN-α on eight circulating B-cell subsets thanks to an original multi-gating approach based on CD19, CD27, IgD, CD10, and CD38 markers in patients with CHB treated with nucleos(t)ide analog alone or in combination with Peg-IFN-α. These dynamic changes were analyzed during the 48-weeks of Peg-IFN-α therapy and up to 2 years after the cessation of treatment. The CD19+CD27-IgD+CD10+CD38high transitional B cells and the CD19+CD27+IgD-CD10-CD38high plasmablasts continuously increased, whereas the CD19+CD27-IgD+CD10-CD38low naive, CD19+CD27+IgD+ natural memory, and CD19+CD27+IgD-CD10-CD38low post-germinal center B cells decreased during the course of Peg-IFNα treatment. Such modulations correlated with a sustained increase in sCD30 levels and the decrease in plasma HBsAg. However, no seroconversion occurred and all parameters returned to baseline after the stop of the treatment. Peg-IFN-α therapy mediates a remodeling of B-cell compartmentalization, without clinical relevance. Our study provides new insights into the immunomodulatory effects of Peg-IFN-α on circulating B-cells, and questioned the benefit of the add-on Peg-IFN-α treatment in CHB. PMID:27281019

  3. Remodeling of B-Cell Subsets in Blood during Pegylated IFNα-2a Therapy in Patients with Chronic Hepatitis B Infection.

    Science.gov (United States)

    Aspord, Caroline; Bruder Costa, Juliana; Jacob, Marie-Christine; Dufeu-Duchesne, Tania; Bertucci, Inga; Pouget, Noelle; Brevot-Lutton, Ophelie; Zoulim, Fabien; Bourliere, Marc; Plumas, Joel; Leroy, Vincent

    2016-01-01

    The ultimate goal of pegylated interferon-alfa-2a (Peg-IFN-α) therapy in chronic hepatitis B (CHB) infection is HBsAg seroconversion. Even though B cells are major mediators of a positive clinical outcome, their modulation during Peg-IFN-α therapy has not yet been described. We investigated here the effects of Peg-IFN-α on eight circulating B-cell subsets thanks to an original multi-gating approach based on CD19, CD27, IgD, CD10, and CD38 markers in patients with CHB treated with nucleos(t)ide analog alone or in combination with Peg-IFN-α. These dynamic changes were analyzed during the 48-weeks of Peg-IFN-α therapy and up to 2 years after the cessation of treatment. The CD19+CD27-IgD+CD10+CD38high transitional B cells and the CD19+CD27+IgD-CD10-CD38high plasmablasts continuously increased, whereas the CD19+CD27-IgD+CD10-CD38low naive, CD19+CD27+IgD+ natural memory, and CD19+CD27+IgD-CD10-CD38low post-germinal center B cells decreased during the course of Peg-IFNα treatment. Such modulations correlated with a sustained increase in sCD30 levels and the decrease in plasma HBsAg. However, no seroconversion occurred and all parameters returned to baseline after the stop of the treatment. Peg-IFN-α therapy mediates a remodeling of B-cell compartmentalization, without clinical relevance. Our study provides new insights into the immunomodulatory effects of Peg-IFN-α on circulating B-cells, and questioned the benefit of the add-on Peg-IFN-α treatment in CHB. PMID:27281019

  4. Neutrophil-to-lymphocyte ratio, calprotectin and YKL-40 in patients with chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Sørensen, Allan Klitgaard; Holmgaard, Dennis Back; Mygind, Lone Hagens;

    2015-01-01

    - and multivariate Cox regression analyses with hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Plasma calprotectin was positively correlated with neutrophil granulocyte count and NLR. No significant association was found between plasma YKL-40 and the cellular biomarkers, irrespective......BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and progressive decline in pulmonary function. Neutrophil-to-lymphocyte ratio (NLR), YKL-40 and calprotectin are biomarkers of inflammation and predict mortality in patients with different inflammatory...

  5. Chronic lymphocytic leukaemia: contemporary conceptions of etiology, pathogenesis and peculiarities of clinical manifestations (review

    Directory of Open Access Journals (Sweden)

    Chesnokova N.P.

    2011-06-01

    Full Text Available The research work presents an analysis of literature review and results of investigations on the problems of etiology, pathogenesis, classification and peculiarities of clinical manifestations of chronic lymphocytic leukaemia. Special attention is paid to both contemporary conceptions of carcinogenesis, reflecting the role of proto-oncogenes activation, an-tioncogenes and apoptosis genes suppression in mechanisms of neoplasia development and «specific mechanisms» of oncogenic transformation induction of B-lymphocytes and the subsequent development of the stages of promotion, progression and marked clinical manifestations of formation. Possibility of further improvement of use of immune phe-notype character and oncomarkers in diagnostics of chronic lymphocytic leukaemia clinical variants and in evaluation of effectiveness of its therapy has been indicated in the article

  6. A case repot of Merkel cell carcinoma on chronic lymphocytic leukemia: differential diagnosis of coexisting lymphadenopathy and indications for early aggressive treatment

    International Nuclear Information System (INIS)

    Chronic lymphocytic leukemia (CLL) is a monoclonal disorder, characterized by a progressive proliferation of functionally incompetent B lymphocytes. There is increased evidence of association between CLL and skin cancers, including the uncommon Merkel cell carcinoma (MCC). A case report of an 84-year old male, who presented with an aggressively recurrent form of MCC on the lower lip, on the background of an 8-year history of untreated CLL. During the recurrences of MCC, coexisting regional lymphadenopathy, posed a problem in the differential diagnosis and treatment of lymph node involvement. Histopathology and immunoistochemistry showed that submandibular lymphadenopathy coexisting with the second recurrence of MCC, was due to B-cell small lymphocytic lymphoma. The subsequent and more aggressive recurrence of the skin tumor had involved the superficial and deep cervical lymph nodes. Surgical excision followed by involved field radiation therapy has been proven effective for both malignancies. MCC has a high incidence of regional lymphadenopathy at presentation (12–45%) and even when it arises on the background of chronic leucemia, lymphadenopathy at presentation should be managed agressively with elective lymph node dissection. We overview the postulated correlation between Merkel tumor and CCL, the differential diagnosis of regional lymphadenopathy during the recurrences of the skin tumor and the strategies of treatment

  7. Turmeric and green tea: a recipe for B-Chronic Lymphocytic Leukemia

    OpenAIRE

    Angelo, Laura S.; Kurzrock, Razelle

    2009-01-01

    Two naturally-occurring compounds--curcumin (the active ingredient in the spice turmeric) and the green tea extract epigallocatechin-3-gallate (EGCG) have marked effects on the apoptotic machinery in chronic lymphocytic leukemia (CLL). These results provide a preclinical foundation for future clinical use of these compounds in this disease.

  8. Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Strefford, J C; Sutton, L-A; Baliakas, P; Agathangelidis, A; Malčíková, J; Plevova, K; Scarfó, L; Davis, Zachary James; Stalika, E; Cortese, D; Cahill, N; Pedersen, L B; di Celle, P F; Tzenou, T; Geisler, C; Panagiotidis, P; Langerak, A W; Chiorazzi, N; Pospisilova, S; Oscier, D; Davi, F; Belessi, C; Mansouri, L; Ghia, P; Stamatopoulos, K; Rosenquist, R

    2013-01-01

    Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B...

  9. Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Gunnarsson, Rebeqa; Mansouri, Larry; Isaksson, Anders;

    2011-01-01

    High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic...

  10. Targeted resequencing for analysis of clonal composition of recurrent gene mutations in chronic lymphocytic leukaemia

    DEFF Research Database (Denmark)

    Jethwa, Alexander; Hüllein, Jennifer; Stolz, Tatjana;

    2013-01-01

    Recurrent gene mutations contribute to the pathogenesis of chronic lymphocytic leukaemia (CLL). We developed a next-generation sequencing (NGS) platform to determine the genetic profile, intratumoural heterogeneity, and clonal structure of two independent CLL cohorts. TP53, SF3B1, and NOTCH1 were...

  11. NF-κB RelA-deficient Lymphocytes: Normal Development of  T Cells and B Cells, Impaired Production of IgA and IgG1 and Reduced Proliferative Responses

    OpenAIRE

    Doi, Takahiro S.; Takahashi, Toshitada; TAGUCHI, Osamu; Azuma, Takachika; Obata, Yuichi

    1997-01-01

    To investigate the function of NF-κB RelA (p65), we generated mice deficient in this NF-κB family member by homologous recombination. Mice lacking RelA showed liver degeneration and died around embryonic day 14.5. To elucidate the role of RelA in lymphocyte development and function, we transplanted fetal liver cells of 13.5-day embryos from heterozygote matings into irradiated SCID mice. Within 4 weeks, both T and B cells had developed in the SCID mice receiving relA−/− fetal liver transplant...

  12. Early B-cell factor 1 (EBF1) is critical for transcriptional control of SLAMF1 gene in human B cells.

    Science.gov (United States)

    Schwartz, Anton M; Putlyaeva, Lidia V; Covich, Milica; Klepikova, Anna V; Akulich, Kseniya A; Vorontsov, Ilya E; Korneev, Kirill V; Dmitriev, Sergey E; Polanovsky, Oleg L; Sidorenko, Svetlana P; Kulakovskiy, Ivan V; Kuprash, Dmitry V

    2016-10-01

    Signaling lymphocytic activation molecule family member 1 (SLAMF1)/CD150 is a co-stimulatory receptor expressed on a variety of hematopoietic cells, in particular on mature lymphocytes activated by specific antigen, costimulation and cytokines. Changes in CD150 expression level have been reported in association with autoimmunity and with B-cell chronic lymphocytic leukemia. We characterized the core promoter for SLAMF1 gene in human B-cell lines and explored binding sites for a number of transcription factors involved in B cell differentiation and activation. Mutations of SP1, STAT6, IRF4, NF-kB, ELF1, TCF3, and SPI1/PU.1 sites resulted in significantly decreased promoter activity of varying magnitude, depending on the cell line tested. The most profound effect on the promoter strength was observed upon mutation of the binding site for Early B-cell factor 1 (EBF1). This mutation produced a 10-20 fold drop in promoter activity and pinpointed EBF1 as the master regulator of human SLAMF1 gene in B cells. We also identified three potent transcriptional enhancers in human SLAMF1 locus, each containing functional EBF1 binding sites. Thus, EBF1 interacts with specific binding sites located both in the promoter and in the enhancer regions of the SLAMF1 gene and is critical for its expression in human B cells. PMID:27424222

  13. Elucidating the CXCL12/CXCR4 signaling network in chronic lymphocytic leukemia through phosphoproteomics analysis.

    Directory of Open Access Journals (Sweden)

    Morgan O'Hayre

    Full Text Available BACKGROUND: Chronic Lymphocytic Leukemia (CLL pathogenesis has been linked to the prolonged survival and/or apoptotic resistance of leukemic B cells in vivo, and is thought to be due to enhanced survival signaling responses to environmental factors that protect CLL cells from spontaneous and chemotherapy-induced death. Although normally associated with cell migration, the chemokine, CXCL12, is one of the factors known to support the survival of CLL cells. Thus, the signaling pathways activated by CXCL12 and its receptor, CXCR4, were investigated as components of these pathways and may represent targets that if inhibited, could render resistant CLL cells more susceptible to chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS: To determine the downstream signaling targets that contribute to the survival effects of CXCL12 in CLL, we took a phosphoproteomics approach to identify and compare phosphopeptides in unstimulated and CXCL12-stimulated primary CLL cells. While some of the survival pathways activated by CXCL12 in CLL are known, including Akt and ERK1/2, this approach enabled the identification of additional signaling targets and novel phosphoproteins that could have implications in CLL disease and therapy. In addition to the phosphoproteomics results, we provide evidence from western blot validation that the tumor suppressor, programmed cell death factor 4 (PDCD4, is a previously unidentified phosphorylation target of CXCL12 signaling in all CLL cells probed. Additionally, heat shock protein 27 (HSP27, which mediates anti-apoptotic signaling and has previously been linked to chemotherapeutic resistance, was detected in a subset (approximately 25% of CLL patients cells examined. CONCLUSIONS/SIGNIFICANCE: Since PDCD4 and HSP27 have previously been associated with cancer and regulation of cell growth and apoptosis, these proteins may have novel implications in CLL cell survival and represent potential therapeutic targets. PDCD4 also represents a

  14. AUTOIMMUNE CYTOPENIAS IN CHRONIC LYMPHOCYTIC LEUKEMIA, FACTS AND MYTHS

    Directory of Open Access Journals (Sweden)

    Pavankumar Tandra

    2013-11-01

    Full Text Available CLL has been defined as presence of more than 5000 small mature appearing monoclonal B lymphocytes with a specific immunophenotype in peripheral blood. It is a well-known fact that CLL is associated with autoimmune cytopenias. CLL cells are CD5+ B lymphocytes, and usually are not the “guilty” cells which produce autoantibodies. T cell defect is another characteristic of CLL and the total number of T cells is increased, and there is inversion of the CD4/CD8 ratio. Autoimmune hemolytic anemia (AIHA is the most common autoimmune complication of CLL and has been reported in 10-25% of CLL patients. However, the stage-adjusted estimated rate of AIHA in CLL is about 5%. Conversely, CLL is three times more common in patients who present with AIHA. Direct agglutinin test (DAT is positive in 7-14% of CLL patients but AIHA may also occur in DAT negative patients. Autoimmune thrombocytopenia (AIT is the second most common complication of CLL and has been reported in 2-3% of patients. DAT is positive in AIT but presence of antiplatelet antibodies is neither diagnostic nor reliable. Autoimmune neutropenia (AIN and pure red cell aplasia (PRCA are very rare complications of CLL and like other autoimmune complications of CLL may occur at any clinical stage. It is believed that most case reports of AIN and PRCA in CLL actually belong to large granular lymphocytic leukemia (LGL. Non-hematologic autoimmune complications of CLL including cold agglutinin disease (CAD, paraneoplastic pemphigus (PNP, acquired angioedema, and anti-myelin associated globulin are rare. Before starting any treatment, clinicians should distinguish between autoimmune cytopenias and massive bone marrow infiltration since autoimmune complications of CLL are not necessarily equal to advanced disease with poor prognosis. According to IWCLL guideline, steroids are the mainstay of treatment of simple autoimmunity. Intravenous immunoglobulin (IVIg, cyclosporine, and rituximab are used in

  15. Expression of MHC class II antigens in human B-cell leukaemia and non-Hodgkin's lymphoma.

    OpenAIRE

    Guy, K.; Krajewski, A S; Dewar, A E

    1986-01-01

    In this review we have summarized our experiences of serological analysis of MHC class II antigen expression in human B cell malignant disease. Cells from a large number of cases of B-cell chronic lymphocytic leukaemia (CLL) and non-Hodgkin's lymphoma (NHL) have been examined for expression of class II antigens. Using a number of monoclonal antibodies which in some cases are specific for class II subregion products (DP, DQ and DR), MHC class II antigens were detected by indirect immunofluores...

  16. T cells in chronic lymphocytic leukaemia display an exhausted phenotype and impaired functionality that can be restored by chemotherapy

    International Nuclear Information System (INIS)

    In chronic lymphocytic leukaemia (CLL), beside a massive accumulation of neoplastic B cells, tumour-induced deficiencies in autologous T cells have been reported that impede efficient tumour control and might even support survival of the malignant clone. Here, we investigated our hypothesis that T cells in CLL, due to the persistent availability of tumour antigen, are exhausted, and that reduction of tumour load by chemotherapy might restore T cell functions. We could show that T cells in CLL patients and in a CLL mouse model display an exhausted phenotype, with high expression of the inhibitory surface receptor PD-1, that is clearly induced by the presence of tumour cells. Although the PD-1 ligand PD-L1 is not expressed on peripheral CLL cells, abundant expression could be shown in lymph node sections. Intriguingly, blocking the PD-1/PD-L1 pathway increased short term tumour lysis in a murine in vivo cytotoxicity assay. Furthermore, we present data that after cytoreduction by fludarabine, a standard chemotherapy agent for CLL, the surviving T cell pool consists mainly of fully functional memory T cells with high proliferative potential and increased secretion of pro-inflammatory Th1 cytokines. Taken together, we conclude that the impaired tumour surveillance observed in CLL might be rooted in the exhaustion of tumour-specific effector T cells. A combination of cytodepletion by chemotherapy and blockade of PD-1 might hence represent a novel therapeutic approach for CLL. (author)

  17. Minimal residual disease detection with tumor-specific CD160 correlates with event-free survival in chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    In chronic lymphocytic leukemia (CLL), the detection of minimal residual disease (MRD) correlates with outcome in the trial setting. However, MRD assessment does not guide routine clinical management and its assessment remains complex. We incorporated detection of the B cell, tumor-specific antigen CD160 to develop a single-tube, flow cytometry assay (CD160FCA) for CLL MRD to a threshold of 10−4 to 10−5. One hundred and eighty-seven patients treated for CLL were enrolled. Utilizing the CD160FCA methodology, there was a high level of comparison between blood and bone marrow (R=0.87, P<0.001). In a validation cohort, CD160FCA and the international standardised approach of the European Research Initiative on CLL group demonstrated high concordance (R=0.91, P<0.01). Patients in complete remission (CR) and CD160FCA negative had longer event-free survival (EFS) (63 vs 16 months, P<0.01) and prolonged time to next treatment (60 vs 15 months, P<0.001) vs MRD positive patients; with a median time to MRD positivity of 36 months. In multivariate analysis, CD160FCA MRD detection was independently predictive of EFS in patients in CR and even predicted EFS in the good-risk cytogenetic subgroup. CD160FCA offers a simple assay for MRD detection in CLL and gives prognostic information across different CLL risk groups

  18. Targeting chronic lymphocytic leukemia cells in the tumor microenviroment: A review of the in vitro and clinical trials to date.

    Science.gov (United States)

    Crassini, Kyle; Mulligan, Stephen P; Best, O Giles

    2015-08-16

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Despite significant advances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemoimmunotherapy-based regimens, most commonly the fludarabine, cyclophosphamide plus rituximab combination, but rates of relapse and refractory disease are high among these patients. Several key signaling pathways are now known to mediate the survival and proliferation of CLL cells in vivo, the most notable of which are the pathways mediated by the B-cell receptor (BCR) and cytokine receptors. A better understanding of the pathogenesis of the disease, the underlying biology of the CLL-cell and the roles of the tumour microenvironment has provided the rationale for trials of a range of novel, more targeted therapeutic agents. In particular, clinical trials of ibrutinib and idelalisib, which target the Brutons tyrosine kinase and the delta isoform of phosphoinositol-3 kinase components of the BCR signaling pathway respectively, have shown extremely promising results. Here we review the current literature on the key signaling pathways and interactions of CLL cells that mediate the survival and proliferation of the leukemic cells. For each we describe the results of the recent clinical trials and in vitro studies of novel therapeutic agents. PMID:26301230

  19. The pleiotropic flavonoid quercetin: from its metabolism to the inhibition of protein kinases in chronic lymphocytic leukemia.

    Science.gov (United States)

    Russo, Gian Luigi; Russo, Maria; Spagnuolo, Carmela

    2014-10-01

    Quercetin is a flavonoid, of the subclass flavonols, possessing potential anticancer properties. It has often been defined as a functionally pleiotropic molecule because it can simultaneously target multiple pathways bypassing or ameliorating the onset of drug resistance in malignant cells. In this context, we reviewed the sometimes paradoxical antioxidant properties of quercetin and the functional role of its glucuronide and/or sulfate conjugates to discuss the low bioavailability of the molecule measured in vivo. We recently demonstrated that quercetin is able to sensitize several leukemia cell lines as well as B cells isolated from patients affected by chronic lymphocytic leukemia (CLL) to death ligand agonists (anti-CD95 and rTRAIL). The flavonol also potentiates the effect of canonical and innovative chemotherapeutic drugs (fludarabine and ABT-737) against CLL. The apoptosis-enhancing activity of quercetin in cell lines and B-CLL cells depends upon the modulated expression and activity of Mcl-1, an anti-apoptotic protein belonging to the Bcl-2 family. Herein, we suggest that the pleotropic activity of quercetin in CLL is obtained by the direct inhibition of key protein kinases, which positively regulate Mcl-1 activity and by indirect downregulation of Mcl-1 mRNA and protein levels acting on its mRNA stability and proteasome-mediated degradation. Finally, we highlighted the pros and cons of quercetin supplementation in cancer therapy and in prevention. PMID:25096193

  20. Chronic lymphocytic leukemia presenting with extreme hyperleukocytosis and thrombosis of the common femoral vein.

    Science.gov (United States)

    Cukierman, Tali; Gatt, Moshe E; Libster, Dianna; Goldschmidt, Neta; Matzner, Yaacov

    2002-09-01

    Very few case reports dealing with chronic lymphocytic leukemia (CLL) and hyperleukocytosis have been reported in the medical literature and none with venous thrombosis as a complication. Here, we describe a 73-year-old woman who presented with newly diagnosed CLL, leukostasis, and hyperleukocytosis (2000 x 10(9)/l), affecting the respiratory and nervous system. In addition, she also had deep vein thrombosis (DVT). Although hypercoagulability and thrombosis are well-described phenomena in solid tumors and in myeloproliferative neoplasms, CLL is generally not associated with an acquired coagulopathy. We hypothesize that in our patient the extreme number of circulating lymphocytes resulted in an abnormal accumulation of lymphocytes possibly causing stasis and occlusion of a larger vessel, which resolved after leukopheresis. The patient has since been successfully maintained with chemotherapy. We conclude that leukopheresis should be considered as the therapy of choice in CLL patients presenting with major complications of leukostasis. PMID:12685846

  1. Cadmium-glutathione complex formation in human t-cell and b-cell lymphocytes after their incubation with organo-cadmium diacetate.

    Science.gov (United States)

    Ullah, Hashmat; Khan, Muhammad Farid; Jan, Syed Umer; Hashmat, Farwa

    2015-11-01

    Cadmium intake is associated with oxidative stress that causes depletion of intracellular as well as extra cellular reduced glutathione. There is strong evidence indicating that reactive oxygen species and reactive nitrogen species generated in the presence of cadmium could be responsible for its toxic effects in many cells and tissues. Depletion of reduced glutathione in various cells, especially in T and B-lymphocytes, causes extreme damage to the antioxidant defense system of body. The aim of this research work was to investigate the metabolic changes that occur in T and B lymphocytes after their incubation with organ cadmium diacetate by using Ellman's spectrophotometric method of thiol quantification. The results of the present study indicate that cadmium depleted T and B lymphocytes GSH to a harmful extent. It is proposed that this depletion is due to the bivalent cadmium glutathione complex formation, oxidation of reduced glutathione (GSH) to its oxidized form, or both. PMID:26639500

  2. Total-body irradiation with 25-MV photons in advanced non-Hodgkin's lymphoma and chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma were treated with total-body irradiation (TBI). One group was treated after chemotherapy failed, while the other group received TBI initially. TBI was ineffective against CLL after chemotherapy failed. All patients with lymphocytic lymphoma who initially responded to chemotherapy but later relapsed were helped by TBI, as were 88 percent of patients with previously untreated lymphocytic lymphomas

  3. Envelope-specific B-cell populations in African green monkeys chronically infected with simian immunodeficiency virus.

    Science.gov (United States)

    Zhang, Ruijun; Martinez, David R; Nguyen, Quang N; Pollara, Justin; Arifin, Trina; Stolarchuk, Christina; Foulger, Andrew; Amos, Josh D; Parks, Robert; Himes, Jonathon E; Wang, Minyue; Edwards, Regina W; Trama, Ashley M; Vandergrift, Nathan; Colvin, Lisa; Dewar, Ken; Juretic, Nikoleta; Wasserscheid, Jessica; Ferrari, Guido; Liao, Hua-Xin; Permar, Sallie R

    2016-01-01

    African green monkeys (AGMs) are natural primate hosts of simian immunodeficiency virus (SIV). Interestingly, features of the envelope-specific antibody responses in SIV-infected AGMs are distinct from that of HIV-infected humans and SIV-infected rhesus monkeys, including gp120-focused responses and rapid development of autologous neutralization. Yet, the lack of genetic tools to evaluate B-cell lineages hinders potential use of this unique non-human primate model for HIV vaccine development. Here we define features of the AGM Ig loci and compare the proportion of Env-specific memory B-cell populations to that of HIV-infected humans and SIV-infected rhesus monkeys. AGMs appear to have a higher proportion of Env-specific memory B cells that are mainly gp120 directed. Furthermore, AGM gp120-specific monoclonal antibodies display robust antibody-dependent cellular cytotoxicity and CD4-dependent virion capture activity. Our results support the use of AGMs to model induction of functional gp120-specific antibodies by HIV vaccine strategies. PMID:27381634

  4. Vorinostat and Decitabine in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia

    Science.gov (United States)

    2014-08-26

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Secondary Acute Myeloid Leukemia; Splenic Marginal Zone Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma

  5. Romidepsin in Treating Patients With Lymphoma, Chronic Lymphocytic Leukemia, or Solid Tumors With Liver Dysfunction

    Science.gov (United States)

    2016-08-24

    Adult Mixed Glioma; Adult Pineal Gland Astrocytoma; Adult Solid Neoplasm; AIDS Related Immunoblastic Lymphoma; AIDS-Related Burkitt Lymphoma; AIDS-Related Diffuse Large Cell Lymphoma; AIDS-Related Diffuse Mixed Cell Lymphoma; AIDS-Related Diffuse Small Cleaved Cell Lymphoma; AIDS-Related Hodgkin Lymphoma; AIDS-Related Lymphoblastic Lymphoma; AIDS-Related Lymphoma; AIDS-Related Primary Central Nervous System Lymphoma; Glioma; Lymphoma; Recurrent Adult Brain Neoplasm; Recurrent Adult Soft Tissue Sarcoma; Recurrent Bladder Carcinoma; Recurrent Breast Carcinoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Colorectal Carcinoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma; Recurrent Melanoma; Recurrent Pancreatic Carcinoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Thyroid Gland Carcinoma; Refractory Chronic Lymphocytic Leukemia; Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma

  6. Clinical significance of HLA-DR+, CD19+, CD10+ immature B-cell phenotype and CD34+ cell detection in bone marrow lymphocytes from children affected with immune thrombocytopenic purpura.

    Science.gov (United States)

    Callea, V; Comis, M; Iaria, G; Sculli, G; Morabito, F; Lombardo, V T

    1997-01-01

    In children with immune thrombocytopenic purpura (ITP), bone marrow lymphocytes can express the common acute lymphoblastic leukemia antigen (CALLA) pattern with no evidence of leukemia or lymphoma. Bone marrow lymphocytes from 23 children and 20 adults affected with ITP were studied to determine the incidence and the clinical impact of lymphocytes with the immature B-cell phenotype and CD34+ cell expression. In this investigation we identified a group consisting of 52% of the children who showed the immature B phenotype, while the remaining 48%, similarly to adult ITP displayed an increase of T-cell antigens. CD34 was positive in 53% of children, but it was present in only half of the patients with the immature B phenotype and it was always absent in adults. IgH genes disclosed a germline configuration in all six patients in the immature B phenotype group. No difference was found in the two groups of children in terms of age, presentation of the disease or final outcome. Finally, no patient in either children's group has developed an acute lymphoproliferative disorder. PMID:9299867

  7. Genetic Counseling for DAPK1 Mutation in a Chronic Lymphocytic Leukemia Family

    OpenAIRE

    Lynch, Henry T.; Ferrara, Kelly; Weisenburger, Dennis; Sanger, Warren; Lynch, Jane F.; Thomé, Stephan

    2008-01-01

    Genetic counseling has become the clinical bedrock of hereditary cancer. Countless advances in molecular genetics contributing to the identification of cancer-causing germline mutations have increased its importance. We report perhaps the world’s first genetic counseling experience involving a family with hereditary chronic lymphocytic leukemia and the cancer-causing mutation in the death-associated protein kinase 1 (DAPK1) gene. This hereditary disorder currently lacks any preventive or cura...

  8. Lymphocytes from Chronically Stressed Mice Confer Antidepressant-Like Effects to Naive Mice

    OpenAIRE

    Brachman, Rebecca A.; Lehmann, Michael L.; Maric, Dragan; Herkenham, Miles

    2015-01-01

    We examined whether cells of the adaptive immune system retain the memory of psychosocial stress and thereby alter mood states and CNS function in the host. Lymphocytes from mice undergoing chronic social defeat stress or from unstressed control mice were isolated and adoptively transferred into naive lymphopenic Rag2−/− mice. Changes in affective behavior, hippocampal cell proliferation, microglial activation states, and blood cytokine levels were examined in reconstituted stress-naive mice....

  9. Chronic intestinal pseudo-obstruction due to lymphocytic intestinal leiomyositis: Case report and literature review

    OpenAIRE

    Uchida, Keiichi; Otake, Kohei; Inoue, Mikihiro; Koike, Yuhki; Matsushita, Kohei; Araki, Toshimitsu; Okita, Yoshiki; Tanaka, Koji; UCHIDA, KATSUNORI; Yodoya, Noriko; Iwamoto, Shotaro; Arai, Katsuhiro; Kusunoki, Masato

    2012-01-01

    Lymphocytic intestinal leiomyositis is a rare entity, which causes chronic intestinal pseudo-obstruction (CIPO) in children. We present the first case of a boy who had pure red cell anemia 1 year before onset. Prolonged ileus developed after gastroenteritis and the patient was diagnosed using a biopsy of the intestinal wall. Findings from the present case indicate that there are three important factors for accurate diagnosis: history of enteritis, positive serum smooth muscle antibody, and ly...

  10. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

    OpenAIRE

    Burger, Jan A.; Landau, Dan A.; Taylor-Weiner, Amaro; Bozic, Ivana; Zhang, Huidan; Sarosiek, Kristopher; Wang, Lili; Stewart, Chip; Fan, Jean; Hoellenriegel, Julia; Sivina, Mariela; Dubuc, Adrian M.; Fraser, Cameron; Han, Yulong; Li, Shuqiang

    2016-01-01

    Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300...

  11. Heightened BTK-dependent cell proliferation in unmutated chronic lymphocytic leukemia confers increased sensitivity to ibrutinib

    OpenAIRE

    Guo, Ailin; Lu, Pin; Galanina, Natalie; Nabhan, Chadi; Smith, Sonali M.; Coleman, Morton; Wang, Y. Lynn

    2015-01-01

    In chronic lymphocytic leukemia (CLL), patients with unmutated immunoglobulin heavy chain variable region gene (UM-CLL) have worse outcomes than mutated CLL (M-CLL) following chemotherapy or chemoimmunotherapy. However, in the era of BCR-targeted therapies, the adverse prognostic impact of unmutated IGHV seems to be diminishing, and there are clinical datasets showing unexpected improved responses in UM-CLL. We investigated the biological differences of BTK activity between these subgroups an...

  12. A critical appraisal of ibrutinib in the treatment of mantle cell lymphoma and chronic lymphocytic leukemia

    OpenAIRE

    Tucker DL; Rule SA

    2015-01-01

    David L Tucker, Simon A Rule Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, UK Abstract: Although chemo-immunotherapy remains at the forefront of first-line treatment for mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), small molecules, such as ibrutinib, are beginning to play a significant role, particularly in patients with multiply relapsed or chemotherapy-refractory disease and where toxicity is an overriding concern. Ibrutinib is a first-in-class, ...

  13. Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib - findings from an investigator initiated phase 2 study

    DEFF Research Database (Denmark)

    Niemann, Carsten U; Herman, Sarah E M; Maric, Irina;

    2016-01-01

    PURPOSE: Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of...... tumor cells from the microenvironment. While the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment. EXPERIMENTAL DESIGN: Patients received single...... agent ibrutinib on an investigator-initiated phase 2 trial. Serial blood and tissue samples were collected pre-treatment and during treatment. Changes in cytokine levels, cellular subsets and microenvironmental interactions were assessed. RESULTS: Serum levels of key chemokines and inflammatory...

  14. What Is Acute Lymphocytic Leukemia (ALL)?

    Science.gov (United States)

    ... White blood cells help the body fight infections. Lymphocytes These are the main cells that make up ... B cells) and T lymphocytes (T cells). B lymphocytes: B lymphocytes protect the body from invading germs ...

  15. Innate B cells: oxymoron or validated concept?

    OpenAIRE

    Ware, Carl F.; Chris Benedict

    2012-01-01

    B lymphocytes promote the initial innate interferon response to viral pathogens without the need for antigen receptor activation. B cell dependent IFN production requires the cytokine, lymphotoxin-β. The LTβ pathway is well known to regulate lymphoid organogenesis and homeostasis by differentiating stromal cells and macrophages. However, in response to viral pathogens these same B cell-regulated populations rapidly produce type 1 interferons. Thus, B cells act as innate effector cells via LTβ...

  16. E2A-Pbx1, the t(1;19) translocation protein of human pre-B-cell acute lymphocytic leukemia, causes acute myeloid leukemia in mice

    OpenAIRE

    Kamps, M P; Baltimore, D

    1993-01-01

    One-quarter of pediatric pre-B-cell leukemias contain the t(1;19) chromosomal translocation, which fuses 5' exons encoding the transactivation domain of the E2A transcription factor gene to 3' exons ecoding the putative DNA-binding region of the unusual homeobox gene, PBX1. To test the leukemic potential of this fused gene, a cDNA encoding its major protein product, p85E2A-Pbx1, was incorporated into a retrovirus construct and introduced into normal mouse marrow progenitors by infection. The ...

  17. Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia.

    Science.gov (United States)

    Del Principe, Maria Ilaria; Dal Bo, Michele; Bittolo, Tamara; Buccisano, Francesco; Rossi, Francesca Maria; Zucchetto, Antonella; Rossi, Davide; Bomben, Riccardo; Maurillo, Luca; Cefalo, Mariagiovanna; De Santis, Giovanna; Venditti, Adriano; Gaidano, Gianluca; Amadori, Sergio; de Fabritiis, Paolo; Gattei, Valter; Del Poeta, Giovanni

    2016-01-01

    In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (Pbax/bcl-2 was correlated with unmutated IGHV (Pbax/bcl-2 (Pbax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules. PMID:26565002

  18. Rituximab in Treating Patients Undergoing Donor Peripheral Blood Stem Cell Transplant for Relapsed or Refractory B-cell Lymphoma

    Science.gov (United States)

    2015-11-23

    B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  19. Adaptive capacities of lymphocytes in Techa riverside residents chronically exposed to radiation

    International Nuclear Information System (INIS)

    The micronuclear test was used to study cytogenetic effects in Techa riverside residents exposed to accidental irradiation (the study group) and residents of uncontaminated regions in the Southern Urals characterized by similar socio-economic status and health care standards (the control group). In the course of the study it was possible to assess the spontaneous level of damage to blood lymphocytes, the role played by the radiation factor in the induction of damage to blood lymphocytes, sensitivity of blood lymphocytes to acute irradiation, and their capacity for adaptive response. It has been shown that the baseline (pre-test) level of damage to lymphocytes observed in exposed residents does not differ significantly from the spontaneous level observed in residents of uncontaminated villages. Lympohocytes from exposed subjects have been noted to mainfest reduced radiosensitivity and capacity for adaptive response as compared to controls. A conclusion is drawn that the chronic radiation exposure factor makes a major contribution to the formation of radiosensitivity and adaptive response induction in exposed persons. (author)

  20. Therapeutic effects of stress-programmed lymphocytes transferred to chronically stressed mice.

    Science.gov (United States)

    Scheinert, Rachel B; Haeri, Mitra H; Lehmann, Michael L; Herkenham, Miles

    2016-10-01

    Our group has recently provided novel insights into a poorly understood component of intercommunication between the brain and the immune system by showing that psychological stress can modify lymphocytes in a manner that may boost resilience to psychological stress. To demonstrate the influence of the adaptive immune system on mood states, we previously showed that cells from lymph nodes of socially defeated mice, but not from unstressed mice, conferred anxiolytic and antidepressant-like effects and elevated hippocampal cell proliferation when transferred into naïve lymphopenic Rag2(-/-) mice. In the present study, we asked whether similar transfer could be anxiolytic and antidepressant when done in animals that had been rendered anxious and depressed by chronic psychological stress. First, we demonstrated that lymphopenic Rag2(-/-) mice and their wild-type C57BL/6 mouse counterparts had similar levels of affect normally. Second, we found that following chronic (14days) restraint stress, both groups displayed an anxious and depressive-like phenotype and decreased hippocampal cell proliferation. Third, we showed that behavior in the open field test and light/dark box was normalized in the restraint-stressed Rag2(-/-) mice following adoptive transfer of lymph node cells from green fluorescent protein (GFP) expressing donor mice previously exposed to chronic (14days) of social defeat stress. Cells transferred from unstressed donor mice had no effect on behavior. Immunolabeling of GFP+ cells confirmed that tissue engraftment had occurred at 14days after transfer. We found GFP+ lymphocytes in the spleen, lymph nodes, blood, choroid plexus, and meninges of the recipient Rag2(-/-) mice. The findings suggest that the adaptive immune system may play a key role in promoting recovery from chronic stress. The data support using lymphocytes as a novel therapeutic target for anxiety states. PMID:27109071

  1. Human Lyb-2 homolog CD72 is a marker for progenitor B-cell leukemias.

    Science.gov (United States)

    Schwarting, R; Castello, R; Moldenhauer, G; Pezzutto, A; von Hoegen, I; Ludwig, W D; Parnes, J R; Dörken, B

    1992-11-01

    S-HCL 2 is the prototype antibody of the recently defined CD72 cluster (human Lyb-2). Under nonreducing conditions, S-HCL 2 monoclonal antibody (mAb) precipitates a glycoprotein of 80-86 kDa. Under reducing conditions, a dimer of 43 and 39 kDa, with core proteins of 40 and 36 kDa, is precipitated. CD72 expression in normal and malignant tissues is different from expression of all other previously described human B-cell antigens. In peripheral blood and bone marrow, the antigen appears to be present on all B lymphocytes, with the exception of plasma cells. In tissue, immunohistochemical staining revealed positivity for all known B-cell compartments; however, pulpa macrophages of the spleen and von Kupffer cells exhibited distinct positivity for CD72 also. Among 83 malignant non-Hodgkin's lymphomas examined by immunohistochemistry (alkaline phosphatase anti-alkaline phosphatase technique), all 54 B-cell lymphomas, including precursor B-cell lymphomas, Burkitt's lymphomas, germinal center lymphomas, chronic lymphocytic leukemias, and hairy cell leukemias, were CD72 positive, but no T-cell lymphomas were. Flow cytometry study of more than 80 mainly acute leukemias (52 B-cell leukemias) showed reactivity with S-HCL 2 mAb over the full range of B-cell differentiation. In particular, very early B cells in cytoplasmic Ig (cIg)-negative, CD19-positive pre-pre-B-cell leukemias and hybrid leukemias (mixed myeloid and B-cell type) were consistently positive for CD72 on the cell surface. Therefore, CD72 may become an important marker for progenitor B-cell leukemias. PMID:1384316

  2. Evolution of B Cell Immunity

    OpenAIRE

    Parra, David; Takizawa, Fumio; Sunyer, J Oriol

    2013-01-01

    Two types of adaptive immune strategies are known to have evolved in vertebrates: the VLR-based system, which is present in jawless organisms and is mediated by VLRA and VLRB lymphocytes, and the BCR/TCR-based system, which is present in jawed species and is provided by B and T cell receptors expressed on B and T cells, respectively. Here we summarize features of B cells and their predecessors in the different animal phyla, focusing the review on B cells from jawed vertebrates. We point out t...

  3. The expression BIRC6 gene in patients with chronic lymphocytic leukemia – a preliminary study

    Directory of Open Access Journals (Sweden)

    Chomik Piotr

    2014-09-01

    Full Text Available The BIRC6 gene encodes the Bruce (Apollon protein. This belongs to the III class of Inhibitors of the Apoptosis Protein (IAP and demonstrates anti-apoptotic activity (binding, inhibiting and degrading the caspases. Moreover, the Bruce protein shows multilevel activities and additional functions. The Bruce protein is involved in the maintenance of cell viability, and it is also suggested that it plays an important role in cell proliferation and diversification. Many researchers have noticed elevated BIRC6 gene expression in cell lines of brain cancer and ovarian carcinoma, leukemia, breast cancer and even in colorectal cancer tissues. Resistance to chemotherapy-inducted apoptosis in cancers characterized by BIRC6 gene over-expression was also reported. The aim of the study was to assess the BIRC6 gene expression in peripheral blood lymphocytes of patients diagnosed with chronic lymphocytic leukemia.

  4. Veltuzumab, an anti-CD20 mAb for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and immune thrombocytopenic purpura.

    Science.gov (United States)

    Milani, Cannon; Castillo, Jorge

    2009-04-01

    Veltuzumab is a humanized, second-generation anti-CD20 mAb currently under development by Immunomedics Inc for the potential treatment of B-cell non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Licensee Nycomed is developing veltuzumab for the potential treatment of rheumatoid arthritis and immune thrombocytopenic purpura (ITP). Veltuzumab contains 90 to 95% human antibody sequences with identical antigen framework regions to epratuzumab (a humanized anti-CD22 mAb) and similar antigen-binding determinants to rituximab (chimeric, anti-CD20 mAb and the first-line treatment of aggressive and indolent NHL). In vitro studies have demonstrated that veltuzumab has enhanced binding avidities and a stronger effect on complement-dependent cytotoxicity compared with rituximab in selected cell lines. In dose-finding phase I/II clinical trials in patients with low-grade NHL, intravenous veltuzumab demonstrated a substantial rate of complete responses in concurrence with shorter and more tolerable infusions compared with rituximab. Currently there has been no evidence of an immune response to repeated administrations, and no serious adverse events related to veltuzumab treatment in patients with NHL. Veltuzumab is undergoing clinical trials using a low-dose subcutaneous formulation in patients with NHL, CLL and ITP. Prospective, randomized clinical trials are needed to clarify the role veltuzumab will play in a market where the therapy of B-cell lymphoproliferative disorders is dominated by rituximab. PMID:19330725

  5. Cytotoxic T-lymphocyte antigen 4 gene polymorphisms and susceptibility to chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Amir Houshang Mohammad Alizadeh; Mehrdad Hajilooi; Mitra Ranjbar; Farahnaz Fallahian; Seyed Mohsen Mousavi

    2006-01-01

    AIM: To assess the three polymorphism regions within cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene, a C/T base exchange in the promoter region-318 (CTLA-4 -318C/T), an A/G substitution in the exon 1 position 49 (CTLA-4 49A/G), a T/C substitution in 1172 (CTLA-4 -1172T/C) in patients with chronic hepatitis B.METHODS: Fifty-one patients with chronic hepatitis B virus infection and 150 healthy subjects were recruited sequentially as they presented to the hepatic clinic. Classification of chronic hepatitis B virus (HBV)-infected patients was as asymptomatic carrier state (26 patients) and chronic hepatitis B (25 patients). Genomic DNA was isolated from anti-coagulated peripheral blood Buffy coat using Miller's salting-out method. The presence of the CTLA-4 gene polymorphisms was determined using polymerase chain reaction amplification refractory mutation system (ARMS).RESULTS: We observed a significant association between -318 genotypes frequency (T+C-, T+C+, T-C+) and susceptibility to chronic hepatitis B (P=0.012,OR=0.49, 95%CI: 0.206-1.162). However, we did not observe a significant association for +49 genotype frequency (T+C+, T+C- T-C+) and -1172 genotype frequency (C+T+, T+C- C+T-) and state of disease.CONCLUSION: Our results suggest that CTLA-4 gene polymorphisms may partially be involved in the susceptibility to chronic hepatitis B.

  6. Persistent virus infection despite chronic cytotoxic T-lymphocyte activation in gamma interferon-deficient mice infected with lymphocytic choriomeningitis virus

    DEFF Research Database (Denmark)

    Bartholdy, C; Christensen, Jan Pravsgaard; Wodarz, D;

    2000-01-01

    The role of gamma interferon (IFN-gamma) in the permanent control of infection with a noncytopathic virus was studied by comparing immune responses in wild-type and IFN-gamma-deficient (IFN-gamma -/-) mice infected with a slowly invasive strain of lymphocytic choriomeningitis virus (LCMV Armstrong......). While wild-type mice rapidly cleared the infection, IFN-gamma -/- mice became chronically infected. Virus persistence in the latter mice did not reflect failure to generate cytotoxic T-lymphocyte (CTL) effectors, as an unimpaired primary CTL response was observed. Furthermore, while ex vivo CTL activity...

  7. Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia.

    Science.gov (United States)

    Opel, Daniela; Schnaiter, Andrea; Dodier, Dagmar; Jovanovic, Marjana; Gerhardinger, Andreas; Idler, Irina; Mertens, Daniel; Bullinger, Lars; Stilgenbauer, Stephan; Fulda, Simone

    2015-12-15

    Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-κB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-κB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)α, as zVAD.fmk, necrostatin-1 or TNFα-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups. PMID:26096065

  8. Efficacy of phosphatidylinositol-3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Göckeritz, Elisa; Kerwien, Susan; Baumann, Michael; Wigger, Marion; Vondey, Verena; Neumann, Lars; Landwehr, Thomas; Wendtner, Clemens M; Klein, Christian; Liu, Ningshu; Hallek, Michael; Frenzel, Lukas P; Krause, Günter

    2015-11-01

    Pharmacological inhibition of phosphatiylinositide-3-kinase (PI3K)-mediated signaling holds great promise for treating chronic lymphocytic leukemia (CLL). Therefore we assessed three structurally related PI3K inhibitors targeting the PI3K-δ isoform for their ability to inhibit the survival of freshly isolated CLL cells. The purely PI3K-δ-selective inhibitor idelalisib was compared to copanlisib (BAY 80-6946) and duvelisib (IPI-145), with isoform target profiles that additionally include PI3K-α or PI3K-γ, respectively. The concentrations leading to half-maximal reduction of the survival of CLL cells were more than ten-fold lower for copanlisib than for idelalisib and duvelisib. At concentrations reflecting the biological availability of the different inhibitors, high levels of apoptotic response among CLL samples were attained more consistently with copanlisib than with idelalisib. Copanlisib selectively reduced the survival of CLL cells compared to T cells and to B cells from healthy donors. In addition copanlisib and duvelisib impaired the migration of CLL cells towards CXCL12 to a greater extent than equimolar idelalisib. Similarly copanlisib and duvelisib reduced the survival of CLL cells in co-cultures with the bone marrow stroma cell line HS-5 more strongly than idelalisib. Survival inhibition by copanlisib and idelalisib was enhanced by the monoclonal CD20 antibodies rituximab and obinutuzumab (GA101), while antibody-dependent cellular cytotoxicity mediated by alemtuzumab and peripheral blood mononuclear cells was not substantially impaired by both PI3K inhibitors for the CLL-derived JVM-3 cell line as target cells. Taken together, targeting the α- and δ- p110 isoforms with copanlisib may be a useful strategy for the treatment of CLL and warrants further clinical investigation. PMID:25912635

  9. Separate developmental programs for HLA-A and -B cell surface expression during differentiation from embryonic stem cells to lymphocytes, adipocytes and osteoblasts.

    Directory of Open Access Journals (Sweden)

    Hardee J Sabir

    Full Text Available A major problem of allogeneic stem cell therapy is immunologically mediated graft rejection. HLA class I A, B, and Cw antigens are crucial factors, but little is known of their respective expression on stem cells and their progenies. We have recently shown that locus-specific expression (HLA-A, but not -B is seen on some multipotent stem cells, and this raises the question how this is in other stem cells and how it changes during differentiation. In this study, we have used flow cytometry to investigate the cell surface expression of HLA-A and -B on human embryonic stem cells (hESC, human hematopoietic stem cells (hHSC, human mesenchymal stem cells (hMSC and their fully-differentiated progenies such as lymphocytes, adipocytes and osteoblasts. hESC showed extremely low levels of HLA-A and no -B. In contrast, multipotent hMSC and hHSC generally expressed higher levels of HLA-A and clearly HLA-B though at lower levels. IFNγ induced HLA-A to very high levels on both hESC and hMSC and HLA-B on hMSC. Even on hESC, a low expression of HLA-B was achieved. Differentiation of hMSC to osteoblasts downregulated HLA-A expression (P = 0.017. Interestingly HLA class I on T lymphocytes differed between different compartments. Mature bone marrow CD4(+ and CD8(+ T cells expressed similar HLA-A and -B levels as hHSC, while in the peripheral blood they expressed significantly more HLA-B7 (P = 0.0007 and P = 0.004 for CD4(+ and CD8(+ T cells, respectively. Thus different HLA loci are differentially regulated during differentiation of stem cells.

  10. Genetically Engineered Lymphocyte Therapy in Treating Patients With Lymphoma That is Resistant or Refractory to Chemotherapy

    Science.gov (United States)

    2015-09-27

    Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  11. Competitive Transfer of αCD19-TCRz-CD28 and αCD19-TCRz-CD137 CAR-T Cells for B-cell Leukemia/Lymphoma

    Science.gov (United States)

    2016-04-25

    Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  12. Lymphocytic Bronchiolitis as Presenting Disorder in an Undiagnosed Adult Patient with Chronic Granulomatous Disease

    Directory of Open Access Journals (Sweden)

    Payam Tabarsi

    2007-12-01

    Full Text Available Chronic Granulomatous Disease (CGD is a rare primary immunodeficiency disease. Although the most affected patients are diagnosed in childhood, there are several reports of the disease presenting in adult patients. Here we present a 40 years old man who was admitted in hospital due to respiratory symptoms and ground glass pattern in high resolution computed tomography of lung. Open lung biopsy revealed lymphocytic bronchiolitis. Because of past medical history of granulomatous lesion in lung and recurrent abscesses of skin and soft tissue, NBT test was conducted which its result revealed that the disorder was compatible with CGD and then it was confirmed by fluorescent cytometry.

  13. Peripheral T-Cell lymphoma manifested as gingival enlargement in a patient with chronic lymphocytic leukemia

    OpenAIRE

    Buddula, Aravind; Assad, Daniel

    2011-01-01

    Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults and is associated with increased risk of malignancy. T-cell lymphoma associated with CLL has never been reported. The case report presents a unique case of peripheral T-cell lymphoma on the gingiva of a patient with CLL. A 66-year-old man with a history of CLL was referred to the Mayo Clinic, Department of Dental Specialties, for evaluation of swelling in the upper left posterior sextant. An intraoral examination...

  14. Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

    OpenAIRE

    Del Principe, Maria Ilaria; Bo, Michele Dal; Bittolo, Tamara; Buccisano, Francesco; Rossi, Francesca Maria; Zucchetto, Antonella; Rossi, Davide; Bomben, Riccardo; Maurillo, Luca; Cefalo, Mariagiovanna; De Santis, Giovanna; Venditti, Adriano; Gaidano, Gianluca; Amadori, Sergio; de Fabritiis, Paolo

    2016-01-01

    In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with we...

  15. p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia.

    OpenAIRE

    Gaidano, G; Ballerini, P.; Gong, J. Z.; Inghirami, G.; Neri, A.; Newcomb, E W; Magrath, I. T.; Knowles, D M; Dalla-Favera, R

    1991-01-01

    We have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies, including acute lymphoblastic leukemia, the major subtypes of non-Hodgkin lymphoma, and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direct sequencing of PCR-amplified fragments. Mutations were found associated with (i) Burkitt lymphoma (9/27 biopsies; 17/27 cell l...

  16. B Cells and Platelets Harbor Prion Infectivity in the Blood of Deer Infected with Chronic Wasting Disease▿ †

    OpenAIRE

    Candace K Mathiason; Hayes-Klug, Jeanette; Hays, Sheila A.; Powers, Jenny; Osborn, David A.; Dahmes, Sallie J.; Miller, Karl V.; Warren, Robert J., II; Mason, Gary L.; Telling, Glenn C.; Young, Alan J; Hoover, Edward A.

    2010-01-01

    Substantial evidence for prion transmission via blood transfusion exists for many transmissible spongiform encephalopathy (TSE) diseases. Determining which cell phenotype(s) is responsible for trafficking infectivity has important implications for our understanding of the dissemination of prions, as well as their detection and elimination from blood products. We used bioassay studies of native white-tailed deer and transgenic cervidized mice to determine (i) if chronic wasting disease (CWD) b...

  17. Proliferative index and expression of CD38, Zap-70, and CD25 in different lymphoid compartments of chronic lymphocytic leukemia patients

    Directory of Open Access Journals (Sweden)

    Olga Khoudoleeva

    2011-01-01

    Full Text Available Olga Khoudoleeva1 Eugeny Gretsov1 Natasha Barteneva2,3 Ivan Vorobjev11Hematology Scientific Center, Russian Academy of Medical Sciences, Moscow, Russia; 2Immune Disease Institute and Program in Cellular and Molecular Biology, Children Hospital of Boston, Boston, MA, USA; 3Department of Pathology, Harvard Medical School, Boston, MA, USAAbstract: Recent studies of chronic lymphocytic leukemia (CLL show that malignant B cells proliferate at a rate similar to normal B lymphocytes. This is in apparent contradiction to the very low proliferation rate found in blood specimens from CLL patients. To address this problem, we studied the expression of Ki-67, CD38, CD25, and Zap-70 in different compartments of CLL patients. Using triple-color flow cytometry, we examined the expression of CD38, CD25, Zap-70, and Ki-67 antigens in the peripheral blood, bone marrow, spleen, and lymph nodes biopsies of patients with CLL, splenic marginal zone lymphoma (SMZL, and nonmalignant diseases. In parallel probes of lymph node/spleen biopsies and blood taken from one and the same patient, Ki-67 expression was 17 times higher. Among the whole cohort, we also found significantly higher Ki-67 expression in biopsies from lymph nodes and spleen (4.95% ± 0.55%, compared with bone marrow (1.88% ± 0.32% and peripheral blood (0.45% ± 0.03%, P < 0.01. In CLL patients, there are statistically significant correlations between the expression of CD38 and Ki-67 in bone marrow (P ≤ 0.01, Zap-70 and Ki-67 in blood (P ≤ 0.01, and Zap-70 and CD38 in blood (P ≤ 0.01. Patients with SMZL also showed a significant correlation between Ki-67 and CD38 expression (P ≤ 0.01 and between Ki-67 and Zap-70 expression (P ≤ 0.01. We show for the first time that proliferation of B lymphocytes in CLL patients is associated primarily with lymph nodes/spleen. Malignant cells in the blood represent only a subpopulation of nonproliferating and less-activated B cells in this disease

  18. The possible role of radiotherapy in chronic lymphocytic leukaemia: a critical review

    International Nuclear Information System (INIS)

    The few clinical studies which have utilized irradiation as a treatment modality for chronic lymphocytic leukaemia (CLL) during the last two decades have led to rather conflicting and sometimes disappointing results. Because new data are emerging (stratification of CLL in various subgroups, better understanding of the role of the normal T-cell subsets, better knowledge of the interaction between irradiation and haematopoiesis, and of the radiosensitivity of the various lymphocyte subpopulations), one can reconsider the possible role radiotherapy, particularly splenic irradiation, can play as an alternative treatment to chemotherapy for CLL. Haematological toxicity is still limiting the use of TBI. The spleen irradiation avoids this drawback. Recent data suggest that this splenic irradiation could be efficient by means of several mechanisms; the successive destruction, fraction after fraction, of the part of the malignant lymphocyte clone present in the spleen is likely to be the main therapeutic explanation, with the knowledge that the lower the differentiation of the malignant clone, the more efficacious the irradiation. But in parallel, the destruction of the large subset of T-suppressors which is constantly present in the spleen may account for the improvement of the peripheral blood count after splenic irradiation, and possibly for a direct effect towards the malignant clone. With respect to these new data, splenic irradiation clearly needs further clinical evaluation in the treatment of CLL. (Auth.)

  19. The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia

    OpenAIRE

    Xargay-Torrent, Sçilvia; López Guerra, Mónica; Rosich, Laia; Montraveta, Arnau; Roldán, Jocabed; Rodríguez, Vanina; Villamor Casas, Neus; Aymerich, Marta; Lagisetti, Chandraiah; Webb, Thomas R.; López Otín, Carlos; Campo, Elías; Colomer, Dolors

    2015-01-01

    Mutations or deregulated expression of the components of the spliceosome can influence the splicing pattern of several genes and contribute to the development of tumors. In this context, we report that the spliceosome modulator sudemycin induces selective cytotoxicity in primary chronic lymphocytic leukemia (CLL) cells when compared with healthy lymphocytes and tumor cells from other B-lymphoid malignancies, with a slight bias for CLL cases with mutations in spliceosome-RNA processing machine...

  20. Separate Developmental Programs for HLA-A and -B Cell Surface Expression during Differentiation from Embryonic Stem Cells to Lymphocytes, Adipocytes and Osteoblasts

    DEFF Research Database (Denmark)

    Sabir, Hardee J; Nehlin, Jan O; Qanie, Diyako;

    2013-01-01

    A major problem of allogeneic stem cell therapy is immunologically mediated graft rejection. HLA class I A, B, and Cw antigens are crucial factors, but little is known of their respective expression on stem cells and their progenies. We have recently shown that locus-specific expression (HLA-A, but...... not -B) is seen on some multipotent stem cells, and this raises the question how this is in other stem cells and how it changes during differentiation. In this study, we have used flow cytometry to investigate the cell surface expression of HLA-A and -B on human embryonic stem cells (hESC), human...... hematopoietic stem cells (hHSC), human mesenchymal stem cells (hMSC) and their fully-differentiated progenies such as lymphocytes, adipocytes and osteoblasts. hESC showed extremely low levels of HLA-A and no -B. In contrast, multipotent hMSC and hHSC generally expressed higher levels of HLA-A and clearly HLA...

  1. Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

    Science.gov (United States)

    Del Principe, Maria Ilaria; Bo, Michele Dal; Bittolo, Tamara; Buccisano, Francesco; Rossi, Francesca Maria; Zucchetto, Antonella; Rossi, Davide; Bomben, Riccardo; Maurillo, Luca; Cefalo, Mariagiovanna; De Santis, Giovanna; Venditti, Adriano; Gaidano, Gianluca; Amadori, Sergio; de Fabritiis, Paolo; Gattei, Valter; Del Poeta, Giovanni

    2016-01-01

    In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (P<0.0001). On the other hand, lower bax/bcl-2 was correlated with unmutated IGHV (P<0.0001), mutated NOTCH1 (P<0.0001) and mutated TP53 (P=0.00007). Significant shorter progression-free survival and overall survival were observed in patients with lower bax/bcl-2 (P<0.0001). Moreover, within IGHV unmutated (168 patients) and TP53 mutated (37 patients) subgroups, higher bax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules. PMID:26565002

  2. Hepatitis C virus - associated B cell non-Hodgkin's lymphoma

    Science.gov (United States)

    Mihăilă, Romeo-Gabriel

    2016-01-01

    The hepatitis C virus (HCV) infected patients are prone to develop bone marrow or various tissue infiltrates with monoclonal B cells, monoclonal B lymphocytosis or different types of B cell non-Hodgkin’s lymphoma (BCNHL), of which the most common are splenic marginal zone BCNHL, diffuse large BCNHL and follicular lymphoma. The association between chronic HCV infection and non Hodgkin’s lymphoma has been observed especially in areas with high prevalence of this viral infection. Outside the limitations of some studies that have been conducted, there are also geographic, environmental, and genetic factors that contribute to the epidemiological differences. Various microenvironmental signals, such as cytokines, viral antigenic external stimulation of lymphocyte receptors by HCV antigens, and intercellular interactions contribute to B cell proliferation. HCV lymphotropism and chronic antigenic stimulation are involved in B-lymphocyte expansion, as mixted cryoglobulinemia or monoclonal gammopathy of undetermined significance, which can progress to BCNHL. HCV replication in B lymphocytes has oncogenic effect mediated by intracellular HCV proteins. It is also involved in an important induction of reactive oxygen species that can lead to permanent B lymphocyte damage, as DNA mutations, after binding to surface B-cell receptors. Post-transplant lymphoproliferative disorder could appear and it has a multiclonal potentiality that may develop into different types of lymphomas. The hematopoietic stem cell transplant made for lymphoma in HCV-infected patients can increase the risk of earlier progression to liver fibrosis and cirrhosis. HCV infected patients with indolent BCNHL who receive antiviral therapy can be potentially cured. Viral clearance was related to lymphoma response, fact that highlights the probable involvement of HCV in lymphomagenesis. Direct acting antiviral drugs could be a solution for the patients who did not tolerate or respond to interferon, as they

  3. Atypical Lymphocytes and Cellular Cannibalism: A Phenomenon, First of its Kind to be Discovered in Chronic Periapical Lesions

    Science.gov (United States)

    Patil, Kaustubh P.; Nayyar, Abhishek Singh; Sasane, Rutuparna S

    2016-01-01

    Introduction Lymphocytes are often termed to be isomorphic, having a monotonous light microscopic appearance. Morphological aspects of lymphocytes in tissue sections thereby are not routinely taken notice of as their morphology seems to vary only in case of lymphoid malignancies, hematological malignancies apart from certain viral infections. Atypical lymphocytes are the lymphocytes with unusual shape, size or overall structure. These are more commonly known as reactive lymphocytes. The unusual histomorphological feature of these cells include larger size than normal lymphocytes; in some cells the size exceeds even 30 microns. The large size is the result of antigenic stimulation of the cell. Alongwith these, the other rare feature which is recently coming under light is “Cellular Cannibalism” which is defined as a large cell enclosing a slightly smaller one within its cytoplasm. Previously, this feature was noted only in cases of malignant tumors. Aim The objectives of this study were to determine the proportion of atypical lymphocytes in chronic periapical granulomas and cysts; to determine the proportionate cellular cannibalism in these periapical lesions. Materials and Methods This was a descriptive, observational study conducted in the Department of Oral Medicine and Radiology and Oral Pathology and Microbiology. Haematoxylin and eosin stained 30 slides of chronic periapical granulomas and 20 slides of cysts reported in the year 2014-15 and the clinical proformas of the patients were retrieved from the files of the Department of Oral Medicine and Radiology and Oral Pathology and Microbiology. These slides were evaluated by 3 experts from the specialization of Oral Pathology and Microbiology to determine the presence of atypical lymphocytes and cellular cannibalism under high power magnification (400X). Results Out of the 30 slides of chronic periapical granulomas, about 12 slides (40%) revealed presence of atypical lymphocytes. In case of slides of chronic

  4. Chronic Δ(9)-Tetrahydrocannabinol Administration Reduces IgE(+)B Cells but Unlikely Enhances Pathogenic SIVmac251 Infection in Male Rhesus Macaques of Chinese Origin.

    Science.gov (United States)

    Wei, Qiang; Liu, Li; Cong, Zhe; Wu, Xiaoxian; Wang, Hui; Qin, Chuan; Molina, Patricia; Chen, Zhiwei

    2016-09-01

    Delta9-tetrahydrocannabinol (Δ(9)-THC) is the major psychoactive component of the cannabis plant. Δ(9)-THC has been used in the active ingredient of Marinol as an appetite stimulant for AIDS patients. Its impact on progression of HIV-1 infection, however, remains debatable. Previous studies indicated that Δ(9)-THC administration enhanced HIV-1 infection in huPBL-SCID mice but seemingly decreased early mortality in simian immunodeficiency virus (SIV) infected male Indian-derived rhesus macaques. Here, we determine the chronic effect of Δ(9)-THC administration using 0.32 mg/kg or placebo (PBO), i.m., twice daily for 428 days on SIVmac251 infected male Chinese-derived rhesus macaques. Sixteen animals were divided into four study groups: Δ(9)-THC(+)SIV(+), Δ(9)-THC(+)SIV(-), PBO/SIV(+) and PBO/SIV(-) (n = 4/group). One-month after daily Δ(9)-THC or PBO administrations, macaques in groups one and three were challenged intravenously with pathogenic SIVmac251/CNS, which was isolated from the brain of a Chinese macaque with end-staged neuroAIDS. No significant differences in peak and steady state plasma viral loads were seen between Δ(9)-THC(+)SIV(+) and PBO/SIV(+) macaques. Regardless of Δ(9)-THC, all infected macaques displayed significant drop of CD4/CD8 T cell ratio, loss of CD4(+) T cells and higher persistent levels of Ki67(+)CD8(+) T cells compared with uninfected animals. Moreover, long-term Δ(9)-THC treatment reduced significantly the frequency of circulating IgE(+)B cells. Only one Δ(9)-THC(+)SIV(+) macaque died of simian AIDS with paralyzed limbs compared with two deaths in the PBO/SIV(+) group during the study period. These findings indicate that chronic Δ(9)-THC administration resulted in reduction of IgE(+)B cells, yet it unlikely enhanced pathogenic SIVmac251/CNS infection in male Rhesus macaques of Chinese origin. PMID:27109234

  5. Subclass of individual IgA-secreting human lymphocytes. Investigation of in vivo pneumococcal polysaccharide-induced and in vitro mitogen-induced blood B cells by monolayer plaque-forming cell assays

    DEFF Research Database (Denmark)

    Heilmann, C; Barington, T; Sigsgaard, T

    1988-01-01

    producing cells was found among IgA anti-pneumococcal polysaccharide-secreting cells. It was thus confirmed that IgA1 is the predominant subclass of blood IgA-secreting cells in general. However, the high percentage of IgA2-secreting cells found after vaccination with pneumococcal polysaccharides suggests......The subclass of individual human IgA B cells was investigated by means of monolayer plaque-forming cell assays permitting analysis of all IgA-secreting cells as well as of cells secreting IgA anti-pneumococcal polysaccharide antibody. Center cells were examined by indirect immunofluorescence...... staining with mouse mAb against either of the two IgA subclasses as primary antibodies and FITC-conjugated rabbit anti-mouse Ig as the second antibody. Blood lymphocytes spontaneously secreting IgA (mean 399/10(6) mononuclear cells) produced mainly IgA1 (73%). A similar distribution of subclasses was...

  6. Epigenetic Control of B Cell Development and B-Cell-Related Immune Disorders.

    Science.gov (United States)

    Bao, Yan; Cao, Xuetao

    2016-06-01

    B lymphocytes are generally recognized as the essential component of humoral immunity and also a regulator of innate immunity. The development of B cells is precisely regulated by a variety of factors via different mechanisms, including cytokine/cytokine receptors, signal transduction molecules, and transcription factors. Recent findings suggest that epigenetic factors, such as DNA methylation, histone modification, and non-coding RNA, play critical roles in establishing B cell lineage-specific gene expression profiles to define and sustain B cell identity and function. Epigenetic modifications are also sensitive to external stimuli and might bridge genetic and environmental factors in the pathogenesis or control of B-cell-related immune disorders, such as autoimmune diseases, lymphoma, and leukemia. Better understanding of the epigenetic mechanisms for regulating B cell development and involving B cell abnormal differentiation and function will shed light on the design of new therapeutic approaches to B-cell-related diseases, and potential candidates of epigenetic modulators may be identified to target epigenetic pathways to prevent or treat B cell disorders. We summarize the relevance of epigenetic marks and landscapes in the stages of B cell development, discuss the interaction of the transcriptional networks and epigenetic changes, and review the involvement of epigenetic risk in the pathogenesis of B-cell-related diseases. Understanding how specific epigenetic alterations contribute to the development of B-cell-related autoimmunity and malignancies is instrumental to control B cell disorders. PMID:26066671

  7. In vitro regulation of immunoglobulin synthesis after marrow transplantation. I. T-cell and B-cell deficiencies in patients with and without chronic graft-versus-host disease

    International Nuclear Information System (INIS)

    Twenty-four patients with aplastic anemia or acute leukemia were treated by marrow grafts from HLA-identical donors after conditioning with high doses of cyclophosphamide and/or today body irradiation. They were studied between 4 and 63 mo (median 14.2) after transplantation. Seventeen patients had chronic graft-versus-host disease (C-GVHD) and 7 were healthy. They were studied for defects in their T- and B-cell function using and indirect hemolytic plaque assay for Ig production after 6 days of culture in the presence of pokeweek mitogen. T or B cells from the patients with or without C-GVHD were cocultured with T or B cells from their HLA-identical marrow donors or unrelated normal controls. Intrinsic B-cell defects, lack of helper T-cell activity, and suppressor T-cell activity were more frequently found in patients with C-GVHD than in healthy patients. Fifteen of the 17 patients with C-GVHD showed on or more defects in their T-and B-cell function compared to only 3 of the 7 patients without C-GVHD. None of the healthy controls, including the marrow donors, showed defects in their T- and B-cell functions. These in vitro findings may be helpful in assessing the process of immune reconstitution and the immunologic aberration found after human marrow transplantation

  8. Association of Helicobacter pylori and iNOS Production by Macrophages and Lymphocytes in the Gastric Mucosa in Chronic Gastritis

    OpenAIRE

    Cherdantseva, Lilia A.; Potapova, Oksana V.; Tatyana V. Sharkova; Belyaeva, Yana Yu.; Shkurupiy, Vyacheslav A.

    2014-01-01

    Helicobacter pylori is one of the most common causes of chronic gastritis. With the development of the disease cellular inflammatory infiltrates composed of lymphocytes, plasma cells, and macrophages are formed in epithelium and lamina propria of the stomach. These cells are capable of secreting a number of active substances, including inducible nitric oxide synthase (iNOS). We examined the relationship between H. pylori and secretion of iNOS by cells of inflammatory infiltrates in chronic ga...

  9. Immunological effects of donor lymphocyte infusion in patients with chronic myelogenous leukemia relapsing after bone marrow transplantation

    Directory of Open Access Journals (Sweden)

    Castro F.A.

    2004-01-01

    Full Text Available Allogeneic bone marrow transplantation (alloBMT is the only curative therapy for chronic myelogenous leukemia (CML. This success is explained by the delivery of high doses of antineoplastic agents followed by the rescue of marrow function and the induction of graft-versus-leukemia reaction mediated by allogeneic lymphocytes against host tumor cells. This reaction can also be induced by donor lymphocyte infusion (DLI producing remission in most patients with CML who relapse after alloBMT. The immunological mechanisms involved in DLI therapy are poorly understood. We studied five CML patients in the chronic phase, who received DLI after relapsing from an HLA-identical BMT. Using flow cytometry we evaluated cellular activation and apoptosis, NK cytotoxicity, lymphocytes producing cytokines (IL-2, IL-4 and IFN-gamma, and unstimulated (in vivo lymphocyte proliferation. In three CML patients who achieved hematological and/or cytogenetic remission after DLI we observed an increase of the percent of activation markers on T and NK cells (CD3/DR, CD3/CD25 and CD56/DR, of lymphocytes producing IL-2 and IFN-gamma, of NK activity, and of in vivo lymphocyte proliferation. These changes were not observed consistently in two of the five patients who did not achieve complete remission with DLI. The percent of apoptotic markers (Fas, FasL and Bcl-2 on lymphocytes and CD34-positive cells did not change after DLI throughout the different study periods. Taken together, these preliminary results suggest that the therapeutic effect of DLI in the chronic phase of CML is mediated by classic cytotoxic and proliferative events involving T and NK cells but not by the Fas pathway of apoptosis.

  10. Primary cutaneous follicle center lymphoma in the setting of chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    S Konda

    2011-01-01

    Full Text Available Primary cutaneous malignancies arising in association with chronic lymphocytic leukemia (CLL are notable for their atypical clinical and histological presentation. We report a 69-year-old man with a 17-year history of CLL who presented for evaluation of a well-defined red to violaceous nodule with a central depressed scar on the left lower extremity. Microscopic examination of a punch biopsy revealed an infiltrate of predominantly small lymphocytes with scattered large, atypical epithelioid cells. Immunohistochemical stains revealed diffuse positive staining of the lesional cells with CD20+ and bcl-6+ and focal positive staining with bcl-2+ (negative CD10 and CD23, findings which, in conjunction with the histology, were most compatible with a diagnosis of primary cutaneous follicle center lymphoma (PCFCL. A review of the clinical charts revealed several prior biopsies with varied diagnoses. In light of the most recent biopsy findings, all previous biopsies were re-reviewed and interpreted as PCFCL arising in the setting of CLL. Features contributing to the diagnostic conundrum in this case included an atypical clinical and histological presentation, lack of pertinent clinical history and multiple presentations at different institutions.

  11. Chronic lymphocytic leukemia and myeloproliferative neoplasms concurrently diagnosed: clinical and biological characteristics.

    Science.gov (United States)

    Todisco, Gabriele; Manshouri, Taghi; Verstovsek, Srdan; Masarova, Lucia; Pierce, Sherry A; Keating, Michael J; Estrov, Zeev

    2016-05-01

    Chronic lymphocytic leukemia (CLL) and myeloproliferative neoplasms (MPN) may occur concomitantly. However, little is known about the pathobiological characteristics and interaction between the neoplastic clones in these rare cases of coinciding malignancies. We retrospectively examined the clinical and biological characteristics of 13 patients with concomitant CLL and MPN--eight primary myelofibrosis (PMF), three essential thrombocytosis (ET), and two polycythemia vera (PV)--who presented to our institution between 1998 and 2014, and tested all patients for MPN-specific aberrations, such as JAK2, MPL and CALR mutations. Along with epidemiological and molecular characterization of this rare condition, we found that JAK2 mutation can be detected 9 years prior to PMF diagnosis, suggesting that PMF clinical phenotype may require several years to develop and CLL/MPN clinical co-occurrence might be sustained by common molecular events. Some features of these patients suggest that pathobiologies of these diseases might be intertwined. PMID:26402369

  12. Biochemical and immunologic heterogeneity of Ia glycoproteins isolated from a chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Ia glycoproteins have been isolated from human chronic lymphocytic leukemic cells (CLL) by Lens culinaris chromatography and by filtration on ACA-34 Ultrogel. Ia antigenic activity, measured by inhibition of the cellular radioimmunoassay, was separated by gel filtration into 2 fractions, peak I and II. Monoclonal antibodies, produced against peak II glycoproteins, appear to recognize different antigenic determinants of Ia molecules. Monoclonal antibody 18a4 reacted with Ia molecules of peaks I and II, whereas monoclonal antibodies 18c2 and 18d5 reacted almost exclusively with peak II molecules both in the cellular radioimmunoassay and by immunoprecipitation. In addition to antigenic differences, minor variations in the apparent m.w. of the Ia polypeptide chains were observed between peaks I and II. These results indicate the existence of antigenically distinct subsets of Ia molecules that are separated by gel filtration

  13. Complementary and alternative medicine use in patients with chronic lymphocytic leukemia: an Italian multicentric survey.

    Science.gov (United States)

    D'Arena, Giovanni; Laurenti, Luca; Coscia, Marta; Cortelezzi, Agostino; Chiarenza, Annalisa; Pozzato, Gabriele; Vigliotti, Maria Luigia; Nunziata, Giuseppe; Fragasso, Alberto; Villa, Maria Rosaria; Grossi, Alberto; Selleri, Carmine; Deaglio, Silvia; La Sala, Antonio; Del Poeta, Giovanni; Simeon, Vittorio; Aliberti, Luig; De Martino, Laura; Giudice, Aldo; Musto, Pellegrino; De Feo, Vincenzo

    2014-04-01

    Complementary and alternative medicine (CAM) is common in patients with cancer and its use is steadily increasing over time. We performed a multicenter survey in which the use of CAM in 442 Italian patients with chronic lymphocytic leukemia (CLL), the commonest form of leukemia in Western countries, was assessed. Data were collected by means of a face-to-face standardized questionnaire with several items. Mean age was 69 years; 258 patients (58%) were male and 184 (42%) female. Seventy-three patients (16.5%) were found to be CAM users. The most common CAM therapies were green tea, aloe formulations and high dose vitamins. Predictors of CAM use were female gender, younger age, higher education level, internet availability and newspaper reading. The reasons for CAM popularity among these patients are complex. Given the number of patients combining therapy with CAM and its possible drug interactions, doctor interest as well as patient education about CAM should be improved. PMID:23829282

  14. The influence of pregnancy on the development of autoimmunity in chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Jønsson, Viggo; Bock, Johannes E; Hilden, Jørgen;

    2006-01-01

    To examine whether pregnancy influences the development of autoimmunity in chronic lymphocytic leukemia (CLL), we studied 591 consecutive CLL patients (202 post-menopausal women and 389 men). The mean observation time for all patients was 3.8 years, corresponding to approximately 2200 person...... men. In female CLL patients, the frequency of autoimmunity and the number of pregnancies and the number of partners were strongly correlated. Each of the major autoimmune types approximately doubled in frequency for each additional pregnancy. The impact of pregnancy on expressed autoimmunity increased...... with each additional sexual partner (the odds of autoimmunity increased 11 times with each long-term sexual partner). The average numbers of pregnancies in female CLL patients with and without autoimmunity were 4.92 and 2.24, respectively (P < 0.001). Coombs' positive autoimmune anemia, a gastric ulcer...

  15. Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia

    Science.gov (United States)

    Blunt, Matthew D.; Steele, Andrew J.

    2015-01-01

    PI3Kδ inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL). However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms. PMID:26500849

  16. Evolving Strategies for the Treatment of Chronic Lymphocytic Leukemia in the Upfront Setting.

    Science.gov (United States)

    Bachow, Spencer H; Lamanna, Nicole

    2016-02-01

    Chronic lymphocytic leukemia (CLL) is a disease of marked clinical heterogeneity, and while some patients have a normal life expectancy, others develop rapidly progressive disease shortly after diagnosis. The current standard for upfront treatment of CLL is chemoimmunotherapy for younger fit patients, FCR (fludarabine, cyclophosphamide, and rituximab) being the prototype. For older patients, BR (bendamustine and rituximab) exhibits excellent activity with decreased toxicity. For the frailest patients, CD20 monoclonal antibodies with or without chlorambucil have proven to be efficacious. The novel oral kinase inhibitors ibrutinib and idelalisib are FDA-approved in the relapsed/refractory setting, and ibrutinib is approved upfront for those with del(17p). These drugs have produced long-term durable responses in the relapsed/refractory setting, and studies are underway using these as single agent upfront or in combination with both chemotherapy and monoclonal antibodies. Here, we review standard upfront therapies and new agents and combinations that are on the horizon for CLL. PMID:26951237

  17. Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia

    Directory of Open Access Journals (Sweden)

    Matthew D. Blunt

    2015-01-01

    Full Text Available PI3Kδ inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL. However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms.

  18. Pharmacotherapeutic Management of Chronic Lymphocytic Leukaemia in Patients with Comorbidities: New Agents, New Hope.

    Science.gov (United States)

    Goede, Valentin; Hallek, Michael

    2015-11-01

    Chronic lymphocytic leukaemia (CLL) is mostly considered a disease of the elderly. As such, many patients present with comorbidities. Several scores allow for a qualitative and quantitative assessment of comorbidity in patients with CLL. Although our knowledge about the impact of comorbidity on outcomes in patients with CLL is still incomplete, it is becoming increasingly apparent that comorbidities could negatively interfere with CLL treatment. Recently, a number of new agents have been approved for use in patients with previously untreated CLL and comorbidities (i.e. obinutuzumab, ofatumumab), as well as in patients with previously treated or high-risk CLL (i.e. idelalisib, ibrutinib). This review discusses the role of comorbidity in patients with CLL, together with the changing treatment landscape for CLL in this patient population. PMID:26446155

  19. An unusual case of composite lymphoma involving chronic lymphocytic leukemia follicular lymphoma and Hodgkin disease.

    Science.gov (United States)

    Copur, M Sitki; Ledakis, Peter; Novinski, Daniel; Fu, Kai; Hutchins, Mark; Frankforter, Scot; Mleczko, Kris; Sanger, Warren G; Chan, Wing C

    2004-05-01

    Composite lymphomas constitute the presence of two different types of non-Hodgkin lymphoma or Hodgkin and non-Hodgkin lymphoma at the same anatomic site. We report an unusual case of a 73-year-old woman who initially presented with a composite lymphoma of chronic lymphocytic leukemia (CLL) and follicular lymphoma. After 5 years of follow-up and intermittent treatment, she developed Hodgkin disease with diffuse liver involvement. Biopsy of the liver showed Reed-Sternberg cells with typical morphology and immunophenotype. While fluorescent in situ hybridization (FISH) analyses for t(14;18) were positive in the lymph node tissue with follicular lymphoma, we were unable to show the same in the liver biopsy specimen. Here, we describe the clinical, morphologic, immunophenotypic, and cytogenetic features of this unusual composite lymphoma case involving CLL and follicular lymphoma, with the subsequent development of a Hodgkin lymphoma. PMID:15291370

  20. Combination of two anti-CD5 monoclonal antibodies synergistically induces complement-dependent cytotoxicity of chronic lymphocytic leukaemia cells

    DEFF Research Database (Denmark)

    Klitgaard, Josephine L; Koefoed, Klaus; Geisler, Christian;

    2013-01-01

    The treatment of chronic lymphocytic leukaemia (CLL) has been improved by introduction of monoclonal antibodies (mAbs) that exert their effect through secondary effector mechanisms. CLL cells are characterized by expression of CD5 and CD23 along with CD19 and CD20, hence anti-CD5 Abs that engage ...

  1. DNA DAMAGE INDUCED BY A OZONE IN PERIPHERAL BLOOD LYMPHOCYTES OF ELDERLY PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

    OpenAIRE

    Kytikova, Oxana; Gvozdenko, Tatyana; Vitkina, Tatyana

    2015-01-01

    We have assessed DNA damage by using various therapeutic concentrations of ozone in the peripheral blood lymphocytes of elderly patients with chronic obstructive pulmonary disease (in vitro). The results of this work demonstrate that ozone induces DNA damage. It was also noticed, that there is a clear dose-dependent increase in DNA damage.

  2. Chronic lymphocytic leukemia-associated chromosomal abnormalities and miRNA deregulation

    Directory of Open Access Journals (Sweden)

    Kiefer Y

    2012-03-01

    Full Text Available Yvonne Kiefer1, Christoph Schulte2, Markus Tiemann2, Joern Bullerdiek11Center for Human Genetics, University of Bremen, Bremen, Germany; 2Hematopathology Hamburg, Hamburg, GermanyAbstract: Chronic lymphocytic leukemia is the most common leukemia in adults. By cytogenetic investigations major subgroups of the disease can be identified that reflect different routes of tumor development. Of these chromosomal deviations, trisomy 12 and deletions of parts of either the long arm of chromosome 13, the long arm of chromosome 11, or the short arm of chromosome 17 are most commonly detected. In some of these aberrations the molecular target has been identified as eg, ataxia telangiectasia mutated (ATM in case of deletions of chromosomal region 11q22~23 and the genes encoding microRNAs miR-15a/16-1 as likely targets of deletions of chromosomal band 13q14.3. Of note, these aberrations do not characterize independent subgroups but often coexist within the metaphases of one tumor. Generally, complex aberrations are associated with a worse prognosis than simple karyotypic alterations. Due to smaller sizes of the missing segment the detection of recurrent deletions is not always possible by means of classical cytogenetics but requires more advanced techniques as in particular fluorescence in situ hybridization (FISH. Nevertheless, at this time it is not recommended to replace classical cytogenetics by FISH because this would miss additional information given by complex or secondary karyotypic alterations. However, the results of cytogenetic analyses allow the stratification of prognostic and predictive groups of the disease. Of these, the group characterized by deletions involving TP53 is clinically most relevant. In the future refined methods as eg, array-based comparative genomic hybridization will supplement the existing techniques to characterize CLL. Keywords: chronic lymphocytic leukemia, chromosomal abnormality, miRNA deregulation

  3. Surface antigen expression and correlation with variable heavy-chain gene mutation status in chronic lymphocytic leukemia.

    Science.gov (United States)

    Vilpo, Juhani; Tobin, Gerard; Hulkkonen, Janne; Hurme, Mikko; Thunberg, Ulf; Sundström, Christer; Vilpo, Leena; Rosenquist, Richard

    2003-01-01

    Recent studies have demonstrated that B-cell chronic lymphocytic leukemia (CLL) consists of two clinical entities with either somatically hypermutated (M-CLL) or unmutated (UM-CLL) immunoglobulin variable heavy-chain (VH) regions. In view of the fact that the cellular biology of these two subsets of disease is currently unexplored, we performed an extensive analysis of the surface antigen expression and correlated this with the VH gene mutation status in a cohort of 32 CLL patients. Using polymerase chain reaction amplification and nucleotide sequencing, the VH genes were shown to be mutated in 10 cases (31%) and unmutated in 22 (69%). The expression of 27 surface membrane antigens in peripheral blood leukemic cells was analyzed by flow cytometry, measuring both the percentage of positive cells as well as the geometric mean fluorescence intensity (GMF). Most of the surface membrane antigens (CD5, CD11c, CD19, CD20, CD21, CD22, CD23, CD25, CD40, CD45, VD79b, CD80, CD95, CD122, CD124, CD126, CD130, CD154, IgM, and IgD) showed a similar expression pattern in both UM-CLL and M-CLL patients. The similarity of M-CLL and UM-CLL, as demonstrated here for the first time with many protein markers, indicates a considerably homogeneous phenotype in both subsets. Furthermore, CD27 was strongly expressed in all cases, which may suggest a memory cell phenotype for both M-CLL and UM-CLL. More positive cells in the UM-CLL group were observed regarding CD38, but CD38 was not a good predictor of VH gene mutation status. Seventy percent of the M-CLL cases, but only 36% of UM-CLL cases, were Ig-lambda+. The most striking differential expression, however, was observed in the two slicing variants of the common leukocyte antigen CD45, namely CD45RO and CD45RA. CD45RO expression was significantly associated with M-CLL, whereas the GMF intensity of CD45RA tended to be associated with UM-CLL. The role of these CD45 splicing variants in the pathogenesis of CLL deserves further investigation

  4. Effect of viral load on T-lymphocyte failure in patients with chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Jing You; Hutcha Sriplung; Alan Geater; Virasakdi Chongsuvivatwong; Lin Zhuang; Hong-Ying Chen; Lan Yu; Bao-Zhang Tang; Jun-Hua Huang

    2008-01-01

    AIM:To investigate peripheral T-lymphocyte subpopulation profile and its correlation with hepatitis B virus (HBV) replication in patients with chronic hepatitis B (CHB).METHODS:Distribution of T-lymphocyte subpopulations in peripheral blood was measured by flow cytometry in 206 CHB patients.HBV markers were detected with ELISA.Serum HBV DNA load was assessed with quantitative real-time polymerase chain reaction (PCR).The relationship between HBV replication and variation in peripheral T-cell subsets was analyzed.RESULTS:CHB patients had significantly decreased CD3,and CD4+ cells and CD4+/CD8+ ratio,and increased CD8+ cells compared with uninfected controls (55.44±12.39 vs 71.07±4.76,30.92±7.48 vs 38.94±3.39,1.01±0.49 vs 1.67±0.33,and 34.39±9.22 vs 24.02±4.35;P<0.001,respectively).Univariate analysis showed a similar pattern of these parameters was significantly associated with high viral load,presence of serum hepatitis B e antigen (HBeAg) expression,liver disease severity,history of maternal HBV infection,and young age at HBV infection,all with P<0.01.There was a significant linear relationship between viral load and these parameters of T-lymphocyte subpopulations (linear trend test P<0.001).There was a negative correlation between the levels of CD3+ and CD4+ cells and CD4+/CD8+ ratio and serum level of viral load in CHB patients (r=-0.68,-0.65 and-0.75,all P<0.0001),and a positive correlation between CD8+ cells and viral load (r=0.70,P<0.0001).There was a significant decreasing trend in CD3+ and CD4+ cells and CD4+/CD8+ratio with increasing severity of hepatocyte damage and decreasing age at HBV infection (linear trend test P<0.01).In multiple regression (after adjustment for age at HBV infection,maternal HBV infection status and hepatocyte damage severity) log copies of HBV DNA maintained a highly significant predictive coefficient on T-lymphocyte subpopulations,and was the strongest predictor of variation in CD3+,CD4+,CD8+ cells and CD4+/CD8

  5. Immunoglobulin heavy chain variable region gene utilization by B cell hybridomas derived from rheumatoid synovial tissue.

    Science.gov (United States)

    Brown, C M; Longhurst, C; Haynes, G; Plater-Zyberk, C; Malcolm, A; Maini, R N

    1992-08-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects synovial joints. Activated B lymphocytes and plasma cells are present in the synovial tissue and are thought to contribute to the immunopathology of the rheumatoid joint. To investigate rheumatoid synovial B lymphocytes, we have generated B cell hybridomas from synovial tissue of an RA patient. Here we describe the immunoglobulin VH gene repertoire of eight IgM- and 10 IgG-secreting synovial-derived hybridomas. The VH4 gene family is highly represented (38.5%) in this panel of hybridomas compared with the frequency of VH4 gene expression in circulating B lymphocytes reported previously (19-22%) and with the VH4 gene frequency we observed in a panel of hybridomas derived in the same manner from the spleen and tonsil of normal individuals (19%). The increased frequency of VH4 gene expression was not due to the expansion of a single B cell clone in vivo as none of these hybridomas was clonally related. Two synovial-derived hybridomas secreted autoantibodies; one (VH3+) secreted an IgM-rheumatoid factor (RF) and the other (VH4+) secreted IgM with polyreactive binding to cytoskeletal proteins and cardiolipin. The antibodies secreted by the remaining synovial-derived hybridomas were not reactive with the autoantigens tested. The VH gene usage in a proportion (5/17) of synovial-derived hybridomas that expressed CD5 antigen provided preliminary evidence that CD5+ B cells in RA synovium have a similar increase of VH4 gene expression reported for CD5+ B cells from normal individuals and patients with chronic lymphocytic leukaemia. PMID:1379132

  6. Cancer Stem Cells of Differentiated B-Cell Malignancies: Models and Consequences

    Energy Technology Data Exchange (ETDEWEB)

    Gross, Emilie; Quillet-Mary, Anne [INSERM, UMR1037-Cancer Research Center of Toulouse, 31300 Toulouse (France); ERL 5294 CNRS, BP3028 CHU Purpan, 31300 Toulouse (France); Université Toulouse III Paul-Sabatier, 31300 Toulouse (France); Ysebaert, Loic; Laurent, Guy [INSERM, UMR1037-Cancer Research Center of Toulouse, 31300 Toulouse (France); ERL 5294 CNRS, BP3028 CHU Purpan, 31300 Toulouse (France); Université Toulouse III Paul-Sabatier, 31300 Toulouse (France); Service d' Hématologie, CHU Purpan, 31300 Toulouse (France); Fournie, Jean-Jacques, E-mail: jean-jacques.fournie@inserm.fr [INSERM, UMR1037-Cancer Research Center of Toulouse, 31300 Toulouse (France); ERL 5294 CNRS, BP3028 CHU Purpan, 31300 Toulouse (France); Université Toulouse III Paul-Sabatier, 31300 Toulouse (France)

    2011-03-25

    The concept of cancer stem cells has revolutionized our current vision of cancer development and was validated in solid tumors and cancers of the primitive hematopoietic compartment. Proof of the principle is still lacking, however, in malignancies of differentiated B-cells. We review here the current literature, which nevertheless suggests hierarchical organizations of the tumor clone for mostly incurable B-cell cancers such as multiple myeloma, lymphomas and B-chronic lymphocytic leukemia. We propose two models accounting for cancer stem cells in these contexts: a “top-to-bottom” clonal hierarchy from memory B-cells and a “bottom-to-top” model of clonal reprogramming. Selection pressure on the growing tumor can drive such reprogramming and increase its genetic diversity.

  7. Cancer Stem Cells of Differentiated B-Cell Malignancies: Models and Consequences

    International Nuclear Information System (INIS)

    The concept of cancer stem cells has revolutionized our current vision of cancer development and was validated in solid tumors and cancers of the primitive hematopoietic compartment. Proof of the principle is still lacking, however, in malignancies of differentiated B-cells. We review here the current literature, which nevertheless suggests hierarchical organizations of the tumor clone for mostly incurable B-cell cancers such as multiple myeloma, lymphomas and B-chronic lymphocytic leukemia. We propose two models accounting for cancer stem cells in these contexts: a “top-to-bottom” clonal hierarchy from memory B-cells and a “bottom-to-top” model of clonal reprogramming. Selection pressure on the growing tumor can drive such reprogramming and increase its genetic diversity

  8. The phosphoinositide 3-kinase signaling pathway in normal and malignant B cells: activation mechanisms, regulation and impact on cellular functions.

    Science.gov (United States)

    Pauls, Samantha D; Lafarge, Sandrine T; Landego, Ivan; Zhang, Tingting; Marshall, Aaron J

    2012-01-01

    The phosphoinositide 3-kinase (PI3K) pathway is a central signal transduction axis controlling normal B cell homeostasis and activation in humoral immunity. The p110δ PI3K catalytic subunit has emerged as a critical mediator of multiple B cell functions. The activity of this pathway is regulated at multiple levels, with inositol phosphatases PTEN and SHIP both playing critical roles. When deregulated, the PI3K pathway can contribute to B cell malignancies and autoantibody production. This review summarizes current knowledge on key mechanisms that activate and regulate the PI3K pathway and influence normal B cell functional responses including the development of B cell subsets, antigen presentation, immunoglobulin isotype switch, germinal center responses, and maintenance of B cell anergy. We also discuss PI3K pathway alterations reported in select B cell malignancies and highlight studies indicating the functional significance of this pathway in malignant B cell survival and growth within tissue microenvironments. Finally, we comment on early clinical trial results, which support PI3K inhibition as a promising treatment of chronic lymphocytic leukemia. PMID:22908014

  9. A 14-year paraneoplastic rash: urticarial vasculitis and dermal binding bullous pemphigoid secondary to chronic lymphocytic leukaemia.

    Science.gov (United States)

    Kassim, J M; Igali, L; Levell, N J

    2015-06-01

    A 72-year-old woman with a 14-year history of urticarial vasculitis (UV) and a 13-year history of bullous pemphigoid (BP) presented with associated progressive chronic lymphocytic leukaemia (CLL). Both skin conditions responded poorly to treatment, until chemotherapy for CLL was commenced. The skin features showed a clear paraneoplastic course, resolving with chemotherapy and recurring when the CLL relapsed and the lymphocyte count rose above 5 × 10(9)/L. No case of UV secondary to CLL, and very few cases of BP related to CLL have been reported, and no paraneoplastic rash of any type lasting 14 years has been reported previously. PMID:25524180

  10. Evaluation of ZAP-70 expression by flow cytometry in chronic lymphocytic leukemia: A multicentric international harmonization process.

    Science.gov (United States)

    Letestu, Remi; Rawstron, Andy; Ghia, Paolo; Villamor, Neus; Boeckx, Nancy; Leuven, Nancy Boeckx; Boettcher, Sebastian; Buhl, Anne Mette; Duerig, Jan; Ibbotson, Rachel; Kroeber, Alexander; Langerak, Anton; Le Garff-Tavernier, Magali; Mockridge, Ian; Morilla, Alison; Padmore, Ruth; Rassenti, Laura; Ritgen, Matthias; Shehata, Medhat; Smolewski, Piotr; Staib, Peter; Ticchioni, Michel; Walker, Clare; Ajchenbaum-Cymbalista, Florence

    2006-07-15

    The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous with some patients requiring early therapy whereas others will not be treated for years. The evaluation of an individual CLL patient's prognosis remains a problematic issue. The presence or absence of somatic mutations in the IgVH genes is currently the gold-standard prognostic factor, but this technique is labor intensive and costly. Genomic studies uncovered that 70 kDa zeta-associated protein (ZAP-70) expression was associated with unmutated IgVH genes and ZAP-70 protein expression was proposed as a surrogate for somatic mutational status. Among the available techniques for ZAP-70 detection, flow cytometry is most preferable as it allows the simultaneous quantification of ZAP-70 protein expression levels in CLL cells and residual normal lymphocyte subsets. However, several factors introduce variability in the results reported from different laboratories; these factors include the anti-ZAP-70 antibody clone and conjugate, the staining procedure, the gating strategy, and the method of reporting the results. The need for standardization of the approach led to the organization of an international working group focused on harmonizing all aspects of the technique. During this workshop, a technical consensus was reached on the methods for cell permeabilization and immunophenotyping procedures. An assay was then designed that allowed comparison of two clones of anti-ZAP-70 antibody and the identification of the expression of this molecule in B, T, and NK cells identified in a four multicolor analysis. This procedure was applied to three stabilized blood samples, provided by the UK NEQAS group to all participating members of this study, in order to minimize variability caused by sample storage and shipment. Analysis was performed in 20 laboratories providing interpretable data from 14 centers. Various gating strategies were used and the ZAP-70 levels were expressed as percentage

  11. Micronucleus assay in human lymphocytes as a bio dosimeter of in vivo acute and chronic exposures

    International Nuclear Information System (INIS)

    To assess the persistence over time of micronuclei (MN) in lymphocytes of cancer patients after radiotherapy and, consequently, to verify the suitability of MN test as a dosimeter for monitoring in vivo ionizing radiation damage, the cytokinesis-blocked MN assay was applied in peripheral blood lymphocytes of cervix and head and neck cancer patients (n = 34). The evaluation of data suggests that: 1) MN frequency increases linearly with the equivalent total-body absorbed dose (R2 = 0,9; P=0,015); 2) The distribution of the MN yields deviates significantly from Poisson with the increase of equivalent total-body dose (σ2/y = 1,14 mean value); 3) The comparison of spontaneous MN frequencies in healthy subjects with those in cancer patients, prior to radiotherapy, shows significant differences (p<0,01); and 4) It is observed a general decline in MN frequencies with time after radiotherapy, with considerable variations between patients. The kinetics of elimination of MN seems to follow a two-term exponential function, with a short and a long term. Patients with the highest equivalent total-body dose (total tumoral dose: 60-80 Gy) initially tend to have the fastest decline. At 6-18 months of follow-up time 11 of the 17 patients, evaluated 2-480 months post-treatment, showed higher frequencies of MN than their respective levels before radiation therapy, indicating persistence of radiation induced cytogenetic damage. Further studies modeling changes in chromosome aberrations with acute and chronic exposures should provide perspectives on biological dosimetry in accident situations in which there is a blood sampling delay and on biological monitoring of human populations exposed to ionizing radiation. (author)

  12. Elevated neutrophil to lymphocyte ratio predicts mortality in medical inpatients with multiple chronic conditions.

    Science.gov (United States)

    Isaac, Vivian; Wu, Chia-Yi; Huang, Chun-Ta; Baune, Bernhard T; Tseng, Chia-Lin; McLachlan, Craig S

    2016-06-01

    Neutrophil to lymphocyte ratio (NLR) is an easy measurable laboratory marker used to evaluate systemic inflammation. Elevated NLR is associated with poor survival and increased morbidity in cancer and cardiovascular disease. However, the usefulness of NLR to predict morbidity and mortality in a hospital setting for patients with multiple chronic conditions has not been previously examined. In this study, we investigate the association between NLR and mortality in multimorbid medical inpatients. Two hundred thirty medical in-patients with chronic conditions were selected from a single academic medical center in Taiwan. Retrospective NLRs were calculated from routine full blood counts previously obtained during the initial hospital admission and at the time of discharge. Self-rated health (using a single-item question), medical disorders, depressive symptoms, and medical service utilization over a 1-year period were included in the analyses. Mortality outcomes were ascertained by reviewing electronic medical records and follow-up. The mortality rate at 2-year follow-up was 23%. Depression (odds ratio [OR] 1.9 [95% CI 1.0-3.7]), poor self-rated health (OR 2.1 [95% CI 1.1-3.9]), being hospitalized 2 or more times in the previous year (OR 2.3 [95% CI 1.2-4.6]), metastatic cancer (OR 4.7 [95% CI 2.3-9.7]), and chronic liver disease (OR 4.3 [95% CI 1.5-12.1]) were associated with 2-year mortality. The median (interquartile range) NLR at admission and discharge were 4.47 (2.4-8.7) and 3.65 (2.1-6.5), respectively. Two-year mortality rates were higher in patients with an elevated NLR at admission (NLR 3 = 27.6%) and discharge (NLR 3 = 29.1%). Multivariate logistic regression demonstrated that an elevated NLR >3.0 at admission (OR 2.3 [95% CI 1.0-5.2]) and discharge (OR 2.3 [95% CI 1.1-5.0]) were associated with mortality independent of baseline age, sex, education, metastatic cancer, liver disease, depression, and previous hospitalization. Increased NLR is associated

  13. Novel Biomarker Proteins in Chronic Lymphocytic Leukemia: Impact on Diagnosis, Prognosis and Treatment

    Science.gov (United States)

    Admoni-Elisha, Lee; Nakdimon, Itay; Shteinfer, Anna; Prezma, Tal; Arif, Tasleem; Arbel, Nir; Melkov, Anna; Zelichov, Ori; Levi, Itai; Shoshan-Barmatz, Varda

    2016-01-01

    In many cancers, cells undergo re-programming of metabolism, cell survival and anti-apoptotic defense strategies, with the proteins mediating this reprogramming representing potential biomarkers. Here, we searched for novel biomarker proteins in chronic lymphocytic leukemia (CLL) that can impact diagnosis, treatment and prognosis by comparing the protein expression profiles of peripheral blood mononuclear cells from CLL patients and healthy donors using specific antibodies, mass spectrometry and binary logistic regression analyses and other bioinformatics tools. Mass spectrometry (LC-HR-MS/MS) analysis identified 1,360 proteins whose expression levels were modified in CLL-derived lymphocytes. Some of these proteins were previously connected to different cancer types, including CLL, while four other highly expressed proteins were not previously reported to be associated with cancer, and here, for the first time, DDX46 and AK3 are linked to CLL. Down-regulation expression of two of these proteins resulted in cell growth inhibition. High DDX46 expression levels were associated with shorter survival of CLL patients and thus can serve as a prognosis marker. The proteins with modified expression include proteins involved in RNA splicing and translation and particularly mitochondrial proteins involved in apoptosis and metabolism. Thus, we focused on several metabolism- and apoptosis-modulating proteins, particularly on the voltage-dependent anion channel 1 (VDAC1), regulating both metabolism and apoptosis. Expression levels of Bcl-2, VDAC1, MAVS, AIF and SMAC/Diablo were markedly increased in CLL-derived lymphocytes. VDAC1 levels were highly correlated with the amount of CLL-cancerous CD19+/CD5+ cells and with the levels of all other apoptosis-modulating proteins tested. Binary logistic regression analysis demonstrated the ability to predict probability of disease with over 90% accuracy. Finally, based on the changes in the levels of several proteins in CLL patients, as

  14. Synergistic Activity of Deguelin and Fludarabine in Cells from Chronic Lymphocytic Leukemia Patients and in the New Zealand Black Murine Model

    Science.gov (United States)

    Rebolleda, Nerea; Losada-Fernandez, Ignacio; Perez-Chacon, Gema; Castejon, Raquel; Rosado, Silvia; Morado, Marta; Vallejo-Cremades, Maria Teresa; Martinez, Andrea; Vargas-Nuñez, Juan A.

    2016-01-01

    B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain. In both of them, deguelin dowregulates AKT, NFκB and several downstream antiapoptotic proteins (XIAP, cIAP, BCL2, BCL-XL and survivin), activating the mitochondrial pathway of apoptosis. Moreover, deguelin inhibits stromal cell-mediated c-Myc upregulation and resistance to fludarabine, increasing fludarabine induced DNA damage. We further show that deguelin has activity in vivo against NZB CLL-like cells in an experimental model of CLL in young NZB mice transplanted with spleen cells from aged NZB mice with lymphoproliferation. Moreover, the combination of deguelin and fludarabine in this model prolonged the survival of transplanted mice at doses of both compounds that were ineffective when administered individually. These results suggest deguelin could have potential for the treatment of human CLL. PMID:27101369

  15. Indolent lymphomas in the pediatric population: follicular lymphoma, IRF4/MUM1+ lymphoma, nodal marginal zone lymphoma and chronic lymphocytic leukemia.

    Science.gov (United States)

    Quintanilla-Martinez, Leticia; Sander, Birgitta; Chan, John K C; Xerri, Luc; Ott, German; Campo, Elias; Swerdlow, Steven H

    2016-02-01

    Indolent lymphomas in the pediatric population were discussed during the 2014 European Association for Haematopathology/Society of Hematopathology workshop in Istanbul, Turkey. This session was focused on pediatric-type follicular lymphoma (FL), and its differential diagnosis with the newly recognized entity of IRF4/MUM1+ lymphomas mainly involving Waldeyer's ring. The differential diagnosis between t(14;18) negative FL grade 1/2 and pediatric-type FL in adults was highlighted. The overlapping pathological and clinical features between FL and nodal marginal zone lymphoma (NMZL) in children and young adults were recognized and morphologic and immunophenotypical criteria helpful for the differential diagnosis were presented. Both pediatric-type FL and NMZL are indolent processes that should be distinguished from atypical lymphoid hyperplasia of the tonsils and lymph nodes. The demonstration of a B cell monoclonal population by molecular studies is strongly recommended for the diagnosis. Recognition of these indolent variants to avoid overtreatment was emphasized. Whereas most indolent lymphomas in the pediatric population show characteristic clinical, pathologic, and genetic features that differ from the adult counterpart, other rare indolent lymphoid tumors such as chronic lymphocytic leukemia (CLL) have similar characteristics. In this report, novel findings, areas of special interest, and diagnostic challenges emerging from the cases submitted to the workshop will be discussed. PMID:26416032

  16. CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia.

    Science.gov (United States)

    Montraveta, Arnau; Lee-Vergés, Eriong; Roldán, Jocabed; Jiménez, Laura; Cabezas, Sandra; Clot, Guillem; Pinyol, Magda; Xargay-Torrent, Sílvia; Rosich, Laia; Arimany-Nardí, Cristina; Aymerich, Marta; Villamor, Neus; López-Guillermo, Armando; Pérez-Galán, Patricia; Roué, Gaël; Pastor-Anglada, Marçal; Campo, Elías; López-Guerra, Mónica; Colomer, Dolors

    2016-02-01

    Clinical responses to bendamustine in chronic lymphocytic leukemia (CLL) are highly heterogeneous and no specific markers to predict sensitivity to this drug have been reported. In order to identify biomarkers of response, we analyzed the in vitro activity of bendamustine and the gene expression profile in primary CLL cells. We observed that mRNA expression of CD69 (CD69) and ITGAM (CD11b) constitute the most powerful predictor of response to bendamustine. When we interrogated the predictive value of the corresponding cell surface proteins, the expression of the activation marker CD69 was the most reliable predictor of sensitivity to bendamustine. Importantly, a multivariate analysis revealed that the predictive value of CD69 expression was independent from other clinico-biological CLL features. We also showed that when CLL cells were co-cultured with distinct subtypes of stromal cells, an upregulation of CD69 was accompanied by a reduced sensitivity to bendamustine. In agreement with this, tumor cells derived from lymphoid tumor niches harbored higher CD69 expression and were less sensitive to bendamustine than their peripheral blood counterparts. Furthermore, pretreatment of CD69 high CLL cases with the B-cell receptor (BCR) pathway inhibitors ibrutinib and idelalisib decreased CD69 levels and enhanced bendamustine cytotoxic effect. Collectively, our findings indicate that CD69 could be a predictor of bendamustine response in CLL patients and the combination of clinically-tested BCR signaling inhibitors with bendamustine may represent a promising strategy for bendamustine low responsive CLL cases. PMID:26701728

  17. Diminished production of interleukin-6 in chronic lymphocytic leukaemia (B-CLL) cells from patients at advanced stages of disease. Tampere CLL Group.

    Science.gov (United States)

    Hulkkonen, J; Vilpo, J; Vilpo, L; Hurme, M

    1998-03-01

    The production of the cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in B-CLL cells from 24 patients at different stages of chronic lymphocytic B-cell leukaemia (B-CLL) was investigated in vitro. In the majority of these cases, low spontaneous IL-6 production was measured. Mitogenic stimulation with phorbol 12-myristate 13-acetate (PMA) or PMA plus interleukin-2 (IL-2) resulted in a tremendous increase in TNF-alpha and IL-6 production in cells representing early stage (Binet A) disease. In contrast, very little, if any, production took place in cells from patients with advanced stage (Binet C) B-CLL. The results from stage B patients were intermediate. The most remarkable difference was recorded in PMA-stimulated (1 ng/ml) IL-6 production. In stimulated 72 h cultures, IL-6 concentrations were 1280 +/- 1080 pg/ml for Binet A (n = 11), 757 +/- 597 pg/ml for Binet B (n = 8) and 46.0 +/- 84.0 pg/ml for Binet C (n = 5). The differences in IL-6 production between stage C v B and stage C v A were both statistically significant (P=0.025). Similar effects, but to a lesser extent, were observed in TNF-alpha production. These results suggest that the varying capacity to produce IL-6 and TNF-alpha may play a role in B-CLL progression and in clinical manifestations of the disease. PMID:9504629

  18. CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia

    Science.gov (United States)

    Roldán, Jocabed; Jiménez, Laura; Cabezas, Sandra; Clot, Guillem; Pinyol, Magda; Xargay-Torrent, Sílvia; Rosich, Laia; Arimany-Nardí, Cristina; Aymerich, Marta; Villamor, Neus; López-Guillermo, Armando; Pérez-Galán, Patricia; Roué, Gaël; Pastor-Anglada, Marçal; Campo, Elías; López-Guerra, Mónica; Colomer, Dolors

    2016-01-01

    Clinical responses to bendamustine in chronic lymphocytic leukemia (CLL) are highly heterogeneous and no specific markers to predict sensitivity to this drug have been reported. In order to identify biomarkers of response, we analyzed the in vitro activity of bendamustine and the gene expression profile in primary CLL cells. We observed that mRNA expression of CD69 (CD69) and ITGAM (CD11b) constitute the most powerful predictor of response to bendamustine. When we interrogated the predictive value of the corresponding cell surface proteins, the expression of the activation marker CD69 was the most reliable predictor of sensitivity to bendamustine. Importantly, a multivariate analysis revealed that the predictive value of CD69 expression was independent from other clinico-biological CLL features. We also showed that when CLL cells were co-cultured with distinct subtypes of stromal cells, an upregulation of CD69 was accompanied by a reduced sensitivity to bendamustine. In agreement with this, tumor cells derived from lymphoid tumor niches harbored higher CD69 expression and were less sensitive to bendamustine than their peripheral blood counterparts. Furthermore, pretreatment of CD69 high CLL cases with the B-cell receptor (BCR) pathway inhibitors ibrutinib and idelalisib decreased CD69 levels and enhanced bendamustine cytotoxic effect. Collectively, our findings indicate that CD69 could be a predictor of bendamustine response in CLL patients and the combination of clinically-tested BCR signaling inhibitors with bendamustine may represent a promising strategy for bendamustine low responsive CLL cases. PMID:26701728

  19. Biometric indices of recirculating lymphocytes after acute and chronic gamma-irradiation

    International Nuclear Information System (INIS)

    The karyometry method was used to study the distribution of mature lymphocytes of lymphatic organs and peripheral blood among classes of nuclear volumes. Radiation injury was accompanied by a selection of populations of short-lived lymphocytes with very big nuclei the content of which was function of cumulative radiation dose. The number of small lymphocytes dependend on the phase of the radiation reaction

  20. Epidemiologia da leucemia linfocítica crônica e leucemia linfocítica crônica familiar Epidemiology of chronic lymphocytic leukemia and familial chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Mihoko Yamamoto

    2005-12-01

    Full Text Available A leucemia linfocítica crônica (LLC é uma doença linfoproliferativa crônica (DLPC que apresenta características epidemiológicas peculiares; acomete indivíduos com idade mais avançada (não ocorre em crianças e é rara abaixo dos 30 anos e a sua incidência varia conforme a origem étnica dos pacientes. É a leucemia mais freqüente nos países ocidentais enquanto muito rara nos orientais. A sua etiologia não está ainda esclarecida, não se conhecendo fatores ambientais que mostrem forte associação com o surgimento da doença. Não tem relação com radiação ionizante (sobreviventes da bomba atômica não apresentaram aumento na incidência da LLC, assim como não foi demonstrada associação com agentes tóxicos ou virais específicos. A LLC familiar é assim denominada quando, pelo menos, dois membros de uma família apresentam LLC e o diagnóstico nestes pacientes costuma ocorrer em idade mais precoce. A ocorrência é maior em parentes de primeiro grau (irmãos, filhos, podendo, porém, afetar parentes mais distantes. Os familiares de pacientes com LLC apresentam maior freqüência de outras DLPC (risco relativo 30x maior e de proliferação monoclonal de linfócitos B (13%-18% e parece que o HLADR1.11 está implicado na LLC familiar, pelo menos em algumas populações.Chronic lymphocytic leukemia (CLL is a chronic lympho-proliferative desorder (CLPD with peculiar epidemiologic characteristics. It is a disease of the elderly, which is very rare in under 30-year-old individuals and absent among children. Its incidence largely varies according to the ethnical origin: CLL is the most common leukemia in Western countries while it is rarely seen in Eastern countries. The etiology of CLL is still unknown. Environmental factors such as exposure to ionizing radiation (atomic bomb survivors did not show an increased incidence of CLL or toxic or viral agents are not associated to the occurrence of CLL. Familiar CLL is characterized when

  1. The B cell antigen receptor and overexpression of MYC can cooperate in the genesis of B cell lymphomas.

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    Yosef Refaeli

    2008-06-01

    Full Text Available A variety of circumstantial evidence from humans has implicated the B cell antigen receptor (BCR in the genesis of B cell lymphomas. We generated mouse models designed to test this possibility directly, and we found that both the constitutive and antigen-stimulated state of a clonal BCR affected the rate and outcome of lymphomagenesis initiated by the proto-oncogene MYC. The tumors that arose in the presence of constitutive BCR differed from those initiated by MYC alone and resembled chronic B cell lymphocytic leukemia/lymphoma (B-CLL, whereas those that arose in response to antigen stimulation resembled large B-cell lymphomas, particularly Burkitt lymphoma (BL. We linked the genesis of the BL-like tumors to antigen stimulus in three ways. First, in reconstruction experiments, stimulation of B cells by an autoantigen in the presence of overexpressed MYC gave rise to BL-like tumors that were, in turn, dependent on both MYC and the antigen for survival and proliferation. Second, genetic disruption of the pathway that mediates signaling from the BCR promptly killed cells of the BL-like tumors as well as the tumors resembling B-CLL. And third, growth of the murine BL could be inhibited by any of three distinctive immunosuppressants, in accord with the dependence of the tumors on antigen-induced signaling. Together, our results provide direct evidence that antigenic stimulation can participate in lymphomagenesis, point to a potential role for the constitutive BCR as well, and sustain the view that the constitutive BCR gives rise to signals different from those elicited by antigen. The mouse models described here should be useful in exploring further the pathogenesis of lymphomas, and in preclinical testing of new therapeutics.

  2. Phospho-specific flow cytometry identifies aberrant signaling in indolent B-cell lymphoma

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    Blix Egil S

    2012-10-01

    Full Text Available Abstract Background Knowledge about signaling pathways in malignant cells may provide prognostic and diagnostic information in addition to identify potential molecular targets for therapy. B-cell receptor (BCR and co-receptor CD40 signaling is essential for normal B cells, and there is increasing evidence that signaling via BCR and CD40 plays an important role in the pathogenesis of B-cell lymphoma. The aim of this study was to investigate basal and induced signaling in lymphoma B cells and infiltrating T cells in single-cell suspensions of biopsies from small cell lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL and marginal zone lymphoma (MZL patients. Methods Samples from untreated SLL/CLL and MZL patients were examined for basal and activation induced signaling by phospho-specific flow cytometry. A panel of 9 stimulation conditions targeting B and T cells, including crosslinking of the B cell receptor (BCR, CD40 ligand and interleukins in combination with 12 matching phospho-protein readouts was used to study signaling. Results Malignant B cells from SLL/CLL patients had higher basal levels of phosphorylated (p-SFKs, p-PLCγ, p-ERK, p-p38, p-p65 (NF-κB, p-STAT5 and p-STAT6, compared to healthy donor B cells. In contrast, anti-BCR induced signaling was highly impaired in SLL/CLL and MZL B cells as determined by low p-SFK, p-SYK and p-PLCγ levels. Impaired anti-BCR-induced p-PLCγ was associated with reduced surface expression of IgM and CD79b. Similarly, CD40L-induced p-ERK and p-p38 were also significantly reduced in lymphoma B cells, whereas p-p65 (NF-κB was equal to that of normal B cells. In contrast, IL-2, IL-7 and IL-15 induced p-STAT5 in tumor-infiltrating T cells were not different from normal T cells. Conclusions BCR signaling and CD40L-induced p-p38 was suppressed in malignant B cells from SLL/CLL and MZL patients. Single-cell phospho-specific flow cytometry for detection of basal as well as activation

  3. CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection.

    OpenAIRE

    FLETCHER, JEAN

    2010-01-01

    PUBLISHED BACKGROUND & AIMS: Increasing age is associated with impaired immune function and in chronic HCV infection specifically, with progressive fibrosis, liver failure, HCC and impaired responses to antiviral therapy. T-lymphocyte telomere length declines with age. We hypothesised that shorter T-lymphocyte telomere length would be associated with poor clinical outcome in HCV infection. METHODS: Circulating T-lymphocyte telomere length, an objective measure of immune senescence, was...

  4. A high number of losses in 13q14 chromosome band is associated with a worse outcome and biological differences in patients with B-cell chronic lymphoid leukemia

    OpenAIRE

    Hernández, José Ángel; Rodríguez, Ana Eugenia; González, Marcos; Benito, Rocío; Fontanillo, Celia; Sandoval, Virgilio; Romero, Mercedes; Martín-Núñez, Guillermo; de Coca, Alfonso García; Fisac, Rosa; Galende, Josefina; Recio, Isabel; Ortuño, Francisco; García, Juan Luis; De Las Rivas, Javier

    2009-01-01

    In B-cell chronic lymphoid leukemia, patients with 13q14 deletion generally have a favorable outcome. The findings of this study suggest that the number of malignant cells with 13q14 deletion may influence the outcome of patients with this cytogenetic abnormality as a single chromosomal aberration. A high number of malignant cells carrying the 13q14 deletion, as assessed by FISH, appears to be associated with short overall survival and time to progression.

  5. Syncytial giant cell hepatitis associated with chronic lymphocytic leukemia: a case report

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    Gupta Eva

    2012-07-01

    Full Text Available Abstract Background Syncytial giant cell hepatitis (GCH is an uncommon and an underreported disease entity. In two previously reported cases of GCH in patients with Chronic Lymphocytic Leukemia (CLL liver failure ensued. Autoimmune and infective causes have been implicated but its etiology remains unclear. Case Presentation A 60-year-old female with CLL presented with acute hepatitis with negative viral and auto-immune serologies and without any prior toxic exposure. Liver biopsy showed typical histological features of GCH. The patient was successfully treated with corticosteroids and intravenous immunoglobulin (IVIG. Her liver enzymes returned to baseline and have remained normal as of the last follow up almost 4 years later. Conclusions Association of GCH with CLL may be under recognized. Clinical suspicion of GCH in CLL patients with serology-negative hepatitis, early liver biopsy and therapeutic intervention may influence outcome. This is the first case report of successful treatment of GCH in CLL patients. Moreover, our case also demonstrates the ability to resume effective CLL therapy post-GCH diagnosis without detriment to the liver.

  6. Treatment of chronic lymphocytic leukemia by total body irradiation alone and combined with chemotherapy

    International Nuclear Information System (INIS)

    Total body irradiation (TBI) offers a new dimension in the treatment of chronic lymphocytic leukemia (CLL), a disease heretofore refractory to effective management. Excellent responses were observed in 50/57 (88%) consecutive patients with active CLL treated since 1964, and complete remissions were achieved in 22/57 (39%). Toxicity was acceptable and was minimized by combining TBI and chemotherapy in attenuated doses of each modality. The responders had a modified natural history of disease as evidenced by prolonged survival, improved quality of life, and even restoration of immunologic competence in some cases. Benefit was particularly evident for patients with a poor prognosis, i.e., those with anemia and/or thrombocytopenia prior to treatment. A median survival of 55 months for the 40 Stage III-IV patients is 2-3 times longer than described for comparable patients in other series. This experience indicates TBI may be the most effective single agent available for the treatment of CLL and warrants consideration in primary therapy

  7. Relationship of blood monocytes with chronic lymphocytic leukemia aggressiveness and outcomes: a multi-institutional study.

    Science.gov (United States)

    Friedman, Daphne R; Sibley, Alexander B; Owzar, Kouros; Chaffee, Kari G; Slager, Susan; Kay, Neil E; Hanson, Curtis A; Ding, Wei; Shanafelt, Tait D; Weinberg, J Brice; Wilcox, Ryan A

    2016-07-01

    Monocyte-derived cells, constituents of the cancer microenvironment, support chronic lymphocytic leukemia (CLL) cell survival in vitro via direct cell-cell interaction and secreted factors. We hypothesized that circulating absolute monocyte count (AMC) reflects the monocyte-derived cells in the microenvironment, and that higher AMC is associated with increased CLL cell survival in vivo and thus inferior CLL patient outcomes. We assessed the extent to which AMC at diagnosis of CLL is correlated with clinical outcomes, and whether this information adds to currently used prognostic markers. We evaluated AMC, clinically used prognostic markers, and time to event data from 1,168 CLL patients followed at the Mayo Clinic, the Duke University Medical Center, and the Durham VA Medical Center. Elevated AMC was significantly associated with inferior clinical outcomes, including time to first therapy (TTT) and overall survival (OS). AMC combined with established clinical and molecular prognostic markers significantly improved risk-stratification of CLL patients for TTT. As an elevated AMC at diagnosis is associated with accelerated disease progression, and monocyte-derived cells in the CLL microenvironment promote CLL cell survival and proliferation, these findings suggest that monocytes and monocyte-derived cells are rational therapeutic targets in CLL. Am. J. Hematol. 91:687-691, 2016. © 2016 Wiley Periodicals, Inc. PMID:27037726

  8. The novel NF-κB inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Nuclear factor-κB (NF-κB) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-κB inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of IκBα by IkB kinases, thus preventing NF-κB release. In this study, we investigated if IMD-0354 can inhibit NF-κB activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-κB were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8–48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-κB in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo

  9. Where does allogeneic stem cell transplantation fit in the treatment of chronic lymphocytic leukemia?

    Science.gov (United States)

    Dreger, Peter; Montserrat, Emili

    2015-03-01

    Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been considered as the treatment of choice for patients with high-risk chronic lymphocytic leukemia (CLL) (i.e., refractory to purine analogs, short response (<24 months) to intensive treatments, and/or presence of 17p/TP53 abnormalities). Currently, new and highly effective therapeutic agents targeting BCR-mediated intracellular signal transduction have been incorporated into the CLL treatment armamentarium. These signal transduction inhibitors (STI) will change the algorithms of high-risk CLL (HR-CLL) management. Despite the limited body of evidence, there is sufficient rationale for withholding alloHSCT in patients with 17p-/TP53mut CLL in first remission. In contrast, the perspectives of patients with relapsed 17p-/TP53mut CLL remain uncertain even if responding to STI. The same accounts for patients with HR-CLL progressing under STI. In both scenarios, it is reasonable to consider alloHSCT, ideally after response to alternative STI regimens. PMID:25651976

  10. Sensitivity of chronic lymphocytic leukemia cells to small targeted therapeutic molecules: An in vitro comparative study.

    Science.gov (United States)

    Sylvan, Sandra Eketorp; Skribek, Henriette; Norin, Stefan; Muhari, Orsolya; Österborg, Anders; Szekely, Laszlo

    2016-01-01

    New drugs targeting important cellular signaling pathways are currently being developed for chronic lymphocytic leukemia (CLL). It is therefore of interest to analyze their in vitro killing capacity in manufacturer-independent, comparative experiments. We here report on the sensitivity of CLL cells to a panel of emerging targeted therapeutics using high-throughput screening based on an automated fluorescence digital scanning system. Fresh CLL cells from 42 patients with indolent or progressive CLL were cultured for 72 hours on microtiter plates in a unique primary cell culture medium. Antitumor effects of 31 small therapeutic molecules (and, as controls, 29 cytostatic agents) at equimolar concentration were compared in a fluorescence survival assay. In vitro sensitivity to each drug exhibited considerable interpatient variability. The highest mean direct killing was observed for one survivin inhibitor (YM-155), two bcl-2 inhibitors (ABT-199, ABT-737), and one selective CDK inhibitor (dinaciclib). Their killing capacity was, in contrast to most cytostatic agents, similarly high in refractory versus untreated CLL patients and was significantly higher on cells with the 17p deletion/TP53 mutation than on cells with other cytogenetic abnormalities (p = 0.02). Sensitivity of bone marrow and lymph node cells was highly correlated with that of blood cells. Even though direct killing may not be the only therapeutic effector function in vivo, results from this head-to-head comparison may help to identify drugs of particular interest for intensified clinical development. PMID:26325331

  11. Automatic detection of axillary lymphadenopathy on CT scans of untreated chronic lymphocytic leukemia patients

    Science.gov (United States)

    Liu, Jiamin; Hua, Jeremy; Chellappa, Vivek; Petrick, Nicholas; Sahiner, Berkman; Farooqui, Mohammed; Marti, Gerald; Wiestner, Adrian; Summers, Ronald M.

    2012-03-01

    Patients with chronic lymphocytic leukemia (CLL) have an increased frequency of axillary lymphadenopathy. Pretreatment CT scans can be used to upstage patients at the time of presentation and post-treatment CT scans can reduce the number of complete responses. In the current clinical workflow, the detection and diagnosis of lymph nodes is usually performed manually by examining all slices of CT images, which can be time consuming and highly dependent on the observer's experience. A system for automatic lymph node detection and measurement is desired. We propose a computer aided detection (CAD) system for axillary lymph nodes on CT scans in CLL patients. The lung is first automatically segmented and the patient's body in lung region is extracted to set the search region for lymph nodes. Multi-scale Hessian based blob detection is then applied to detect potential lymph nodes within the search region. Next, the detected potential candidates are segmented by fast level set method. Finally, features are calculated from the segmented candidates and support vector machine (SVM) classification is utilized for false positive reduction. Two blobness features, Frangi's and Li's, are tested and their free-response receiver operating characteristic (FROC) curves are generated to assess system performance. We applied our detection system to 12 patients with 168 axillary lymph nodes measuring greater than 10 mm. All lymph nodes are manually labeled as ground truth. The system achieved sensitivities of 81% and 85% at 2 false positives per patient for Frangi's and Li's blobness, respectively.

  12. Prognostic signature and clonality pattern of recurrently mutated genes in inactive chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    An increasing numbers of patients are being diagnosed with asymptomatic early-stage chronic lymphocytic leukemia (CLL), with no treatment indication at baseline. We applied a high-throughput deep-targeted analysis, especially designed for covering widely TP53 and ATM genes, in 180 patients with inactive disease at diagnosis, to test the independent prognostic value of CLL somatic recurrent mutations. We found that 40/180 patients harbored at least one acquired variant with ATM (n=17, 9.4%), NOTCH1 (n=14, 7.7%), TP53 (n=14, 7.7%) and SF3B1 (n=10, 5.5%) as most prevalent mutated genes. Harboring one ‘sub-Sanger' TP53 mutation granted an independent 3.5-fold increase of probability of needing treatment. Those patients with a double-hit ATM lesion (mutation+11q deletion) had the shorter median time to first treatment (17 months). We found that a genomic variable: TP53 mutations, most of them under the sensitivity of conventional techniques; a cell phenotypic factor: CD38-positive expression; and a classical marker as β2-microglobulin, remained as the unique independent predictors of outcome. The high-throughput determination of TP53 status, particularly in this set of patients frequently lacking high-risk chromosomal aberrations, emerges as a key step, not only for prediction modeling, but also for exploring mutation-specific therapeutic approaches and minimal residual disease monitoring

  13. Chronic lymphocytic thyroiditis and BRAF V600E in papillary thyroid carcinoma.

    Science.gov (United States)

    Kim, Seo Ki; Woo, Jung-Woo; Lee, Jun Ho; Park, Inhye; Choe, Jun-Ho; Kim, Jung-Han; Kim, Jee Soo

    2016-01-01

    It has been reported that papillary thyroid carcinoma (PTC) with chronic lymphocytic thyroiditis (CLT) is less associated with extrathyroidal extension (ETE), advanced tumor stage and lymph node (LN) metastasis. Other studies have suggested that concurrent CLT could antagonize PTC progression, even in BRAF-positive patients. Since the clinical significance of the BRAF mutation has been particularly associated with conventional PTC, the purpose of this study was to determine the clinical significance of CLT according to BRAF mutation status in conventional PTC patients. We retrospectively reviewed the medical records of 3332 conventional PTC patients who underwent total thyroidectomy with bilateral central neck dissection at the Thyroid Cancer Center of Samsung Medical Center between January 2008 and June 2015. In this study, the prevalence of BRAF mutation was significantly less frequent in conventional PTC patients with CLT (76.9% vs 86.6%). CLT was an independent predictor for low prevalence of ETE in both BRAF-negative (OR=0.662, P=0.023) and BRAF-positive (OR=0.817, P=0.027) conventional PTC patients. In addition, CLT was an independent predictor for low prevalence of CLNM in both BRAF-negative (OR=0.675, P=0.044) and BRAF-positive (OR=0.817, P=0.030) conventional PTC patients. In conclusion, BRAF mutation was significantly less frequent in conventional PTC patients with CLT. However, CLT was an independent predictor for less aggressiveness in conventional PTC patients regardless of BRAF mutation status. PMID:26598713

  14. State-of-the-Art Treatment and Novel Agents in Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Cramer, Paula; Hallek, Michael; Eichhorst, Barbara

    2016-01-01

    Chemoimmunotherapy is the established first-line treatment of patients with chronic lymphocytic leukemia (CLL) who do not display the high-risk genetic features del(17p) and/or TP53 mutation: Physically fit patients without or with only mild comorbidities should receive fludarabine, cyclophosphamide and rituximab, while bendamustine and rituximab can be considered in fit elderly patients of over 65 years and in patients with a higher risk of infections. Patients with relevant coexisting conditions should receive chlorambucil with a CD20 antibody, preferably obinutuzumab. Patients with a del(17p) and/or TP53 mutation respond poorly to conventional chemo(immuno)therapies. However, the recently approved BTK and PI3K inhibitors ibrutinib and idelalisib have the best efficacy ever documented in patients with these high-risk genomic alterations and/or refractory CLL. The choice between ibrutinib and idelalisib should be based on the patients' comorbidities and concomitant medications since both agents have a distinct toxicity profile, although they are generally well tolerated in the majority of patients. For treatment of patients with a late relapse, chemoimmunotherapy instead of kinase inhibitors is still a reasonable approach, but has to be determined for every patient individually. Further targeted drugs and their combinations are currently being evaluated in clinical trials and have the potential to eradicate all residual CLL cells and thus lead to a cure of CLL. PMID:26890007

  15. Pitting new treatments for chronic lymphocytic leukemia against old ones: how do they fare?

    Science.gov (United States)

    Shvidel, Lev; Berrebi, Alain

    2016-03-01

    Significant progress has been made in the treatment of chronic lymphocytic leukemia (CLL) patients during the last two decades. In this review we present a personal case study for discussion on contemporary management in CLL. Presently immunochemotherapy using fludarabine, cyclophosphamide, and rituximab (FCR) is the standard upfront regimen for physically fit patients requiring treatment. Patients older than 65 years can be treated with modified doses of FCR, bendamustine, or chlorambucil combined with anti-CD20 antibody. This treatment can be repeated at relapse when the duration of response is over 2 years. Patients at high risk (with 17p deletion or early relapse) need alternative treatment with novel agents, e.g. ibrutinib or idelalisib. However, the optimal use of the novel agents in terms of duration, combinations, and long-term adverse effects is unknown. In selected eligible patients at high risk, allogeneic transplantation should be considered. Clinical trials in all stages of treatment are encouraged. PMID:26613391

  16. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

    Science.gov (United States)

    Puente, Xose S.; Pinyol, Magda; Quesada, Víctor; Conde, Laura; Ordóñez, Gonzalo R.; Villamor, Neus; Escaramis, Georgia; Jares, Pedro; Beà, Sílvia; González-Díaz, Marcos; Bassaganyas, Laia; Baumann, Tycho; Juan, Manel; López-Guerra, Mónica; Colomer, Dolors; Tubío, José M. C.; López, Cristina; Navarro, Alba; Tornador, Cristian; Aymerich, Marta; Rozman, María; Hernández, Jesús M.; Puente, Diana A.; Freije, José M. P.; Velasco, Gloria; Gutiérrez-Fernández, Ana; Costa, Dolors; Carrió, Anna; Guijarro, Sara; Enjuanes, Anna; Hernández, Lluís; Yagüe, Jordi; Nicolás, Pilar; Romeo-Casabona, Carlos M.; Himmelbauer, Heinz; Castillo, Ester; Dohm, Juliane C.; de Sanjosé, Silvia; Piris, Miguel A.; de Alava, Enrique; Miguel, Jesús San; Royo, Romina; Gelpí, Josep L.; Torrents, David; Orozco, Modesto; Pisano, David G.; Valencia, Alfonso; Guigó, Roderic; Bayés, Mónica; Heath, Simon; Gut, Marta; Klatt, Peter; Marshall, John; Raine, Keiran; Stebbings, Lucy A.; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.; Gut, Ivo; López-Guillermo, Armando; Estivill, Xavier; Montserrat, Emili; López-Otín, Carlos; Campo, Elías

    2012-01-01

    Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution1,2. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes3,4. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer. PMID:21642962

  17. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.

    Science.gov (United States)

    Burger, Jan A; Landau, Dan A; Taylor-Weiner, Amaro; Bozic, Ivana; Zhang, Huidan; Sarosiek, Kristopher; Wang, Lili; Stewart, Chip; Fan, Jean; Hoellenriegel, Julia; Sivina, Mariela; Dubuc, Adrian M; Fraser, Cameron; Han, Yulong; Li, Shuqiang; Livak, Kenneth J; Zou, Lihua; Wan, Youzhong; Konoplev, Sergej; Sougnez, Carrie; Brown, Jennifer R; Abruzzo, Lynne V; Carter, Scott L; Keating, Michael J; Davids, Matthew S; Wierda, William G; Cibulskis, Kristian; Zenz, Thorsten; Werner, Lillian; Dal Cin, Paola; Kharchencko, Peter; Neuberg, Donna; Kantarjian, Hagop; Lander, Eric; Gabriel, Stacey; O'Brien, Susan; Letai, Anthony; Weitz, David A; Nowak, Martin A; Getz, Gad; Wu, Catherine J

    2016-01-01

    Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance. PMID:27199251

  18. Evaluation of chronic lymphocytic leukemia by BAC-based microarray analysis

    Directory of Open Access Journals (Sweden)

    McDaniel Lisa D

    2011-02-01

    Full Text Available Abstract Background Chronic lymphocytic leukemia (CLL is a highly variable disease with life expectancies ranging from months to decades. Cytogenetic findings play an integral role in defining the prognostic significance and treatment for individual patients. Results We have evaluated 25 clinical cases from a tertiary cancer center that have an established diagnosis of CLL and for which there was prior cytogenetic and/or fluorescence in situ hybridization (FISH data. We performed microarray-based comparative genomic hybridization (aCGH using a bacterial artificial chromosome (BAC-based microarray designed for the detection of known constitutional genetic syndromes. In 15 of the 25 cases, aCGH detected all copy number imbalances identified by prior cytogenetic and/or FISH studies. For the majority of those not detected, the aberrations were present at low levels of mosaicism. Furthermore, for 15 of the 25 cases, additional abnormalities were detected. Four of those cases had deletions that mapped to intervals implicated in inherited predisposition to CLL. For most cases, aCGH was able to detect abnormalities present in as few as 10% of cells. Although changes in ploidy are not easily discernable by aCGH, results for two cases illustrate the detection of additional copy gains and losses present within a mosaic tetraploid cell population. Conclusions Our results illustrate the successful evaluation of CLL using a microarray optimized for the interrogation of inherited disorders and the identification of alterations with possible relevance to CLL susceptibility.

  19. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia.

    Science.gov (United States)

    Rossi, Davide; Rasi, Silvia; Fabbri, Giulia; Spina, Valeria; Fangazio, Marco; Forconi, Francesco; Marasca, Roberto; Laurenti, Luca; Bruscaggin, Alessio; Cerri, Michaela; Monti, Sara; Cresta, Stefania; Famà, Rosella; De Paoli, Lorenzo; Bulian, Pietro; Gattei, Valter; Guarini, Anna; Deaglio, Silvia; Capello, Daniela; Rabadan, Raul; Pasqualucci, Laura; Dalla-Favera, Riccardo; Foà, Robin; Gaidano, Gianluca

    2012-01-12

    Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here, we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of newly diagnosed CLL were used as training (n = 309) and validation (n = 230) cohorts. NOTCH1 mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1 mutations led to a 3.77-fold increase in the hazard of death and to shorter overall survival (OS; P independent predictor of OS after controlling for confounding clinical and biologic variables. The independent prognostic value of NOTCH1 mutations was externally confirmed in the validation series. The poor prognosis conferred by NOTCH1 mutations was attributable, at least in part, to shorter treatment-free survival and higher risk of Richter transformation. Although NOTCH1 mutated patients were devoid of TP53 disruption in more than 90% cases in both training and validation series, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL. NOTCH1 mutations are an independent predictor of CLL OS, tend to be mutually exclusive with TP53 abnormalities, and identify cases with a dismal prognosis. PMID:22077063

  20. Evaluation of 13q14 Status in Patients with Chronic Lymphocytic Leukemia Using Single Nucleotide Polymorphism-Based Techniques

    OpenAIRE

    Hanlon, Katy; Ellard, Sian; Rudin, Claudius E.; Thorne, Susan; Davies, Teresa; Harries, Lorna W.

    2009-01-01

    Deletions of chromosome 13q14 are common in chronic lymphocytic leukemia and other cancers, demonstrating the importance of this region in tumorigenesis. We report the use of two single-nucleotide polymorphism (SNP)-based techniques to determine 13q loss of heterozygosity (LOH) status in 15 patients with CLL: (i) digital SNP (dSNP), where analysis of heterozygous SNPs detects allelic imbalances, and (ii) DNA sequencing, where LOH is identified by comparison of allelic peak heights in normal a...

  1. Ibrutinib: an evidence-based review of its potential in the treatment of advanced chronic lymphocytic leukemia

    OpenAIRE

    Chavez JC; Sahakian E; Pinilla-Ibarz J

    2013-01-01

    Julio C Chavez, Eva Sahakian, Javier Pinilla-IbarzH Lee Moffitt Cancer and Research Institute, Division of Malignant Hematology, and University of South Florida, Tampa, FL, USAAbstract: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable course, and remains an incurable disease. Frequent relapses and eventual resistance to fludarabine characterize symptomatic CLL and portends a dismal prognosis for patients. Growing evidence has shown that signaling pathways such as ...

  2. The Diagnostic Value of Flow Cytometry Imunophenotyping in an Albanian Patient Population with a Preliminary Clinical Diagnosis of Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Valentina Semanaj

    2014-03-01

    Conclusion: Flow cytometry immunophenotyping is a fundamental examination for the final diagnosis of chronic lymphocytic leukemia. The expression of CD38+ in CLL patients stands for a more advanced clinical stage.

  3. Magnetic resonance imaging may simulate progressive multifocal leucoencephalopathy in a patient with chronic lymphocytic leukemia after fludarabine therapy

    Directory of Open Access Journals (Sweden)

    Kalita J

    2008-01-01

    Full Text Available A 60-year-old male with chronic lymphatic leukemia (CLL after 6 months of fludarabine therapy was admitted with status epilepticus and developed left hemiplegia. His magnetic resonance imaging revealed multiple T2 hyperintense lesions in the right frontal and left parieto-occipital lesion, simulating progressive multifocal leucoencephalopathy (PML. Cerebrospinal fluid Polymerase Chain Reaction (PCR for JC virus was negative. We suggest the possible role of fludarabine in producing PML-like lesions in patients with Chronic Lymphocytic Leukemia (CLL.

  4. Impact of chronic lymphocytic thyroiditis on the prognosis of differentiated thyroid cancer

    International Nuclear Information System (INIS)

    Full text: The association of chronic lymphocytic thyroiditis (CLT) and differentiated thyroid cancer, and its prognosis significance remain controversial. We investigate the prognosis impact of this association by reviewing our series of patients being followed for differentiated thyroid cancer (DTC) at the department of nuclear medicine of Sahloul. Among the 350 patients followed in our department, 30 (8.5%) had histologically proved CLT, with infiltration of the non- tumoral thyroid tissue. A second group of 60 patients (without evidence of lymphocytic infiltration) was selected randomly and used as controls. The median of follow-up for these two groups was 4 years. The frequency of papillary thyroid cancer was significantly higher in the group with CTL (90% vs 74%; p=0.05). The larger diameter of the tumor didn't differ significantly (p= 0.36) between the group with TLC (mean=2.7; SD=1.98) and the control group 3.08 (SD=1.66). There was also no significant difference in capsular infiltration (37% vs 36%; p=0.96), nodal metastases (47% vs 43%; p=0.74), multicentric tumors (37% vs 38%; p=0.99) and bilateral tumors (20% vs 22%; p=0.9). At initial presentation, distant metastases were less frequent in patients with coexisting CLT and DTC (3% vs 12%, p<1%). Nevertheless, if we consider only patients with papillary thyroid cancer, the difference was not statistically significant (0% vs 6%; p=0.23). During the follow-up (mean 4 years), there was no significant difference in nodal relapse (20% vs 8% p=0.1), and distant metastasis (6% vs 3%: p=0.45). No death was noted in the first group, and two were observed in the second (patients with follicular thyroid cancer). The most striking result of this study is the total absence of significant impact of CLT on the prognosis of DTC. Our results seem to be on opposite to those of the majority of authors, underlying the complexity of this entity. We think that some factors specific to our population (iodine diet, ethnical

  5. Ibrutinib in Treating Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma in Patients With HIV Infection

    Science.gov (United States)

    2015-08-18

    Adult B Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; HIV Infection; Intraocular Lymphoma; Multicentric Angiofollicular Lymphoid Hyperplasia; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Plasma Cell Myeloma; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  6. Effects of thyroxine on cardiac function and lymphocyte β-adrenoceptors in patients with chronic congestive heart failure

    Institute of Scientific and Technical Information of China (English)

    卢新政; 黄峻; 张晓文; 李新华; 王赤京; 张佩生; 陈永生

    2003-01-01

    Objective To explore the effects of thyroid hormone (TH) on cardiac function and peripheral lymphocyte β-adrenoceptors (β-Ars) of patients with chronic congestive heart failure (CHF). Methods Twenty-eight patients with class Ⅲ or Ⅳ advanced CHF due to dilated cardiomyopathy (DCM) or ischemic cardiomyopathy (ICM) were randomly divided into groups A and B. L-thyroxine (L-T50) was administered to group B. Exercise tolerance, chest X-rays, and echocardiographic parameters were obtained before and after one month of treatment, Ficoll-hypaque solution was used to separate peripheral lymphocytes, and 125I-pindolol radioligand binding was used to measure β-AR levels in peripheral lymphocytes. Results L-T50 therapy improved cardiac output [CO, (2.98±0.31)L/min vs (3.24±0.28) L/min, P<0.01], left ventricular ejection fraction (LVEF, 26.21%±3.21% vs 37.93%±9.01%, P<0.01), and decreased isovolumetric relaxation time (IVRT, 0.12±0.04 vs 0.10±0.02, P<0.01). Serum TH levels and the maximal number of β-AR binding sites (βmax ) in peripheral lymphocytes were lower in patients with CHF than in normal healthy people, but L-T50 administration induced a β-AR up-regulation on peripheral lymphocyte surfaces. L-T50 was well tolerated without episodes of ischemia or arrhythmia. There was no significant change in heart rate or metabolic rate.Conclusion TH administration improves cardiac function and β-AR expression in peripheral lymphocytes of patients with CHF.

  7. A Novel Natural Product, KL-21, Inhibits Proliferation and Induces Apoptosis in Chronic Lymphocytic Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Aysun Adan Gökbulut

    2015-06-01

    Full Text Available INTRODUCTION: The aims of this study were to examine the cytotoxic and apoptotic effects of KL-21, a novel plant product (produced by Naturin Natural Products, İzmir, Turkey, on 232B4 chronic lymphocytic leukemia (CLL cells and to determine the cytotoxic effects on healthy BEAS-2B human bronchial epithelial cells. METHODS: The cytotoxic effect of KL-21 was determined by MTT cell proliferation assay. Changes in caspase-3 enzyme activity were measured using the caspase-3 colorimetric assay. Changes in mitochondrial membrane potential were determined using the JC-1 dye-based method. Annexin V-FITC/PI double staining was performed to measure the apoptotic cell population. Effects of KL-21 on cell cycle profiles of CLL cells were investigated by flow cytometry. RESULTS: We detected time- and concentration-dependent increases in the cytotoxic effect of KL-21 on 232B4 CLL cells. However, we also showed that, especially at higher concentrations, KL-21 was less cytotoxic towards BEAS-2B healthy cells than towards CLL cells. Annexin-V/PI double staining results showed that the apoptotic cell population increased in 232B4 cells. Increasing concentrations of KL-21 increased caspase-3 enzyme activity and induced loss of mitochondrial membrane potential. KL-21 administration resulted in small increases in the percentage of the cells in the G0/G1 phase while it decreased the S phase cell population up to 1 mg/mL. At the highest concentration, most of the cells accumulated in the G0/G1 phase. DISCUSSION AND CONCLUSION: KL-21 has a growth-inhibitory effect on 232B4 CLL cells. KL-21 causes apoptosis and cell cycle arrest at G0/G1.

  8. A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy.

    Science.gov (United States)

    Awan, Farrukh T; Jones, Jeffrey A; Maddocks, Kami; Poi, Ming; Grever, Michael R; Johnson, Amy; Byrd, John C; Andritsos, Leslie A

    2016-06-01

    Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m(2) followed by a 4-h infusion of 30 mg/m(2) once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies.Registration number at ClinicalTrials.gov: NCT00377104. PMID:27118540

  9. Spontaneous Immunity Against the Receptor Tyrosine Kinase ROR1 in Patients with Chronic Lymphocytic Leukemia.

    Directory of Open Access Journals (Sweden)

    Mohammad Hojjat-Farsangi

    Full Text Available ROR1 is a receptor tyrosine kinase expressed in chronic lymphocytic leukemia (CLL and several other malignancies but absent in most adult normal tissues. ROR1 is considered an onco-fetal antigen. In the present study we analysed spontaneous humoral and cellular immunity against ROR1 in CLL patients.Antibodies against ROR1 were analysed in 23 patients and 20 healthy donors by ELISA and Western blot. Purified serum IgG from patients was tested for cytotoxicity against CLL cells using the MTT viability assay. A cellular immune response against ROR1 derived HLA-A2 restricted 9 aa and 16 aa long peptides were analysed using peptide loaded dendritic cells co-cultured with autologous T cells from CLL patients (n = 9 and healthy donors (n = 6. IFN-γ, IL-5 and IL-17A-secreting T cells were assessed by ELISPOT and a proliferative response using a H3-thymidine incorporation assay.The majority of CLL patients had antibodies against ROR1. Significantly higher titers of anti-ROR1 antibodies were noted in patients with non-progressive as compared to progressive disease. The extracellular membrane-close ROR1 KNG domain seemed to be an immunodominant epitope. Ten patients with high titers of anti-ROR1 binding antibodies were tested for cytotoxicity. Five of those had cytotoxic anti-ROR1 antibodies against CLL cells. ROR1-specific IFN-γ and IL-17A producing T cells could be detected in CLL patients, preferentially in non-progressive as compared to patients with progressive disease (p<0.05.ROR1 seemed to spontaneously induce a humoral as well as a T cell response in CLL patients. The data support the notion that ROR1 might be a specific neo-antigen and may serve as a target for immunotherapy.

  10. Molecular characterization of resistant chronic lymphocytic leukemia (CLL): function of a new phosphorylated form of Ku70

    International Nuclear Information System (INIS)

    We have identified a new form of phospho-S27-S33-Ku70 constitutively over expressed in a subset of chronic lymphocytic leukemia (CLL) B cells resistant to apoptosis induced by DNA double strand breaks (DSB). Ku70 is one of the essential proteins involved in the maintenance of genomic stability through its role in DNA double strand break repair (non-homologous end-joining, NHEJ) and in telomeric protection. Laboratory previously established that resistant CLL cells disclose an up-regulated NHEJ DNA repair and an impaired structure of telomeres. The goal of this thesis was to characterize the biological function(s) of this new form of Ku70. For this purpose we have constructed specific EBV-based vectors (siRNA / cDNA) enabling a simultaneous inhibition of endogenous Ku70 and an expression of different forms (mutated, wild, phospho-mimetic at ser27-33) of Ku70 resistant to siRNA. Thus, we showed: i) a strict co-localisation of phospho-Ku70 with γ-H2AX foci; ii) that DSB induces the phosphorylation of Ku70 within minutes after genotoxic stress in heterodimer complex Ku70/Ku80. This phosphorylation necessitates both the physical interaction and the activity of pS2056-DNA-PKcs and/or ATM, linking phospho-Ku70 to NHEJ-mediated DNA DSB repair; iii) cells expressing mutated A27-A33-Ku70 exhibit a delayed G2/M cell cycle arrest, slower kinetic of DNA repair, lower level of genotoxic stress-induced chromosomal aberrations, and a higher cellular impedance correlated with translocation of transcriptional factor β-catenin from cytoplasmic membrane to the nucleus. Together, these data unveil an involvement of phospho-Ku70 in fast and inaccurate DNA repair; new paradigm for NHEJ regulation and to the control of resistance and maintenance of malignant cells.In parallel, we have initiated experimental approaches to explore other potential roles of phospho-Ku70. Especially, we were interested to determine whether it could play a role in an initiation of cell senescence induced by

  11. Targeting neoplastic B cells and harnessing microenvironment: the "double face" of ibrutinib and idelalisib.

    Science.gov (United States)

    Maffei, Rossana; Fiorcari, Stefania; Martinelli, Silvia; Potenza, Leonardo; Luppi, Mario; Marasca, Roberto

    2015-01-01

    Tyrosine kinase inhibitors (TKIs) targeting signaling molecules downstream B cell receptor (BCR) are powerfully spreading in the therapeutic landscape of B cell lymphoproliferative disease, due to a manageable toxicity profile and encouraging clinical effectiveness. In particular, ibrutinib, previously called PCI-32765, is a potent inhibitor of Bruton tyrosine kinase (Btk), recently approved for the treatment of relapsed mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Moreover, idelalisib (formerly GS-1101 and CAL-101) is a selective reversible inhibitor of the p110δ isoform of phosphoinositol 3 kinase (PI3K) approved for the treatment of patients with relapsed follicular lymphoma (FL) and CLL. These agents directly affect the neoplastic clone, disrupting the supportive platform provided by BCR signaling cascade and by other microenvironmental mutualistic interactions, and also interfering with chemokine gradients and adhesive properties of neoplastic B cells. In the present review, we describe the clinical efficacy of ibrutinib and idelalisib in CLL and B cell non-Hodgkin lymphoma (B-NHL), then focusing on the mode of action (MOA) of these TKIs towards the neoplastic B cell compartment. At last, the review would further expand the view on potential additional targets of ibrutinib and idelalisib belonging to other microenvironmental cellular elements. PMID:26022368

  12. Cardiac tamponade mimicking tuberculous pericarditis as the initial presentation of chronic lymphocytic leukemia in a 58-year-old woman: a case report

    Directory of Open Access Journals (Sweden)

    Nathan Sandeep

    2010-08-01

    Full Text Available Abstract Introduction Chronic lymphocytic leukemia is an indolent disease that often presents with complaints of lymphadenopathy or is detected as an incidental laboratory finding. It is rarely considered in the differential diagnosis of patients presenting with tamponade or a large, bloody pericardial effusion. In patients without known cancer, a large, bloody pericardial effusion raises the possibility of tuberculosis, particularly in patients from endemic areas. However, the signs, symptoms and laboratory findings of pericarditis related to chronic lymphocytic leukemia can mimic tuberculosis. Case Presentation We report the case of a 58-year-old African American-Nigerian woman with a history of travel to Nigeria and a positive tuberculin skin test who presented with cardiac tamponade. She had a mild fever, lymphocytosis and a bloody pericardial effusion, but cultures and stains were negative for acid-fast bacteria. Assessment of blood by flow cytometry and pericardial biopsy by immunohistochemistry revealed CD5 (+ and CD20 (+ lymphocytes in both tissues, demonstrating this to be an unusual manifestation of early stage chronic lymphocytic leukemia. Conclusion Although most malignancies that involve the pericardium clinically manifest elsewhere before presenting with tamponade, this case illustrates the potential for early stage chronic lymphocytic leukemia to present as a large pericardial effusion with tamponade. Moreover, the presentation mimicked tuberculosis. This case also demonstrates that it is possible to treat chronic lymphocytic leukemia-related pericardial tamponade by removal of the fluid without chemotherapy.

  13. Persistent Polyclonal B Cell Lymphocytosis B Cells Can Be Activated through CD40-CD154 Interaction

    Directory of Open Access Journals (Sweden)

    Emmanuelle Dugas-Bourdages

    2014-01-01

    Full Text Available Persistent polyclonal B cell lymphocytosis (PPBL is a rare disorder, diagnosed primarily in adult female smokers and characterized by an expansion of CD19+CD27+IgM+ memory B cells, by the presence of binucleated lymphocytes, and by a moderate elevation of serum IgM. The clinical course is usually benign, but it is not known whether or not PPBL might be part of a process leading to the emergence of a malignant proliferative disorder. In this study we sought to investigate the functional response of B cells from patients with PPBL by use of an optimal memory B cell culture model based on the CD40-CD154 interaction. We found that the proliferation of PPBL B cells was almost as important as that of B cells from normal controls, resulting in high immunoglobulin secretion with in vitro isotypic switching. We conclude that the CD40-CD154 activation pathway is functional in the memory B cell population of PPBL patients, suggesting that the disorder may be due to either a dysfunction of other cells in the microenvironment or a possible defect in another B cell activation pathway.

  14. FDA Approves New Drug for Chronic Lymphocytic Leukemia in Patients with a Specific Chromosomal Abnormality

    Science.gov (United States)

    ... diagnosed each year. CLL is characterized by the progressive accumulation of abnormal lymphocytes, a type of white ... orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity ...

  15. E-cadherin gene re-expression in chronic lymphocytic leukemia cells by HDAC inhibitors

    International Nuclear Information System (INIS)

    The tumor suppressor gene E-cadherin gene is frequently silenced in chronic lymphocytic leukemia (CLL) cells and results in wnt-pathway activation. We analyzed the role of histone epigenetic modifications in E-cadherin gene silencing. CLL specimens were treated with histone deacetylase inhibitor (HDACi) MS-275 and analyzed for E-cadherin expression with western blot and RT-PCR analysis. The downstream effects of HDACi treated leukemic cells were studied by analyzing the effect on wnt-pathway signaling. HDACi induced alterations in E-cadherin splicing were investigated by transcript specific real time PCR analysis. Treatment of CLL specimens with histone deacetylase inhibitors (HDACi) treatment resulted in an increase of the E-cadherin RNA transcript (5 to 119 fold increase, n=10) in eight out of ten CLL specimens indicating that this gene is down regulated by histone hypoacetylation in a majority of CLL specimens. The E-cadherin re-expression in CLL specimens was noted by western blot analysis as well. Besides epigenetic silencing another mechanism of E-cadherin inactivation is aberrant exon 11 splicing resulting in an alternatively spliced transcript that lacks exon 11 and is degraded by the non-sense mediated decay (NMD) pathway. Our chromatin immunoprecipitation experiments show that HDACi increased the acetylation of histones H3 and H4 in the E-cadherin promoter region. This also affected the E-cadherin exon 11 splicing pattern as HDACi treated CLL specimens preferentially expressed the correctly spliced transcript and not the exon 11 skipped aberrant transcript. The re-expressed E- cadherin binds to β-catenin with inhibition of the active wnt-beta-catenin pathway in these cells. This resulted in a down regulation of two wnt target genes, LEF and cyclinD1 and the wnt pathway reporter. The E-cadherin gene is epigenetically modified and hypoacetylated in CLL leukemic cells. Treatment of CLL specimens with HDACi MS-275 activates transcription from this silent

  16. Surface antigen expression in chronic lymphocytic leukemia: clustering analysis, interrelationships and effects of chromosomal abnormalities.

    Science.gov (United States)

    Hulkkonen, J; Vilpo, L; Hurme, M; Vilpo, J

    2002-02-01

    Chronic lymphocytic leukemia (CLL) is a phenotypically distinguishable form of B-lymphoid leukemias. The regularity of surface membrane antigen expression patterns, their interrelationships as well as the effects of the three frequent chromosomal aberrations, ie 11q deletion, 13q deletion and trisomy 12, were investigated in 35 classic CLL cases by flow cytometry. The two-way cluster analysis of 31 individual antigens revealed three expression patterns: (1) most cells in most cases positive (CD5, CD19, CD20, CD23, CD27, CD40, CD45, CD45RA); (2) most cells in most cases negative (CD10, CD14, CD34, CD122, CD154, mIgG); and (3) a mixed pattern with a variable number of positive cases and a variable percentage of positive cells in individual cases (CD11c, CD21, CD22, CD25, CD38, CD45RO, CD79b, CD80, CD95, CD124, CD126, CD130, FMC7, mIgD, mIgkappa, mIglambda, mIgM). The expressions of several antigens were strongly interdependent, even when antigens belonged to entirely different gene families. Such antigen pairs were: CD11c/CD21; CD19/CD45; CD19/CD79b; CD22/CD45RA; CD23/Igkappa; CD25/mIgM; CD27/CD45; CD45/CD79b; CD45RA/Igkappa. In contrast, the expression of some antigens was mutually exclusive, the best examples being CD45RA/CD45RO, CD38/CD80 and CD45RA/CD80. Deletion of chromosome arm 11q attenuated expression of splicing variant CD45RA, but enhanced CD45RO expression. In contrast, cases of trisomy 12 were associated with enhanced CD45RA and attenuated CD45RO expression. Similarly, trisomy 12 was associated with enhanced CD27 and mIgkappa expression. The variable levels of signaling surface membrane antigens, their interactions and interference by genetic aberrations are likely to affect the clinical progression and drug response of CLL. PMID:11840283

  17. Epstein-Barr virus DNA load in chronic lymphocytic leukemia is an independent predictor of clinical course and survival

    OpenAIRE

    Visco, Carlo; Falisi, Erika; Young, Ken H; Pascarella, Michela; Perbellini, Omar; Carli, Giuseppe; Novella, Elisabetta; Rossi, Davide; Giaretta, Ilaria; Cavallini, Chiara; Scupoli, Maria Teresa; De Rossi, Anita; D'Amore, Emanuele Stefano Giovanni; Rassu, Mario; Gaidano, Gianluca

    2015-01-01

    The relation between Epstein-Barr virus (EBV) DNA load and clinical course of patients with chronic lymphocytic leukemia (CLL) is unknown. We assessed EBV DNA load by quantitative PCR at CLL presentation in mononuclear cells (MNC) of 220 prospective patients that were enrolled and followed-up in two major Institutions. In 20 patients EBV DNA load was also assessed on plasma samples. Forty-one age-matched healthy subjects were tested for EBV DNA load on MNC. Findings were validated in an indep...

  18. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib

    OpenAIRE

    Lipsky, Andrew H.; Farooqui, Mohammed Z.H.; Tian, Xin; Martyr, Sabrina; Cullinane, Ann M.; Nghiem, Khanh; Sun, Clare; Valdez, Janet; Niemann, Carsten U.; Herman, Sarah E. M.; Saba, Nakhle; Soto, Susan; Marti, Gerald; Uzel, Gulbu; Holland, Steve M.

    2015-01-01

    Ibrutinib is associated with bleeding-related adverse events of grade ≤2 in severity, and infrequently with grade ≥3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤2 bleeding-related adverse events in 55% of 85 patients. No grade ≥3 events occur...

  19. The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia

    OpenAIRE

    de Jong, Jan; Sukbuntherng, Juthamas; Skee, Donna; Murphy, Joe; O’Brien, Susan; Byrd, John C.; James, Danelle; Hellemans, Peter; Loury, David J.; Jiao, Juhui; Chauhan, Vijay; Mannaert, Erik

    2015-01-01

    Purpose To assess ibrutinib pharmacokinetics under fasted and fed conditions, impact of food-intake timing, and the safety and tolerability. Methods Three studies were analyzed. Study 1 was a randomized, open-label, single-dose, four-way crossover study in 44 healthy participants. Study 2 was a randomized, repeat-dose crossover study in 16 patients with previously treated chronic lymphocytic leukemia (CLL). Ibrutinib dose was 420 mg in both studies. Study 3 was an open-label, sequential study...

  20. Molecular Characterization of Chronic Lymphocytic Leukemia Patients with a High Number of Losses in 13q14

    OpenAIRE

    Rodríguez, Ana Eugenia; Hernández, Jose Ángel; Benito, Rocío; Gutiérrez, Norma C.; García, Juan Luis; Hernández-Sánchez, María; Risueño, Alberto; Sarasquete, M. Eugenia; Fermiñán, Encarna; Fisac, Rosa; de Coca, Alfonso García; Martín-Núñez, Guillermo; de las Heras, Natalia; Recio, Isabel; Gutiérrez, Oliver

    2012-01-01

    Background Patients with chronic lymphocytic leukemia and 13q deletion as their only FISH abnormality could have a different outcome depending on the number of cells displaying this aberration. Thus, cases with a high number of 13q- cells (13q-H) had both shorter overall survival and time to first therapy. The goal of the study was to analyze the genetic profile of 13q-H patients. Design and Methods: A total of 102 samples were studied, 32 of which served as a validation cohort and five were ...

  1. Pro-Apoptotic Activity of New Honokiol/Triphenylmethane Analogues in B-Cell Lymphoid Malignancies.

    Science.gov (United States)

    Mędra, Aleksandra; Witkowska, Magdalena; Majchrzak, Agata; Cebula-Obrzut, Barbara; Bonner, Michael Y; Robak, Tadeusz; Arbiser, Jack L; Smolewski, Piotr

    2016-01-01

    Honokiol and triphenylmethanes are small molecules with anti-tumor properties. Recently, we synthesized new honokiol analogues (HAs) that possess common features of both groups. We assessed the anti-tumor effectiveness of HAs in B-cell leukemia/lymphoma cells, namely in chronic lymphocytic leukemia (CLL) cells ex vivo and in pre-B-cell acute lymphoblastic leukemia (Nalm-6), Burkitt lymphoma (BL; Raji), diffuse large B-cell lymphoma (DLBCL; Toledo) and multiple myeloma (MM; RPMI 8226) cell lines. Four of these compounds appeared to be significantly active against the majority of cells examined, with no significant impact on healthy lymphocytes. These active HAs induced caspase-dependent apoptosis, causing significant deregulation of several apoptosis-regulating proteins. Overall, these compounds downregulated Bcl-2 and XIAP and upregulated Bax, Bak and survivin proteins. In conclusion, some of the HAs are potent tumor-selective inducers of apoptosis in ex vivo CLL and in BL, DLBCL and MM cells in vitro. Further preclinical studies of these agents are recommended. PMID:27483232

  2. Isolation and characterisation of T lymphocytes from sural nerve biopsies in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.

    OpenAIRE

    Ben-Smith, A.; Gaston, J S; Barber, P. C.; Winer, J B

    1996-01-01

    OBJECTIVES: To characterise cultured T lymphocytes from nerve biopsies in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Sural nerve biopsies, obtained from six patients with Guillain-Barré syndrome, four with CIDP, and six controls with other neuropathies, were cultured with 20 U/ml recombinant interleukin-2 (IL-2) for eight weeks. Flow cytometry was used to determine the phenotype of cultured T lymphocytes. Their proliferative re...

  3. Impact of chronic lymphocytic thyroiditis co-existing with differentiated thyroid cancer on the effectiveness of remnants ablation

    International Nuclear Information System (INIS)

    Full text: Some stages of chronic lymphocytic thyroiditis (CLT) are functionally characterized by an organification defect with large intra thyroid inorganic iodide pool, which can be discharged during perchlorate test. Fluorescent scan study indicates that most patients with CLT have decreased stable iodine store in the thyroid gland. The aim of our study was to investigate the possible consequences of these organification abnormalities during remnants ablation in patients with coexisting differentiated thyroid cancer (DTC) and chronic lymphocytic thyroiditis. We reviewed our series of patients of DTC being followed at the department of nuclear medicine of the university hospital Sahloul. Among the 350 patients with DTC, 30 (8.5%) had histologically proved chronic lymphocytic thyroiditis, with infiltration of the non-tumoral thyroid tissue. A second group of 60 patients (without evidence of lymphocytic infiltration) was selected randomly and used as control. The median of follow-up for these two groups was 4 years. All patients had undergone total thyroidectomy followed by scintigraphy 4-6 weeks later. In patients with thyroid remnants, standard ablative dose of 3.7 GBq of I-131 (100 mCi) was administrated with 6 months duration between all therapies, until the negativity of thyroid bed activity on follow up survey scan performed 48 to 72 hours after administering 2 to 3 mCi of I-131. Thyroglobulin (Tg) serum level was not considered as a criterion of ablation, because of the frequency of anti-thyroid antibodies in CLT. In the group with CLT, 3 patients had negative postoperative neck scintigraphy. Complete ablation was achieved with a single standard dose in 14, two standard doses in 5, and more than 200 mCi in two patients (300 in one and 400 in two). In five patients, ablation is not yet achieved. In the control group, ablation was obtained with 100 mCi in 43 patients, 200 mCi in 9, and 300 mCi in 3. In five patients ablation has not been achieved. Considering

  4. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib

    DEFF Research Database (Denmark)

    Lipsky, Andrew H; Farooqui, Mohammed Z H; Tian, Xin;

    2015-01-01

    Ibrutinib is associated with bleeding-related adverse events of grade ≤2 in severity, and infrequently with grade ≥3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated t......Ibrutinib is associated with bleeding-related adverse events of grade ≤2 in severity, and infrequently with grade ≥3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator......-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤2 bleeding-related adverse events in 55% of 85 patients. No grade ≥3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months...... 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not...

  5. In vitro screening for synergism of high-linear energy transfer Bi-213-radiotherapy with other therapeutic agents for the treatment of B-Cell chronic lymphocytic leukemia

    NARCIS (Netherlands)

    Vandenbulcke, Katia; Thierens, Hubert; De Vos, Filip; Philippe, Jan; Offner, Fritz; Janssens, Ann; Apostolidis, Christos; Morgenstern, Alfred; Bacher, Klaus; de Gelder, Virginie; Dierckx, Rudi A.; Slegers, Guido

    2006-01-01

    Background: External beam radiotherapy and beta-radioimmunotherapy (RIT) are effective treatments for lymphoid malignancies. The development of RIT with alpha-emitters is attractive, owing to the high (LET) nature and short path length of alpha particles allowing for higher tumor cell kill and lower

  6. Overexpression of the VAV proto-oncogene product is associated with B-cell chronic lymphocytic leukaemia displaying loss on 13q

    OpenAIRE

    Prieto-Sánchez, Rosario M.; Hernández, José Ángel; García, Juan L.; Gutiérrez, Norma Carmen; San Miguel, Jesús F.; Bustelo, Xosé R; Hernández, Jesús M.

    2006-01-01

    This work was supported by the US National Cancer Institute (5RO1-CA73735-08 to XRB), the Biomedicine Program of the Spanish Ministry of Education and Science (SAF2003-00028 to XRB), the Fondo de Investigaciones Sanitarias of the Spanish Health Ministry FIS-FEDER (PI020103 and PI02/1358 to XRB and JMH, respectively), and the Council from Castilla y León (‘Proyectos de Biomedicina del SACYL’). RMP-S is a student of the Molecular and Cellular Cancer Biology graduate program of the CIC and the U...

  7. miR-155 as a Biomarker in B-Cell Malignancies

    Science.gov (United States)

    Due, Hanne; Svendsen, Pernille; Bødker, Julie Støve; Schmitz, Alexander; Bøgsted, Martin; Johnsen, Hans Erik; El-Galaly, Tarec Christoffer; Roug, Anne Stidsholt; Dybkær, Karen

    2016-01-01

    MicroRNAs have the potential to be useful biomarkers in the development of individualized treatment since they are easy to detect, are relatively stable during sample handling, and are important determinants of cellular processes controlling pathogenesis, progression, and response to treatment of several types of cancers including B-cell malignancies. miR-155 is an oncomiR with a crucial role in tumor initiation and development of several B-cell malignancies. The present review elucidates the potential of miR-155 as a diagnostic, prognostic, or predictive biomarker in B-cell malignancies using a systematic search strategy to identify relevant literature. miR-155 was upregulated in several malignancies compared to nonmalignant controls and overexpression of miR-155 was further associated with poor prognosis. Elevated expression of miR-155 shows potential as a diagnostic and prognostic biomarker in diffuse large B-cell lymphoma and chronic lymphocytic leukemia. Additionally, in vitro and in vivo studies suggest miR-155 as an efficient therapeutic target, supporting its oncogenic function. The use of inhibiting anti-miR structures indicates promising potential as novel anticancer therapeutics. Reports from 53 studies prove that miR-155 has the potential to be a molecular tool in personalized medicine. PMID:27294145

  8. The tumor microenvironment shapes hallmarks of mature B-cell malignancies.

    Science.gov (United States)

    Shain, K H; Dalton, W S; Tao, J

    2015-09-01

    B-cell tumorigenesis results from a host of known and unknown genetic anomalies, including non-random translocations of genes that normally function as determinants of cell proliferation or cell survival to regions juxtaposed to active immunoglobulin heavy chain enhancer elements, chromosomal aneuploidy, somatic mutations that further affect oncogenic signaling and loss of heterozygosity of tumor-suppressor genes. However, it is critical to recognize that even in the setting of a genetic disease, the B-cell/plasma cell tumor microenvironment (TME) contributes significantly to malignant transformation and pathogenesis. Over a decade ago, we proposed the concept of cell adhesion-mediated drug resistance to delineate a form of TME-mediated drug resistance that protects hematopoietic tumor cells from the initial effect of diverse therapies. In the interim, it has been increasingly appreciated that TME also contributes to tumor initiation and progression through sustained growth/proliferation, self-renewal capacity, immune evasion, migration and invasion as well as resistance to cell death in a host of B-cell malignancies, including mantle cell lymphoma, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia, chronic lymphocytic leukemia and multiple myeloma. Within this review, we propose that TME and the tumor co-evolve as a consequence of bidirectional signaling networks. As such, TME represents an important target and should be considered integral to tumor progression and drug response. PMID:25639873

  9. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia

    Science.gov (United States)

    Levine, Ross L.; Loriaux, Marc; Huntly, Brian J. P.; Loh, Mignon L.; Beran, Miroslav; Stoffregen, Eric; Berger, Roland; Clark, Jennifer J.; Willis, Stephanie G.; Nguyen, Kim T.; Flores, Nikki J.; Estey, Elihu; Gattermann, Norbert; Armstrong, Scott; Look, A. Thomas; Griffin, James D.; Bernard, Olivier A.; Heinrich, Michael C.; Gilliland, D. Gary; Druker, Brian; Deininger, Michael W. N.

    2005-01-01

    Activating mutations in tyrosine kinases have been identified in hematopoietic and nonhematopoietic malignancies. Recently, we and others identified a single recurrent somatic activating mutation (JAK2V617F) in the Janus kinase 2 (JAK2) tyrosine kinase in the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML)/atypical chronic myelogenous leukemia (aCML), myelodysplastic syndrome (MDS), B-lineage acute lymphoblastic leukemia (ALL), T-cell ALL, and chronic lymphocytic leukemia (CLL). Analysis of 222 patients with AML identified JAK2V617F mutations in 4 patients with AML, 3 of whom had a preceding MPD. JAK2V617F mutations were identified in 9 (7.8%) of 116 CMML/a CML samples, and in 2 (4.2%) of 48 MDS samples. We did not identify the JAK2V617F disease allele in B-lineage ALL (n = 83), T-cell ALL (n = 93), or CLL (n = 45). These data indicate that the JAK2V617F allele is present in acute and chronic myeloid malignancies but not in lymphoid malignancies. PMID:16081687

  10. Modulation of B-cell receptor and microenvironment signaling by a guanine exchange factor in B-cell malignancies

    Institute of Scientific and Technical Information of China (English)

    Wei Liao; Sanjai Sharma

    2016-01-01

    Objective: Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cells over-express a guanine exchange factor (GEF), Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from Ras so that GTP can bind and activate Ras. This study aims to study the mechanism of action of Rasgrf-1 in B-cell malignancies. Methods: N-terminus truncated Rasgrf-1 variants have a higher GEF activity as compared to the full-length transcript therefore a MCL cell line with stable over-expression of truncated Rasgrf-1 was established. The B-cell receptor (BCR) and chemokine signaling pathways were compared in the Rasgrf-1 over-expressing and a control transfected cell line. Results: Cells over-expressing truncated form of Rasgrf-1 have a higher proliferative rate as compared to control transfected cells. BCR was activated by lower concentrations of anti-IgM antibody in Rasgrf-1 over-expressing cells as compared to control cells indicating that these cells are more sensitive to BCR signaling. BCR signaling also phosphorylates Rasgrf-1 that further increases its GEF function and amplifies BCR signaling. This activation of Rasgrf-1 in over-expressing cells resulted in a higher expression of phospho-ERK, AKT, BTK and PKC-alpha as compared to control cells. Besides BCR, Rasgrf-1 over-expressing cells were also more sensitive to microenvironment stimuli as determined by resistance to apoptosis, chemotaxis and ERK pathway activation. Conclusions: This GEF protein sensitizes B-cells to BCR and chemokine mediated signaling and also upregulates a number of other signaling pathways which promotes growth and survival of these cells.

  11. Trafficking of B cell antigen in lymph nodes

    DEFF Research Database (Denmark)

    Gonzalez, Santiago F.; Degn, Søren Egedal; Pitcher, Lisa A.; Woodruff, Matthew; Heesters, Balthasar A.; Carroll, Michael C.

    2011-01-01

    The clonal selection theory first proposed by Macfarlane Burnet is a cornerstone of immunology ( 1 ). At the time, it revolutionized the thinking of immunologists because it provided a simple explanation for lymphocyte specificity, immunological memory, and elimination of self-reactive clones ( 2...... microscopy ( 4, 5 ) have provided new insights into the trafficking of B cells and their antigen. In this review, we summarize these advances in the context of our current view of B cell circulation and activation....

  12. Antibody responses to vaccination and immune function in patients with haematological malignancies - studies in patients with chronic lymphocytic leukaemia autologous stem cell recipients

    OpenAIRE

    Velden, A.M.T. van der

    2007-01-01

    This thesis concerns the antibody responses to vaccination and immune function of patients with several forms of haematological diseases. Antibody responses in patients with chronic lymphocytic leukaemia (CLL) and in autologous stem cell transplant recipients were studied. In the autologous stem cell transplantation (aSCT) group, immune reconstitution after aSCT was analysed in detail during 15 months following transplantation. The first part of the thesis concerns patients with chronic lymph...

  13. Monitoring B cell subsets and alloreactivity in kidney transplantation

    OpenAIRE

    Crespo Barrio, Marta; Heidtc, Sebastiaan; Redondo Pach??n, Mar??a Dolores; Pascual Santos, Julio

    2015-01-01

    B cells are the precursors of antibody producing plasma cells that can give rise to the formation of donor-specific antibodies. However, recent data suggest that besides their role in antibody production, B cells participate in antibody-independent responses, potentially leading to allograft rejection or allograft tolerance. The presence of CD20+ B cells in kidney graft biopsies has been shown during severe acute rejection episodes and during chronic rejection. Furthermore, operationally tole...

  14. Active caspase-3 detection to evaluate apoptosis induced by Verbena officinalis essential oil and citral in chronic lymphocytic leukaemia cells

    Directory of Open Access Journals (Sweden)

    Laura De Martino

    2011-10-01

    Full Text Available Verbena officinalis L., Verbenaceae, commonly known as vervain, is a plant widely used in medicine. Despite of its widespread use in different traditional practices, the mechanisms of pharmacological actions of the plant and its volatile oil are still unclear. We evaluated the pro-apoptotic activity of V. officinalis essential oil and of its main component, citral, on lymphocytes collected from ten patients with chronic lymphocytic leukaemia (CLL, a disease in which a faulty apoptotic mechanism is still retained one of the primary pathogenic events, by adding to treated mononuclear cells, annexin-V, propidium iodide, and CD19. Apoptosis was also evaluated using anti-active-caspase-3 monoclonal antibody after permeabilization of the cells. Both V. officinalis essential oil and citral were found able to induce apoptosis in CLL cells and to activate caspase-3, which is considered the way by means they active apoptosis in B neoplastic cells. This data further support evidences that indicate natural compounds as possible lead structure to develop new therapeutic agents for CLL.

  15. Cryoglobulinemia in a patient with chronic lymphocytic leukemia - A case report and review of literature of renal involvement in CLL.

    Science.gov (United States)

    Arora, Swaty; Levitan, Daniel; Regmi, Narottam; Sidhu, Gurinder; Gupta, Raavi; Nicastri, Anthony D; Saggi, Subodh J; Braverman, Albert

    2016-09-01

    The incidence of glomerulonephritis, as a manifestation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), has always been considered low. Though renal infiltration is usually detected at post-mortem, it does not often interfere with kidney function [1]. Though immunoglobulin (Ig) levels in most CLL patients are subnormal, small monoclonal Ig peaks are occasionally detected in serum. They were present in a number of reported CLL nephropathy patients, and not all were cryoglobulins; serum and glomerular staining were concordant for Ig type [2,3,4]. Myeloma, which secretes monoclonal light chains, causes nephropathy in 25% of patients. But the little presumably secreted by small plasma cell clones, without myeloma, may also be nephrotoxic. The same is true of the low secretory CLL cells, which may occasionally be associated with cryoglobulins and other nephrotoxic Igs [5]. We report a patient with early stage CLL (Rai stage 0) with cryoglobulins, which led to membranoproliferative glomerulonephritis (MPGN), and death. We located reports of 51 patients with CLL-associated nephrotic syndrome or nephropathy, mostly from MPGN related to local Ig deposits. In those patients screened for cryoglobulins, about half tested positive. Many were early stage cases, where MPGN developed long after CLL presentation, and responded to its treatment. As early diagnosis and treatment CLL-related nephropathy may be curative, we propose a prospective study to determine the incidence of hyperalbuminuria development after presentation. PMID:27519936

  16. The level of T lymphocyte subpopulation and cytokines in senile patients with stable chronic obstructive pulmonary disease

    International Nuclear Information System (INIS)

    To investigate the level of T-lymphocyte subsets(CD3+, CD4+, CD8+ )and serum IL-4, IL-8 and TNF-α in senile patients with stable chronic obstructive pulmonary disease(COPD) and provide basis in observing the inflammatory process of COPD, 50 senile patients with stable COPD and 40 senile healthy persons as control group were selected, and levels of IL-4, IL-8 and TNF-α in serum were detected by RIA method, the T-lymphocyte subset (CD3+, CD4+, CD8+)of peripheral blood was measured by flow cytometry. The levels of CD3+, CD4+ in COPD group were lower than in control group (P+ IL-8 were also slightly higher in COPD group compared with that in control group, but the difference between them is not significant. CD3+, CD4+ were lower and IL-4, TNF-α were higher in COPD group than those in control group, which means that abnormal cellular immunity function and inflammatory process still existed in the stable period of COPD. (authors)

  17. PARP1 expression, activity and ex vivo sensitivity to the PARP inhibitor, talazoparib (BMN 673), in chronic lymphocytic leukaemia.

    Science.gov (United States)

    Herriott, Ashleigh; Tudhope, Susan J; Junge, Gesa; Rodrigues, Natalie; Patterson, Miranda J; Woodhouse, Laura; Lunec, John; Hunter, Jill E; Mulligan, Evan A; Cole, Michael; Allinson, Lisa M; Wallis, Jonathan P; Marshall, Scott; Wang, Evelyn; Curtin, Nicola J; Willmore, Elaine

    2015-12-22

    In chronic lymphocytic leukemia (CLL), mutation and loss of p53 and ATM abrogate DNA damage signalling and predict poorer response and shorter survival. We hypothesised that poly (ADP-ribose) polymerase (PARP) activity, which is crucial for repair of DNA breaks induced by oxidative stress or chemotherapy, may be an additional predictive biomarker and a target for therapy with PARP inhibitors.We measured PARP activity in 109 patient-derived CLL samples, which varied widely (192 - 190052 pmol PAR/10⁶ cells) compared to that seen in healthy volunteer lymphocytes (2451 - 7519 pmol PAR/10⁶ cells). PARP activity was associated with PARP1 protein expression and endogenous PAR levels. PARP activity was not associated with p53 or ATM loss, Binet stage, IGHV mutational status or survival, but correlated with Bcl-2 and Rel A (an NF-kB subunit). Levels of 8-hydroxy-2'-deoxyguanosine in DNA (a marker of oxidative damage) were not associated with PAR levels or PARP activity. The potent PARP inhibitor, talazoparib (BMN 673), inhibited CD40L-stimulated proliferation of CLL cells at nM concentrations, independently of Binet stage or p53/ATM function.PARP activity is highly variable in CLL and correlates with stress-induced proteins. Proliferating CLL cells (including those with p53 or ATM loss) are highly sensitive to the PARP inhibitor talazoparib. PMID:26539646

  18. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    O'Brien, Susan M; Lamanna, Nicole; Kipps, Thomas J; Flinn, Ian; Zelenetz, Andrew D; Burger, Jan A; Keating, Michael; Mitra, Siddhartha; Holes, Leanne; Yu, Albert S; Johnson, David M; Miller, Langdon L; Kim, Yeonhee; Dansey, Roger D; Dubowy, Ronald L; Coutre, Steven E

    2015-12-17

    Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m(2) weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930. PMID:26472751

  19. Highlights in the treatment of chronic lymphocytic leukemia from the 2014 meeting of the American Society of Hematology.

    Science.gov (United States)

    Molica, Stefano

    2015-06-01

    The latest Annual Meeting of the American Society of Hematology, held in San Francisco, included data on novel-targeted agents active in the treatment of chronic lymphocytic leukemia (CLL). MABTENANCE and PROLONG study suggest that either rituximab or ofatumumab improves progression-free survival in CLL. According to final analysis of CLL-10 trial, rituximab and bendamustine may have a role in the upfront treatment of fit elderly patients. Further insight into the use of ibrutinib, a first-in-class covalent Bruton’s tyrosine kinase-inhibitor that is currently approved for patients with relapsed/refractory CLL and with del(17p), was also presented. Idelalisib, a selective inhibitor of PI3K delta, demonstrated its activity with manageable toxicity in previously untreated patients ≥65 years with CLL or small lymphocytic lymphoma. Finally, a series Phase I/II studies of BCL-2 inhibitor (i.e., venetoclax, GDC-0199) used alone or in combination provide promising results in patients with relapsed/refractory CLL. PMID:25804936

  20. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations

    DEFF Research Database (Denmark)

    Farooqui, Mohammed Z H; Valdez, Janet; Martyr, Sabrina;

    2015-01-01

    BACKGROUND: Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53...... aberrations. METHODS: In this investigator-initiated, single-arm phase 2 study, we enrolled eligible adult patients with active CLL with TP53 aberrations at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Patients received 28-day cycles of ibrutinib 420 mg orally once daily until...... one (2%) patient. INTERPRETATION: The activity and safety profile of single-agent ibrutinib in CLL with TP53 aberrations is encouraging and supports its consideration as a novel treatment option for patients with this high-risk disease in both first-line and second-line settings. FUNDING: Intramural...

  1. Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients

    DEFF Research Database (Denmark)

    Mansouri, Larry; Grabowski, Pawel; Degerman, Sofie; Svenson, Ulrika; Gunnarsson, Rebeqa; Cahill, Nicola; Smedby, Karin Ekström; Geisler, Christian; Juliusson, Gunnar; Roos, Göran; Rosenquist, Richard

    2013-01-01

    Most previous studies on telomere length (TL) in chronic lymphocytic leukemia (CLL) are based on referral cohorts including a high proportion of aggressive cases. Here, the impact of TL was analyzed in a population-based cohort of newly diagnosed CLL (n = 265) and in relation to other prognostic ...

  2. Expressions of HSP 70 and NF-κB in the peripheral blood lymphocyte of chronic gastritis patients of different syndrome patterns

    Institute of Scientific and Technical Information of China (English)

    胡玲

    2012-01-01

    Objective To study the expressions of heat shock protein 70 (HSP 70) and nuclear factor-kappa B(NF-κB) in the peripheral blood lymphocyte of chronic gastritis (CG) patients of Pi-Wei hygropyrexia syndrome (PWHS) and Pi-qi deficiency syndrome(PQDS),and to explore their correlation with Helicobacter pylori(Hp) infection. Methods

  3. Plasma alemtuzumab levels in patients with chronic lymphocytic leukemia treated with alemtuzumab combined with chemotherapy reflect the efficacy of the treatment - an hypothesis

    DEFF Research Database (Denmark)

    Vojdeman, Fie Juhl; Jurlander, Jesper; Van't Veer, Mars;

    2013-01-01

    ABSTRACT In the HOVON68 trial comparing subcutaneous low-dose alemtuzumab (LD-A) used together with fludarabine (F) and cyclophosphamide (C) with FC alone in high-risk chronic lymphocytic leukemia (CLL), LD-AFC resulted in significantly more clinical and molecular responses than FC, but also in...

  4. Adhesion of Human B Cells to Germinal Centers in Vitro Involves VLA-4 and INCAM-110

    Science.gov (United States)

    Freedman, Arnold S.; Munro, J. Michael; Rice, G. Edgar; Bevilacqua, Michael P.; Morimoto, Chikao; McIntyre, Bradley W.; Rhynhart, Kurt; Pober, Jordan S.; Nadler, Lee M.

    1990-08-01

    Human B lymphocytes localize and differentiate within the microenvironment of lymphoid germinal centers. A frozen section binding assay was developed for the identification of those molecules involved in the adhesive interactions between B cells and lymphoid follicles. Activated human B cells and B cell lines were found to selectively adhere to germinal centers. The VLA-4 molecule on the lymphocyte and the adhesion molecule INCAM-110, expressed on follicular dendritic cells, supported this interaction. This cellular interaction model can be used for the study of how B cells differentiate.

  5. Issues in diagnosis of small B cell lymphoid neoplasms involving the bone marrow and peripheral blood. Report on the Bone Marrow Workshop of the XVIIth meeting of the European Association for Haematopathology and the Society for Hematopathology.

    Science.gov (United States)

    Porwit, Anna; Fend, Falko; Kremer, Marcus; Orazi, Attilio; Safali, Mükerrem; van der Walt, Jon

    2016-09-01

    Small B cell lymphoid neoplasms are the most common lymphoproliferative disorders involving peripheral blood (PB) and bone marrow (BM). The Bone Marrow Workshop (BMW) organized by the European Bone Marrow Working Group (EBMWG) of the European Association for Haematopathology (EAHP) during the XVIIth EAHP Meeting in Istanbul, October 2014, was dedicated to discussion of cases illustrating how the recent advances in immunophenotyping, molecular techniques and cytogenetics provide better understanding and classification of these entities. Submitted cases were grouped into following categories: (i) cases illustrating diagnostic difficulties in chronic lymphocytic leukaemia (CLL); (ii) cases of BM manifestations of small B cell lymphoid neoplasms other than CLL; (iii) transformation of small B cell lymphoid neoplasms in the BM; and (iv) multiclonality and composite lymphomas in the BM. This report summarizes presented cases and conclusions of the BMW and provides practical recommendations for classification of the BM manifestations of small B cell lymphoid neoplasms based on the current state of knowledge. PMID:27208429

  6. B cells and immunological tolerance.

    Science.gov (United States)

    Manjarrez-Orduño, Nataly; Quách, Tâm D; Sanz, Iñaki

    2009-02-01

    Work from multiple groups continues to provide additional evidence for the powerful and highly diverse roles, both protective and pathogenic, that B cells play in autoimmune diseases. Similarly, it has become abundantly clear that antibody-independent functions may account for the opposing influences that B cells exercise over other arms of the immune response and ultimately over autoimmunity itself. Finally, it is becoming apparent that the clinical impact of B-cell depletion therapy may be, to a large extent, determined by the functional balance between different B-cell subsets that may be generated by this therapeutic intervention. In this review, we postulate that our perspective of B-cell tolerance and our experimental approach to its understanding are fundamentally changed by this view of B cells. Accordingly, we first discuss current knowledge of B-cell tolerance conventionally defined as the censoring of autoantibody-producing B cells (with an emphasis on human B cells). Therefore, we discuss a different model that contemplates B cells not only as targets of tolerance but also as mediators of tolerance. This model is based on the notion that the onset of clinical autoimmune disease may require a B-cell gain-of-pathogenic function (or a B-cell loss-of-regulatory-function) and that accordingly, disease remission may depend on the restoration of the physiological balance between B-cell pathogenic and protective functions. PMID:19148217

  7. A thirteen year old female with primary T-cell rich B-cell lymphoma of bone masquerading as chronic recurrent multifocal osteomyelitis

    Directory of Open Access Journals (Sweden)

    Saadiya Haque

    2009-09-01

    Full Text Available Primary lymphoma of the bone (PLB accounts for 2% of all non-Hodgkin’s lymphomas, and until recently it had not been well characterized in literature. Most cases present in adulthood (average age 50, with localized painful lesions in the long bones, cranium, or axial skeleton. We describe a case of multifocal PLB in an adolescent female. In this case, the initial presentation, with migratory large joint polyarthralgias and bone pain, mimicked chronic recurrent multifocal osteomyelitis (CRMO. Had a biopsy not been performed the diagnosis would have been missed.

  8. Cytotoxic T lymphocytes mediate chronic inflammation of the nasal mucosa of patients with atypical allergic rhinitis

    Directory of Open Access Journals (Sweden)

    Shuqi Qiu

    2011-01-01

    Full Text Available Background : The prevalence of chronic rhinitis is increasing rapidly; its pathogenesis is to be further understood; immune inflammation is one of the possible causative factors. Antigen specific CD8+ T cells play a critical role in the induction of chronic inflammation. Aims : This study aimed to investigate the role of antigen specific CD8+ T cells in the pathogenesis of chronic atypical allergic rhinitis. Material and Methods : Nasal mucosal epithelial surface scratching samples were obtained from patients with chronic obstruction atypical allergic rhinitis. Exosomes were purified from the scratching samples and examined by immune gold electron microscopy. The effect of exosomes on modulating dendritic cell′s properties, the effect of exosome-pulsed dendritic cells on naïve T cell differentiation and the antigen specific CD8+ T cell activation were observed by cell culture models. Results : Exosomes purified from patients with chronic atypical allergic rhinitis carried microbial products, Staphylococcal enterotoxin B (SEB, and airborne antigen, Derp1. Dendritic cells pulsed by SEB/Derp1-carrying exosomes showed high levels of CD80, CD86 and the major histocompatibility class I (MHCI. Exosome-pulsed dendritic cells could induce the naïve CD3+ T cells to differentiate into CD8+ T cells. Upon the exposure to a specific antigen, the CD8+ T cells released granzyme B and perforin; more than 30% antigen specific CD8+ T cells proliferated. Conclusions : Antigen specific CD8+ T cells play an important role in the pathogenesis of chronic obstruction atypical allergic rhinitis.

  9. Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells.

    Science.gov (United States)

    Zent, Clive S; Taylor, Ronald P; Lindorfer, Margaret A; Beum, Paul V; LaPlant, Betsy; Wu, Wenting; Call, Timothy G; Bowen, Deborah A; Conte, Michael J; Frederick, Lori A; Link, Brian K; Blackwell, Sue E; Veeramani, Suresh; Baig, Nisar A; Viswanatha, David S; Weiner, George J; Witzig, Thomas E

    2014-07-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab-containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short-duration regimen combining pentostatin, alemtuzumab, and low-dose high-frequency rituximab designed to decrease the risk of treatment-associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13-) (n = 3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy, with only five (13%) patients having treatment-limiting toxicity and no treatment-related deaths. Twenty-two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression-free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B-cell lymphoma (n = 6). Correlative studies showed that low-dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low-dose high-frequency rituximab is a tolerable and effective therapy for CLL and that low-dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. PMID:24723493

  10. Innate response activator B cells: origins and functions.

    Science.gov (United States)

    Chousterman, Benjamin G; Swirski, Filip K

    2015-10-01

    Innate response activator (IRA) B cells are a subset of B-1a derived B cells that produce the growth factors granulocyte macrophage colony stimulating factor and IL-3. In mouse models of sepsis and pneumonia, B-1a B cells residing in serosal sites recognize bacteria, migrate to the spleen or lung, and differentiate to IRA B cells that then contribute to the host response by amplifying inflammation and producing polyreactive IgM. In atherosclerosis, IRA B cells accumulate in the spleen, where they promote extramedullary hematopoiesis and activate classical dendritic cells. In this review, we focus on the ontogeny and function of IRA B cells in acute and chronic inflammation. PMID:25957266

  11. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity.

    Science.gov (United States)

    Lampson, Benjamin L; Kasar, Siddha N; Matos, Tiago R; Morgan, Elizabeth A; Rassenti, Laura; Davids, Matthew S; Fisher, David C; Freedman, Arnold S; Jacobson, Caron A; Armand, Philippe; Abramson, Jeremy S; Arnason, Jon E; Kipps, Thomas J; Fein, Joshua; Fernandes, Stacey; Hanna, John; Ritz, Jerome; Kim, Haesook T; Brown, Jennifer R

    2016-07-14

    Idelalisib is a small-molecule inhibitor of PI3Kδ with demonstrated efficacy for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as front-line therapy, we enrolled 24 subjects in a phase 2 study consisting of 2 months of idelalisib monotherapy followed by 6 months of combination therapy with idelalisib and the anti-CD20 antibody ofatumumab. After a median follow-up period of 14.7 months, hepatotoxicity was found to be a frequent and often severe adverse event. A total of 19 subjects (79%) experienced either grade ≥1 ALT or AST elevation during the study, and 13 subjects (54%) experienced grade ≥3 transaminitis. The median time to development of transaminitis was 28 days, occurring before ofatumumab introduction. Younger age and mutated immunoglobulin heavy chain status were significant risk factors for the development of hepatotoxicity. Multiple lines of evidence suggest that this hepatotoxicity was immune mediated. A lymphocytic infiltrate was seen on liver biopsy specimens taken from 2 subjects with transaminitis, and levels of the proinflammatory cytokines CCL-3 and CCL-4 were higher in subjects experiencing hepatotoxicity. All cases of transaminitis resolved either by holding the drug, initiating immunosuppressants, or both, and rates of recurrent toxicity were lower in patients taking steroids when idelalisib was reinitiated. A decrease in peripheral blood regulatory T cells was seen in patients experiencing toxicity on therapy, which is consistent with an immune-mediated mechanism. These results suggest that caution should be taken as drugs within this class are developed for CLL, particularly in younger patients who have not received prior disease-specific therapy. This study was registered at www.clinicaltrials.gov as #NCT02135133. PMID:27247136

  12. [The characteristic of proliferative activity of thymocytes and peripheral blood lymphocytes in the offspring of females with experimental chronic liver diseases of various aetiology].

    Science.gov (United States)

    Briukhin, G V; Fedosov, A A

    2006-01-01

    The aim of the study was a comparative analysis of the proliferative activity of thymocytes and peripheral blood lymphocytes in the offspring of female rats with chronic liver pathology of various genesis. In adult female Wistar rats toxic and autoimmune forms of liver lesions were modeled. The offspring of these experimental animals was studied at different time points of postnatal ontogenesis. Proliferative activity of thymocytes and lymphocytes was estimated by counting the proportion of cells with multiple nucleolar organizing regions (AgNORs) and using the cytofluorometric method with acridine orange. In the offspring of experimental animals, the depression of proliferative activity of thymocytes as well as the increase of the proliferative activity of peripheral blood lymphocytes were found at all the time points studied. This was indicated by a change in a relative number of AgNORs-activated cells and a decrease of nucleic acid content in cortical thymocytes. PMID:17201321

  13. Marginal zone B-cells, a gatekeeper of innate immunity.

    Science.gov (United States)

    Zouali, Moncef; Richard, Yolande

    2011-01-01

    To maintain the integrity of an organism constantly challenged by pathogens, the immune system is endowed with a variety of cell types. B lymphocytes were initially thought to only play a role in the adaptive branch of immunity. However, a number of converging observations revealed that two B-cell subsets, marginal zone (MZ) and B1 cells, exhibit unique developmental and functional characteristics, and can contribute to innate immune responses. In addition to their capacity to mount a local antibody response against type-2 T-cell-independent (TI-2) antigens, MZ B-cells can participate to T-cell-dependent (TD) immune responses through the capture and import of blood-borne antigens to follicular areas of the spleen. Here, we discuss the multiple roles of MZ B-cells in humans, non-human primates, and rodents. We also summarize studies - performed in transgenic mice expressing fully human antibodies on their B-cells and in macaques whose infection with Simian immunodeficiency virus (SIV) represents a suitable model for HIV-1 infection in humans - showing that infectious agents have developed strategies to subvert MZ B-cell functions. In these two experimental models, we observed that two microbial superantigens for B-cells (protein A from Staphylococcus aureus and protein L from Peptostreptococcus magnus) as well as inactivated AT-2 virions of HIV-1 and infectious SIV preferentially deplete innate-like B-cells - MZ B-cells and/or B1 B-cells - with different consequences on TI and TD antibody responses. These data revealed that viruses and bacteria have developed strategies to deplete innate-like B-cells during the acute phase of infection and to impair the antibody response. Unraveling the intimate mechanisms responsible for targeting MZ B-cells in humans will be important for understanding disease pathogenesis and for designing novel vaccine strategies. PMID:22566852

  14. Cost-effectiveness of adding rituximab to fludarabine and cyclophosphamide for treatment of chronic lymphocytic leukemia in Ukraine

    Directory of Open Access Journals (Sweden)

    Mandrik O

    2015-08-01

    Full Text Available Olena Mandrik,1 Isaac Corro Ramos,2 Saskia Knies,1,3 Maiwenn Al,1,2 Johan L Severens1,2 1Institute of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, the Netherlands; 2Institute of Medical Technology Assessment (iMTA, Erasmus University Rotterdam, Rotterdam, the Netherlands; 3National Health Care Institute, Diemen, the Netherlands Abstract: The aim of this study was to assess the cost-effectiveness, from a health care perspective, of adding rituximab to fludarabine and cyclophosphamide scheme (FCR versus FC for treatment-naïve and refractory/relapsed Ukrainian patients with chronic lymphocytic leukemia. A decision-analytic Markov cohort model with three health states and 1-month cycle time was developed and run within a life time horizon. Data from two multinational, prospective, open-label Phase 3 studies were used to assess patients' survival. While utilities were generalized from UK data, local resource utilization and disease-associated treatment, hospitalization, and side effect costs were applied. The alternative scenario was performed to assess the impact of lower life expectancy of the general population in Ukraine on the incremental cost-effectiveness ratio (ICER for treatment-naïve patients. One-way, two-way, and probabilistic sensitivity analyses were conducted to assess the robustness of the results. The ICER (in US dollars of treating chronic lymphocytic leukemia patients with FCR versus FC is US$8,704 per quality-adjusted life year gained for treatment-naïve patients and US$11,056 for refractory/relapsed patients. When survival data were modified to the lower life expectancy of the general population in Ukraine, the ICER for treatment-naïve patients was higher than US$13,000. This value is higher than three times the current gross domestic product per capita in Ukraine. Sensitivity analyses have shown a high impact of rituximab costs and a moderate impact of differences in utilities on the ICER

  15. Using the geometric mean fluorescence intensity index method to measure ZAP-70 expression in patients with chronic lymphocytic leukemia

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    Wu YJ

    2016-02-01

    Full Text Available Yu-Jie Wu, Hui Wang, Jian-Hua Liang, Yi Miao, Lu Liu, Hai-Rong Qiu, Chun Qiao, Rong Wang, Jian-Yong Li Department of Hematology, First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, People’s Republic of China Abstract: Expression of ζ-chain-associated protein kinase 70 kDa (ZAP-70 in chronic lymphocytic leukemia (CLL is associated with more aggressive disease and can help differentiate CLL from cases expressing mutated or unmutated immunoglobulin heavy chain variable region (IgHV genes. However, standardizing ZAP-70 expression by flow cytometric analysis has proved unsatisfactory. The key point is that ZAP-70 is weakly expressed with a continuous expression pattern rather than a clear discrimination between positive and negative CLL cells, which means that the resulting judgment is subjective. Thus, in this study, we aimed at assessing the reliability and repeatability of ZAP-70 expression using the geometric mean fluorescence intensity (geo MFI index method based on flow cytometry with 256-channel resolution in a series of 402 CLL patients and to compare ZAP-70 with other biological and clinical prognosticators. According to IgHV mutational status, we were able to confirm that the optimal cut-off point for the geo MFI index was 3.5 in the test set. In multivariate analyses that included the major clinical and biological prognostic markers for CLL, the prognostic impact of ZAP-70 expression appeared to have stronger discriminatory power when the geo MFI index method was applied. In addition, we found that ZAP-70-positive patients according to the geo MFI index method had shorter time to first treatment or overall survival (P=0.0002, P=0.0491. This is the first report showing that ZAP-70 expression can be evaluated by a new approach, the geo MFI index, which could be a useful prognostic method as it is more reliable, less subjective, and therefore better associated with improvement of CLL prognostication

  16. Studies of lymphocyte growth and differentiation. Progress report, September 1, 1975--July 31, 1976

    Energy Technology Data Exchange (ETDEWEB)

    Rubin, A.D.

    1976-01-01

    Studies were continued on ribonuclear protein synthesis and the assembly of ribosomes in resting and stimulated lymphocytes. We demonstrated the interdependency of protein synthesis and RNA synthesis in the formation and processing of nascent ribonuclear protein particles. We further explored lymphocyte nuclei in a cell-free system. By isolating lymphocyte chromatin we showed a direct effect of PHA on the ability of this nuclear structure to incorporate radioactivity into acid precipitable RNA. We returned to our previous studies on the delayed response of chronic lymphocytic leukemia (CLL) lymphocytes to PHA. We traced this alternate response identifying it as a characteristic of the CLL cell. The evidence questioned the generally accepted conclusion that CLL represents a B cell malignancy. We went on further to describe delayed reacting lymphocytes in the circulation of patients with nodular lymphoma and acute lymphoblastic leukemia (ALL). The ALL, unlike the lymphoma and CLL cells, showed a normal magnitude of response, even though it was delayed. We described the technique which might be employed as a diagnostic test for detecting abnormal lymphocytes in patients with lymphocytic lymphoma and leukemia and could help distinguish these diseases from benign lymphoid hyperplasia and other forms of non-lymphocytic leukemia.

  17. Jaw1/LRMP, a germinal centre-associated marker for the immunohistological study of B-cell lymphomas.

    Science.gov (United States)

    Tedoldi, S; Paterson, J C; Cordell, J; Tan, S-Y; Jones, M; Manek, S; Dei Tos, A P; Roberton, H; Masir, N; Natkunam, Y; Pileri, S A; Facchetti, F; Hansmann, M-L; Mason, D Y; Marafioti, T

    2006-08-01

    Jaw1, also known as lymphoid-restricted membrane protein (LRMP), is an endoplasmic reticulum-associated protein. High levels of Jaw1/LRMP mRNA have been found in germinal centre B-cells and in diffuse large B-cell lymphomas of 'germinal centre' subtype. This paper documents Jaw1/LRMP expression at the protein level in human tissues by immunohistochemical and western blotting analysis using an antibody reactive with paraffin-embedded tissues. Jaw1/LRMP was highly expressed in germinal centre B-cells (in keeping with gene expression data), in 'monocytoid B-cells', and in splenic marginal zone B-cells. It was absent, or present at only low levels, in mature T-cells, although cortical thymocytes were weakly positive. Among lymphoid neoplasms, Jaw1/LRMP was found in germinal centre-derived lymphomas (follicle centre lymphoma, Burkitt's lymphoma, lymphocyte-predominant Hodgkin's disease) but not in T-cell neoplasms (with the exception of a single T lymphoblastic lymphoma). Classical Hodgkin's disease and myeloma lacked Jaw1/LRMP but many cases of chronic lymphocytic leukaemia (but not mantle zone lymphoma) were Jaw1/LRMP-positive. Approximately half of the marginal zone lymphomas were Jaw1/LRMP-positive. In diffuse large B-cell lymphomas, Jaw1/LRMP was found in three-quarters (24/32) of the cases classified phenotypically as being of 'germinal centre' type, but it was also expressed in almost half (13/28) of the 'non-germinal centre' cases. A similar proportion of 'non-germinal centre' cases were positive for the protein products of two other genes expressed highly in germinal centre cells (HGAL/GCET2 and PAG). The fact that all three of these proteins are expressed in a significant proportion of diffuse large B-cell lymphomas assigned to the 'non-germinal centre' category indicates that the immunophenotypic categorization of diffuse large B-cell lymphoma according to cellular origin may be more complicated than currently understood. Finally, the expression of Jaw1/LRMP

  18. Chromosome aberrations in human lymphocytes, chronically exposed to different doses of gamma radiation in vitro

    International Nuclear Information System (INIS)

    Man's blood, not stimulated with phytohemagglutinin has been subjected to a chronic gamma irradiation from the 226Ra(99 mg) source at the temperature of 37 deg C. The obtained metaphase plates have been used to carry out the quantitative analysis of separate types of structural chromosomal aberrations. Quantitative results on aberrant cells have been statistically processed. It is established, that the increase of dose rate lends to the increase in the share of those dicentrics, that appeared as a result of one-trail process, while that output of two-trail dicentrics remains constant

  19. 慢性淋巴细胞白血病治疗进展:第57届美国血液学会年会报道%Treatment progress of chronic lymphocytic leukemia: reports from the 57th American Society of Hematology annual meeting

    Institute of Scientific and Technical Information of China (English)

    李悦; 徐卫; 李建勇

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a chronic B-cell lymphoproliferative clonal disease with a highly heterogeneous clinical course. In recent years, with the emerging of immunochemotherapy, bcl-2 inhibitor, B-cell receptor signal transduction kinase inhibitors and the chimeric antigen receptor-T cell (CAR-T), more and more improvements were made in CLL therapy and remission. This report addressed the progress of CLL therapy in the 57th American Society of Hematology annual meeting.%慢性淋巴细胞白血病(CLL)是一种高度异质性的慢性B淋巴细胞克隆增殖性疾病.近年来,随着化学免疫、bcl-2抑制剂、BCR信号通路抑制剂、PD-1抑制剂和嵌合抗原受体的T细胞(CAR-T)等新型药物及治疗方法不断涌现,CLL的治疗效果和缓解程度不断提高.文章就2015年第57届美国血液学会(ASH)年会CLL的治疗进展进行报道.

  20. Subacute herpes simplex virus type 1 encephalitis as an initial presentation of chronic lymphocytic leukemia and multiple sclerosis: a case report

    Directory of Open Access Journals (Sweden)

    Corman Lourdes C

    2011-02-01

    Full Text Available Abstract Introduction Herpes simplex virus type 1 encephalitis presents acutely in patients who are immunocompetent. We report what we believe to be the first published case of a subacute course of herpes simplex virus type 1 encephalitis in a patient with asymptomatic chronic lymphocytic leukemia who subsequently developed multiple sclerosis. Case presentation A 49-year-old Caucasian woman with a history of fever blisters presented to the emergency department with a history of left temporal headache for four weeks, and numbness of the left face and leg for two weeks. A complete blood count revealed white blood cell count of 11,820 cells/mL, with an absolute lymphocyte count of 7304 cells/mL. The cerebrospinal fluid contained 6 white blood cells/μL, 63 red blood cells/μL, 54 mg glucose/dL, and 49 mg total protein/dL. Magnetic resonance imaging of the brain revealed meningoencephalitis and bilateral ventriculitis. Cerebrospinal fluid polymerase chain reaction for herpes simplex virus type 1 was positive, and the patient's symptoms resolved after ten days of treatment with parenteral aciclovir. Incidental findings on peripheral blood smear and flow cytometry testing confirmed chronic lymphocytic leukemia. One month later, she developed bilateral numbness of the hands and feet; a repeat cerebrospinal fluid polymerase chain reaction for herpes simplex virus type 1 at this time was negative. A repeat magnetic resonance imaging scan showed an expansion of the peri-ventricular lesions, and the cerebrospinal fluid contained elevated oligoclonal bands and myelin basic protein. A brain biopsy revealed gliosis consistent with multiple sclerosis, and the patient responded to treatment with high-dose parenteral steroids. Conclusion Herpes simplex virus type 1 encephalitis is a rare presentation of chronic lymphocytic leukemia. Our patient had an atypical, subacute course, presumably due to immunosuppression from chronic lymphocytic leukemia. This unusual

  1. Cytomegalovirus infection does not impact on survival or time to first treatment in patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Parry, Helen Marie; Damery, Sarah; Hudson, Christopher; Maurer, Matthew J; Cerhan, James R; Pachnio, Annette; Begum, Jusnara; Slager, Susan L; Fegan, Christopher; Man, Stephen; Pepper, Christopher; Shanafelt, Tait D; Pratt, Guy; Moss, Paul A H

    2016-08-01

    Human cytomegalovirus (HCMV) is a widely prevalent herpes virus which establishes a state of chronic infection. The establishment of CMV-specific immunity controls viral reactivation and leads to the accumulation of very large numbers of virus-specific T cells which come to dominate the immune repertoire. There is concern that this may reduce the immune response to heterologous infections and HCMV infection has been associated with reduced survival in elderly people. Patients with chronic lymphocytic leukemia (B-CLL) suffer from a state of immune suppression but have a paradoxical increase in the magnitude of the CMV-specific T cell and humoral immune response. As such, there is now considerable interest in how CMV infection impacts on the clinical outcome of patients with B-CLL. Utilizing a large prospective cohort of patients with B-CLL (n = 347) we evaluated the relationship between HCMV seropositivity and patient outcome. HCMV seropositive patients had significantly worse overall survival than HCMV negative patients in univariate analysis (HR = 2.28, 95% CI: 1.34-3.88; P = 0.002). However, CMV seropositive patients were 4 years older than seronegative donors and this survival difference was lost in multivariate modeling adjusted for age and other validated prognostic markers (P = 0.34). No significant difference was found in multivariate modeling between HCMV positive and negative patients in relation to the time to first treatment (HR = 1.12, 95% CI: 0.68-1.84; P = 0.65). These findings in a second independent cohort of 236 B-CLL patients were validated. In conclusion no evidence that HCMV impacts on the clinical outcome of patients with B-CLL was found. Am. J. Hematol. 91:776-781, 2016. © 2016 Wiley Periodicals, Inc. PMID:27124884

  2. Role of T-lymphocytes and pro-inflammatory mediators in the pathogenesis of chronic obstructive pulmonary disease

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    Aneal Gadgil

    2008-11-01

    Full Text Available Aneal Gadgil, Steven R DuncanDivision of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USAAbstract: Chronic obstructive pulmonary disease (COPD is the fourth leading cause of death in the US and a major worldwide healthcare problem. The pathophysiologic mechanisms that drive development and progression of this disease are complex and only poorly understood. While tobacco smoking is the primary risk factor, other disease processes also appear to play a role. Components of the innate immune system (eg, macrophages and neutrophils have long been believed to be important in the development of COPD. More recent evidence also suggests involvement of the adaptive immune system in pathogenesis of this disease. Here we will review the literature supporting the participation of T-cells in the development of COPD, and comment on the potential antigenic stimuli that may account for these responses. We will further explore the prospective contributions of T-cell derived mediators that could contribute to the inflammation, alveolar wall destruction, and small airway fibrosis of advanced COPD. A better understanding of these complex immune processes will lead to new insights that could result in improved preventative and/or treatment strategies.Keywords: COPD, T-lymphocytes, adaptive immunity, cytokines

  3. MicroRNAs in chronic lymphocytic leukemia: miRacle or miRage for prognosis and targeted therapies?

    Science.gov (United States)

    Van Roosbroeck, Katrien; Calin, George A

    2016-04-01

    Chronic lymphocytic leukemia (CLL) is a heterogeneous disease and has a highly variable clinical course with survival ranging from a couple of months to several decades. MicroRNAs (miRNAs), small non-coding RNAs that regulate transcription and translation of genes, have been found to be involved in CLL initiation, progression, and resistance to therapy. In addition, they can be used as prognostic biomarkers and as targets for novel therapies. In this review, we describe the association between miRNAs and the cytogenetic aberrations commonly found in CLL, as well as with other prognostic factors. We describe the presence of miRNAs as extracellular entities in the plasma and serum of CLL patients and discuss their role in resistance to therapy. Finally, we will explore the potential of targeted miRNA therapy for the treatment of CLL, with a special emphasis on MRX34, the first miRNA mimic that is currently being evaluated for clinical use. PMID:27040698

  4. Analysis of racial variations in disease characteristics, treatment patterns, and outcomes of patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Nabhan, Chadi; Chaffee, Kari G; Slager, Susan L; Galanina, Natalie; Achenbach, Sara J; Schwager, Susan M; Kay, Neil E; Shanafelt, Tait D

    2016-07-01

    The impact of race on outcomes of patients with chronic lymphocytic leukemia (CLL), the most common leukemia in the west, is not well studied. We aimed to understand racial variations in clinical and disease characteristics, treatment patterns, and outcomes in patients with CLL. We utilized the Mayo Clinic CLL database to perform an analysis of these characteristics and natural history of non-white (NW) compared to white (W) CLL patients. Differences by race in median overall survival (OS) and time-to-first-treatment (TTFT) were investigated. Of the 4215 CLL patients, 4114 (97.6%) were W and 101 (2.4%) were NW. NW patients were younger (median age at diagnosis 59.4 vs. 63.4; P = 0.003) and more likely to have an elevated LDH (28.0% vs. 16.2%; P = 0.02). No differences in prognostic parameters were noted. No major differences were observed in treatment selection. OS and TTFT were similar between both groups. In the largest analysis of NW-CLL patients in North America, and contrary to historical retrospective reports, W and NW patients appear to have comparable outcomes when treated similarly. These findings suggest previously noted outcome differences may be due to disparities in access to care and management rather than differences in disease biology. Am. J. Hematol. 91:677-680, 2016. © 2016 Wiley Periodicals, Inc. PMID:27013143

  5. Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia.

    Science.gov (United States)

    Wendtner, Clemens-Martin; Hillmen, Peter; Mahadevan, Daruka; Bühler, Andreas; Uharek, Lutz; Coutré, Steven; Frankfurt, Olga; Bloor, Adrian; Bosch, Francesc; Furman, Richard R; Kimby, Eva; Gribben, John G; Gobbi, Marco; Dreisbach, Luke; Hurd, David D; Sekeres, Mikkael A; Ferrajoli, Alessandra; Shah, Sheetal; Zhang, Jennie; Moutouh-de Parseval, Laure; Hallek, Michael; Heerema, Nyla A; Stilgenbauer, Stephan; Chanan-Khan, Asher A

    2012-03-01

    Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL. PMID:21879809

  6. Ionizing radiation exposures in treatments of solid neoplasms are not associated with subsequent increased risks of chronic lymphocytic leukemia.

    Science.gov (United States)

    Radivoyevitch, Tomas; Sachs, Rainer K; Gale, Robert Peter; Smith, Mitchell R; Hill, Brian T

    2016-04-01

    Exposure to ionizing radiation is not thought to cause chronic lymphocytic leukemia (CLL). Challenging this notion are recent data suggesting CLL incidence may be increased by radiation exposure from the atomic bombs (after many decades), uranium mining and nuclear power facility accidents. To assess the effects of therapeutic ionizing radiation for the treatment of solid neoplasms we studied CLL risks in data from the Surveillance, Epidemiology, and End Results (SEER) Program. Specifically, we compared the risks of developing CLL in persons with a 1(st) non-hematologic cancer treated with or without ionizing radiation. We controlled for early detection effects on CLL risk induced by surveillance after 1(st) cancer diagnoses by forming all-time cumulative CLL relative risks (RR). We estimate such CLL RR to be 1.20 (95% confidence interval, 1.17, 1.23) for persons whose 1(st) cancer was not treated with ionizing radiation and 1.00 (0.96, 1.05) for persons whose 1(st) cancer was treated with ionizing radiations. These results imply that diagnosis of a solid neoplasm is associated with an increased risk of developing CLL only in persons whose 1(st) cancer was not treated with radiation therapy. PMID:26922774

  7. High neutrophil-lymphocyte ratio indicates poor prognosis for acute-on-chronic liver failure after liver transplantation

    Science.gov (United States)

    Lin, Bing-Yi; Zhou, Lin; Geng, Lei; Zheng, Zhi-Yun; Jia, Jun-Jun; Zhang, Jing; Yao, Jia; Zheng, Shu-Sen

    2015-01-01

    AIM: To investigate the significance of pre-transplant neutrophil-lymphocyte ratio (NLR) in determining the prognosis of liver transplant (LT) recipients with acute-on-chronic liver failure (ACLF). METHODS: Data were collected from the liver transplantation data bank. The NLR values and other conventional inflammatory markers were evaluated for their ability to predict the prognosis of 153 patients with ACLF after LT. The NLR cut-off value was based on a receiver operating characteristic curve analysis. A Kaplan-Meier curve analysis and univariate and multivariate Cox regression models were used to define the independent risk factors for poor outcomes. RESULTS: The optimal NLR cut-off value was 4.6. Out of 153 patients, 83 (54.2%) had an NLR ≥ 4.6. The 1-, 3-, and 5-year overall survival rates were 94.3%, 92.5% and 92.5%, respectively, in the normal NLR group and 74.7%, 71.8% and 69.8%, respectively, in patients with high NLRs (P < 0.001). Furthermore, there was a significant difference in infectious complications after LT between the high and normal NLR groups. There were no significant differences for other complications. In the multivariate Cox regression model, a high NLR was defined as a significant predictor of poor outcomes for LT. CONCLUSION: A high NLR is a convenient and available predictor for prognosis of LT patients and can potentially optimize the current criteria for LT in ACLF. PMID:25805939

  8. TP53 mutations are early events in chronic lymphocytic leukemia disease progression and precede evolution to complex karyotypes.

    Science.gov (United States)

    Lazarian, Gregory; Tausch, Eugen; Eclache, Virginie; Sebaa, Amel; Bianchi, Vincent; Letestu, Remi; Collon, Jean-Francois; Lefebvre, Valerie; Gardano, Laura; Varin-Blank, Nadine; Soussi, Thierry; Stilgenbauer, Stephen; Cymbalista, Florence; Baran-Marszak, Fanny

    2016-10-15

    TP53 abnormalities lead to resistance to purine analogues and are found in over 40% of patients with refractory chronic lymphocytic leukemia (CLL). At diagnosis, no more than 5% of patients carry the 17p deletion, most cases harbour mutations within the other TP53 allele. The incidence of a TP53 mutation as the only alteration is approximately 5%, but this depends on the sensitivity of the technique. Recently, having a complex karyotype has been considered a strong adverse prognostic factor. However, there are no longitudinal studies simultaneously examining the presence of the 17p deletion, TP53 mutations and karyotype abnormalities. We conducted a retrospective longitudinal study of 31 relapsed/refractory CLL patients. Two to six blood samples per patient were analyzed, with a median follow-up of 8 years. In this report, we assessed the sequence of events of TP53 clonal evolution and correlated the presence of TP53 abnormalities to genetic instability during progression and treatment. Next-generation sequencing allowed the early detection of TP53 mutated clones and was able to be performed on a routine basis, demonstrating an excellent correlation between the Illumina and Ion Torrent technologies. We concluded that TP53 mutations are early events and precede clonal evolution to complex karyotypes. We strongly recommend the early and iterated detection of TP53 mutations in progressive cases. PMID:27270786

  9. Autologous Stem Cell Transplantation for Chronic Lymphocytic Leukemia - Still a Valid Treatment Option, or is the Game Over?

    Science.gov (United States)

    McClanahan, Fabienne; Dreger, Peter

    2012-01-01

    Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has been established as the current standard of care for young and fit patients with chronic lymphocytic leukemia (CLL). In the early nineties of the last century, long before the advent of fludarabine or antibody-based strategies, there was realistic hope that myeloablative therapy followed by autologous stem cell transplantation (autoSCT) might be an effective and potentially curative front-line treatment option for suitable patients with CLL. Since then, several prospective trials have disenthralled this hope: although autoSCT can prolong event and progression-free survival if used as part of early front-line treatment, it does not improve overall survival, while it is associated with an increased risk of late adverse events such as secondary malignancies. In addition, autoSCT lacks the potential to overcome the negative impact of biomarkers that confer resistance to chemotherapy or early relapse. The role of autoSCT has also been explored in the context of FCR, and it was demonstrated that its effect is inferior to the currently established optimal treatment regimen. In view of ongoing attempts to improve on FCR, promising clinical activity of new substances even in relapsed/ refractory CLL patients, exciting novel cell therapy approaches and advantages in the understanding of the disease and detection of Minimal Residual Disease (MRD), autoSCT has lost its place as a standard treatment option for CLL. PMID:23205259

  10. AUTOLOGOUS STEM CELL TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA STILL A VALID TREATMENT OPTION, OR IS THE GAME OVER ?

    Directory of Open Access Journals (Sweden)

    Fabienne McClanahan

    2012-01-01

    Full Text Available

    Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR has been established as the current standard of care for young and fit patients with chronic lymphocytic leukemia (CLL. In the early nineties of the last century, long before the advent of fludarabine or antibody-based strategies, there was realistic hope that myeloablative therapy followed by autologous stem cell transplantation (autoSCT might be an effective and potentially curative front-line treatment option for suitable patients with CLL. Since then, several prospective trials have disenthralled this hope: although autoSCT can prolong event and progression-free survival if used as part of early front-line treatment, it does not improve overall survival, while it is associated with an increased risk of late adverse events such as secondary malignancies. In addition, autoSCT lacks the potential to overcome the negative impact of biomarkers that confer resistance to chemotherapy or early relapse. The role of autoSCT has also been explored in the context of FCR, and it was demonstrated that its effect is inferior to the currently established optimal treatment regimen. In view of ongoing attempts to improve on FCR, promising clinical activity of new substances even in relapsed/ refractory CLL patients, exciting novel cell therapy approaches and advantages in the understanding of the disease and detection of Minimal Residual Disease (MRD, autoSCT has lost its place as a standard treatment option for CLL.

  11. Integrating oncogeriatric tools into the management of chronic lymphocytic leukemia: current state of the art and challenges for the future.

    Science.gov (United States)

    Merli, Francesco; Mammi, Caterina; Ilariucci, Fiorella

    2015-07-01

    Although the achievement of deep and long lasting remissions is a realistic goal of therapy in the fit patient with chronic lymphocytic leukemia (CLL), this disease typically affects elderly patients who also show one or more concomitant pathological conditions or functional limitations that have an additive effects on the reduction of patient's life expectancy and represent major limitations in the adoption of standard therapies. In these unfit but typical patients with CLL, the goals of treatment may vary from achieving good remissions without severe toxicity to simple palliation. Differently from the past when the definition of patient medical status was mainly based on age and was left to the subjective assessment of the physician, today there are several tools to define in a standardized, reproducible, and multidimensional way the initial patient assessment and to plan treatment goals in an objective way. In this review, an overview of the current approaches to the definition of the medical fitness of the patient is provided along with some practical suggestions to integrate these tools in the clinical approach to elderly patients with CLL. PMID:25986721

  12. Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A.

    Science.gov (United States)

    Zonta, Francesca; Pagano, Mario Angelo; Trentin, Livio; Tibaldi, Elena; Frezzato, Federica; Trimarco, Valentina; Facco, Monica; Zagotto, Giuseppe; Pavan, Valeria; Ribaudo, Giovanni; Bordin, Luciana; Semenzato, Gianpietro; Brunati, Anna Maria

    2015-06-11

    Aberrant protein kinase activities, and the consequent dramatic increase of Ser/Thr and -Tyr phosphorylation, promote the deregulation of the survival pathways in chronic lymphocytic leukemia (CLL), which is crucial to the pathogenesis and progression of the disease. In this study, we show that the tumor suppressor protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatases, is in an inhibited form because of the synergistic contribution of 2 events, the interaction with its physiologic inhibitor SET and the phosphorylation of Y307 of the catalytic subunit of PP2A. The latter event is mediated by Lyn, a Src family kinase previously found to be overexpressed, delocalized, and constitutively active in CLL cells. This Lyn/PP2A axis accounts for the persistent high level of phosphorylation of the phosphatase's targets and represents a key connection linking phosphotyrosine- and phosphoserine/threonine-mediated oncogenic signals. The data herein presented show that the disruption of the SET/PP2A complex by a novel FTY720-analog (MP07-66) devoid of immunosuppressive effects leads to the reactivation of PP2A, which in turn triggers apoptosis of CLL cells. When used in combination with SFK inhibitors, the action of MP07-66 is synergistically amplified, providing a new option in the therapeutic strategy for CLL patients. PMID:25931585

  13. Combination of Targeted Drugs to Control Chronic Lymphocytic Leukemia: Harnessing the Power of New Monoclonal Antibodies in Combination With Ibrutinib.

    Science.gov (United States)

    Cramer, Paula; Langerbeins, Petra; Hallek, Michael

    2016-01-01

    The landscape of treatment for chronic lymphocytic leukemia is rapidly changing at present. Considerable improvement has been achieved with the introduction of the anti-CD20 antibodies, and chemoimmunotherapy has now become an established standard for patients without the high-risk features del(17p)/TP53 mutation. Also, the outcome of patients with these adverse genetic aberrations was dramatically improved with the introduction of the kinase inhibitors ibrutinib and idelalisib. Different combinations of these and additional novel agents are currently evaluated in clinical trials. The combination of the Bruton tyrosine kinase inhibitor ibrutinib with an anti-CD20 antibody is an attractive option, because both drugs act synergistically: ibrutinib redistributes the CLL cells from their homing organs to the peripheral blood, and obinutuzumab eliminates the leukemic cells in the blood with particular efficiency. Adding the Bcl-2 antagonist venetoclax could further intensify the treatment of CLL. This combination might hold the potential to achieve a deep remission with an eradication of residual CLL cells and thus lead to long-term remissions of CLL. PMID:26841018

  14. Association of interleukin-6 and interleukin-8 with poor prognosis in elderly patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Yoon, Ju-Yoon; Lafarge, Sandrine; Dawe, Dave; Lakhi, Sunjay; Kumar, Rajat; Morales, Carmen; Marshall, Aaron; Gibson, Spencer B; Johnston, James B

    2012-09-01

    In population studies, the relative survival in chronic lymphocytic leukemia (CLL) decreases with age. In this study, we demonstrated in a cohort of 189 patients from a CLL clinic that overall survival was lower in the sub-cohort of patients aged ≥ 70 years, but causes of death were similar for all age groups, being progressive CLL, secondary malignancies and infections. As normal individuals age, the plasma levels of inflammatory cytokines, such as interleukin-6 (IL-6) and IL-8, can increase. In our patients with CLL, IL-6, IL-8 and tumor necrosis factor-α (TNF-α) levels increased with age to a greater degree than in normal individuals, and the levels correlated closely with plasma β(2)-microglobulin and with one another. In addition, in patients ≥ 70 years, IL-6 was found to be a better prognostic marker than immunoglobulin variable heavy chain gene (IgV(H)) status. In vitro studies demonstrated that IL-6 and IL-8 could enhance the binding of CLL cells to stromal cells, suggesting that their clinical activity may be mediated through their effects on the microenvironment. Thus, plasma IL-6 is an important prognostic marker for the elderly with CLL, and this study highlights that the utility of prognostic markers may depend on patient age. PMID:22475215

  15. Promoter hypomethylation and expression is conserved in mouse chronic lymphocytic leukemia induced by decreased or inactivated Dnmt3a

    Science.gov (United States)

    Haney, Staci L.; Upchurch, G. Michael; Opavska, Jana; Klinkebiel, David; Hlady, Ryan A.; Suresh, Abhinav; Pirruccello, Samuel J.; Shukla, Vipul; Lu, Runqing; Costinean, Stefan; Rizzino, Angie; Karpf, Adam R.; Joshi, Shantaram; Swanson, Patrick; Opavsky, Rene

    2016-01-01

    SUMMARY DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that by 16 months of age, 65% of Dnmt3a+/− mice develop a CLL-like disease and 15% of mice develop non-malignant myeloproliferation. Genome-wide methylation analysis reveals that reduced Dnmt3a levels induce promoter hypomethylation at similar loci in Dnmt3a+/− and Dnmt3aΔ/Δ CLL, suggesting that promoters are particularly sensitive to Dnmt3a levels. Gene-expression analysis identified 26 hypomethylated and over-expressed genes common to both Dnmt3a+/− and Dnmt3aΔ/Δ CLL as putative oncogenic drivers. Our data provide evidence that Dnmt3a is a haplo-insufficient tumor suppressor in CLL and highlights the importance of deregulated molecular events in disease pathogenesis. PMID:27134162

  16. Epstein-Barr virus DNA load in chronic lymphocytic leukemia is an independent predictor of clinical course and survival.

    Science.gov (United States)

    Visco, Carlo; Falisi, Erika; Young, Ken H; Pascarella, Michela; Perbellini, Omar; Carli, Giuseppe; Novella, Elisabetta; Rossi, Davide; Giaretta, Ilaria; Cavallini, Chiara; Scupoli, Maria Teresa; De Rossi, Anita; D'Amore, Emanuele Stefano Giovanni; Rassu, Mario; Gaidano, Gianluca; Pizzolo, Giovanni; Ambrosetti, Achille; Rodeghiero, Francesco

    2015-07-30

    The relation between Epstein-Barr virus (EBV) DNA load and clinical course of patients with chronic lymphocytic leukemia (CLL) is unknown. We assessed EBV DNA load by quantitative PCR at CLL presentation in mononuclear cells (MNC) of 220 prospective patients that were enrolled and followed-up in two major Institutions. In 20 patients EBV DNA load was also assessed on plasma samples. Forty-one age-matched healthy subjects were tested for EBV DNA load on MNC. Findings were validated in an independent retrospective cohort of 112 patients with CLL. EBV DNA load was detectable in 59%, and high (≥2000 copies/µg DNA) in 19% of patients, but it was negative in plasma samples. EBV DNA load was significantly higher in CLL patients than in healthy subjects (P variables, except for 11q deletion (P = .004), CD38 expression (P = .003), and NOTCH1 mutations (P = .05). High EBV load led to a 3.14-fold increase in the hazard ratio of death and to a shorter overall survival (OS; P = .001). Poor OS was attributable, at least in part, to shorter time-to-first-treatment (P = .0008), with no higher risk of Richter's transformation or second cancer. Multivariate analysis selected high levels of EBV load as independent predictor of OS after controlling for confounding clinical and biological variables. EBV DNA load at presentation is an independent predictor of OS in patients with CLL. PMID:26087198

  17. Plumbagin reduces chronic lymphocytic leukemia cell survival by downregulation of Bcl-2 but upregulation of the Bax protein level.

    Science.gov (United States)

    Fu, Chunling; Gong, Yanqing; Shi, Xuanxuan; Sun, Zengtian; Niu, Mingshan; Sang, Wei; Xu, Linyan; Zhu, Feng; Wang, Ying; Xu, Kailin

    2016-09-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, and mainly originates from an accumulation of abnormal B cells caused by the dysregulation of cell proliferation and apoptosis rates. The aberration of apoptosis-related genes in CLL cells results in defective apoptosis of CLL cells in response to traditional therapeutic medicine. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), a natural compound from Plumbago zeylinica, has been shown to exhibit pro-apoptotic activities in tumor cells. In the present study, we report that plumbagin effectively inhibited CLL cell viability with a lower dose compared to fludarabine, and inhibited cell proliferation in a dose-dependent manner. In addition, plumbagin promoted accumulation of MEC-1 cells in the S phase, and blocked cell cycle transition of HG3 cells from G0/G1 to S phase. Molecularly, plumbagin markedly induced CLL cell apoptosis through reduction of Bcl-2, but through an increase in the Bax protein level. These results suggest that plumbagin may be considered as a potential anticancer agent for CLL therapy. PMID:27461100

  18. Immunophenotyping of peripheral blood lymphocytes at children and adolescents with Hashimoto's thyroiditis

    International Nuclear Information System (INIS)

    Two-color immunophenotyping of lymphocyte subsets using a lysed whole blood method was performed in 46 children and adolescents with Hashimoto's thyroiditis (HT) from contaminated areas and in 18 children from 'clean' areas of Belarus. 46 healthy children of matched age and sex distribution were used as control group. Analysis of lymphocyte subsets in children with HT living in contamination areas shower a considerable decrease in the levels of total lymphocytes, CD8+ T cells (T-suppressors), total B cells, and CD5+ B cells together with an activation of NK and CD56+, CD8+CD57+T cells (T-killers not restricted by HLA antigens). The study of cellular immunity in children with different doses of ionizing radionuclides revealed that prolonged influence of very small doses of ionizing radiation resulted in significant changes in lymphocyte subsets; interestingly, B cell subsets were the first to react to such influence while stability of T-killers and NK was the highest. These changes were the greatest in children with HT with the highest dose of incorporated radionuclides. Significant correlation between the levels of main lymphocyte subsets and the doses of accumulated radionuclides observed in this study also indicated that their relation was dose-dependent. The results of the study suggest that 1) lymphocyte subsets are different in their reaction to chronic internal irradiation which, evidently, is determined by their proliferation activity, degree of differentiation, and function; 2) increase in the dose of incorporated radionuclides in children and adolescents with HT leads to different reaction of sells- a decrease in T-suppressors, B cells and activation of cells responsible for nonspecific cytotoxicity- T-killers unrestricted by HLA antigens and NK; 3) children and adolescents with HT from contaminated regions have much more pronounced imbalance of cellular immunity and activation of cellular cytotoxic reactions damaging the thyroid tissue than those with HT

  19. Deficiency of complement factor MBL in a patient required cardiac surgery after an acute myocardial infarction with underlining chronic lymphocytic leukemia

    OpenAIRE

    Lai, Lawrence T.; Lee, Daniel C.; Ko, Wilson; Shevde, Ketan; Zhang, Ming

    2008-01-01

    Increasing evidence suggests that Mannan-binding lectin (MBL), the initial factor of the lectin pathway of complement, plays a role in cardiovascular diseases, i.e. inversely associated with risk of myocardial infarction (MI). In the present case, a patient with MBL deficiency underwent coronary artery bypass grafting (CABG) after an acute MI with underlining chronic lymphocytic leukemia (CLL). Post-operatively, the patient had a cerebral vascular accident and eventually expired. Analysis of ...

  20. A Proline/Arginine-Rich End Leucine-Rich Repeat Protein (PRELP) Variant Is Uniquely Expressed in Chronic Lymphocytic Leukemia Cells

    OpenAIRE

    Eva Mikaelsson; Anders Österborg; Mahmood Jeddi-Tehrani; Parviz Kokhaei; Mahyar Ostadkarampour; Reza Hadavi; Mehran Gholamin; Mehdi Akhondi; Fazel Shokri; Hodjattallah Rabbani; Håkan Mellstedt

    2013-01-01

    Proline/arginine-rich end leucine-rich repeat protein (PRELP) belongs to the small leucine-rich proteoglycan (SLRP) family, normally expressed in extracellular matrix of collagen-rich tissues. We have previously reported on another SLRP, fibromodulin (FMOD) in patients with chronic lymphocytic leukemia (CLL). PRELP is structurally similar to FMOD with adjacent localization on chromosome 1 (1q32.1). As cluster-upregulation of genes may occur in malignancies, the aim of our study was to analyze...

  1. A Systemic Capillary Leak Syndrome (Clarkson Syndrome) in a Patient with Chronic Lymphocytic Leukemia: A Case Report in an Out-of-Hospital Setting

    OpenAIRE

    Manon Durand Bechu; Antoine Rouget; Christian Recher; Elie Azoulay; Vincent Bounes

    2016-01-01

    Systemic Capillary Leak Syndrome (SCLS) is a rare disease with poor prognosis, characterized by the occurrence of mucocutaneous and visceral edema with hypotension, hemoconcentration, and unexpected hypoalbuminemia. The disease can be idiopathic (Clarkson syndrome) or secondary to other diseases and treatments. We describe this syndrome in a prehospitalized, 63-year-old patient with chronic lymphocytic leukemia and an idiopathic form of SCLS manifesting as hypovolemic shock. Initial care is h...

  2. Case 212: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids.

    Science.gov (United States)

    Bag, Asim K; Davenport, Jake J; Hackney, James R; Roy, Rasmoni; Fathallah-Shaykh, Hassan M

    2014-12-01

    History A previously healthy 23-year-old white man presented to the emergency department of our hospital with a 2-month history of dysarthria, progressively worsening vertigo, and difficulty walking. A diagnosis of retinitis pigementosa was made in this patient's childhood. He did not have any history of congenital syphilis. He did not have a history of nausea or vomiting, fever, weight loss, headache, photophobia, seizure, extremity weakness, or sensory disturbance. Physical examination revealed dysarthria, dysmetria, and ataxia. Kernig and Brudzinski signs were absent, and pathergy test results were negative. Laboratory evaluation revealed normal complete and differential blood counts and normal serum chemistry, including a normal serum angiotensin-converting enzyme level. Analysis of his serum was negative for antinuclear antibody (or ANA), cytoplasmic antineutrophil cvtoplasmic antibody (or cANCA), Sjögren syndrome antigens A and B (SS-A and SS-B, respectively), antitissue transglutaminase and antiendomysial antibodies, and paraneoplastic profile. Serum analysis was also negative for human immunodeficiency virus type 1 and type 2 RNA, Venereal Disease Research Laboratory (VDRL) test, rapid plasma regain (RPR), and fluorescent treponemal antibody absorption. Cerebrospinal fluid (CSF) analysis revealed clear fluid, a normal glucose level (64 mg/dL [3.6 mmol/L]; normal range, 40-70 mg/dL [2.2-3.9 mmol/L]), an elevated protein level (97 mg/dL; normal range, 12-60 mg/dL), and an elevated white blood cell count (7/mm(3) [0.007 ×10(9)/L] in tube 1 and 17/mm(3) [0.017 × 10(9)/L] in tube 2) with 84% lymphocytes. CSF immunoglobulin G level was elevated (30.1 mg/dL; normal, RPR test results for CSF were negative. CSF did not grow any bacteria, fungus, or acid-fast bacillus at culture. CSF flow cytometry did not reveal a monoclonal lymphoid population. Initial imaging included brain magnetic resonance (MR) imaging. Computed tomography (CT) images of the chest, abdomen

  3. T-dependent B-cell activation is signalled by an early increase in potassium influx

    DEFF Research Database (Denmark)

    Owens, T; Kaplan, J G

    1982-01-01

    (previously demonstrated when B and T lymphocytes were separately stimulated) also occurs when B cells are stimulated through cooperation with mitogen-activated T cells, and is also detectable early in culture. T-dependent activation of B cells is therefore detectable considerably earlier than by conventional...

  4. Recombinant human interleukin 2 acts as a B cell growth and differentiation promoting factor

    OpenAIRE

    Emmrich, F.; Moll, Heidrun; Markus M Simon

    2009-01-01

    Human B cells appropriately activated by a B cell mitogen are rendered susceptible to human Interleukin 2 (IL-2) as demonstrated with recombinant human IL-2 (rec. h IL-2). They show increased proliferation and drastically enhanced immunoglobulin secretion. Susceptibility to IL-2 is accompanied with the expression of the IL-2 receptor (Tac antigen) on B cells. The data suggest that IL-2 is one of the lymphokines directly involved in the activation of B lymphocytes.

  5. Apoptosis induced by Magnolia Grandiflora extract in chlorambucil-resistant B-chronic lymphocytic leukemia cells

    Directory of Open Access Journals (Sweden)

    Marin Gustavo

    2010-01-01

    Full Text Available Background: B-cell chronic lymphocitic leukemia (B-CLL still remains as an uncurable disease. Even the newest antineoplastic agents have demonstrated limitations in their efficacy. For this reason, further research of new compounds must be done. New pharmacological properties can be obtained from a great diversity botanical species. Among these products, Magnolia Grandiflora receives our attention since it mainly contains Honokiol which had demonstrated effect against B-CLL cells activating different cell death pathways. Aim: To test the ability of Magnolia Grandiflora extracts to induce apoptosis of B-CLL cells in vitro. Materials and Methods: Herb′s extraction: Twenty grams of powdered material were submitted to three consecutives decoctions with 500 ml of distilled water (96 °C, filtered and followed by ultrafiltration with cellulose membrane, lyophilized and reconstituted in AIM-V medium at a final concentration of 10 mg/ml solution. B-CLL chlorambucil- resistant cells were separated and cultivated in the presence of Magnolia′s extract. Samples of cells were taken from the cultures at 24, 48 and 72 h for apoptosis analysis by flow cytometry measuring positive annexin V (0.1 μg/ml cells. Statistics: Apoptosis values were represented by the mean plus or minus SD (± SD for five independent experiments. Statistical significance was determined by Student′s t -test. A P value of 0.05 or less was considered as significant. Results and Conclusion: This article discusses the apoptosis properties of Magnolia on B-CLL cells. The evidence suggests a potentially effective repertoire for B-CLL treatment. This herb extract might have promising therapy strategies in treating B-CLL or other hematological disease resistant to alkylating agents in clinical practice.

  6. Lymphocyte cytosolic protein 1 regulates proliferation of diffuse large B-cell lymphoma cells%淋巴细胞溶质蛋白1调控弥漫性大B细胞淋巴瘤细胞的增殖初探

    Institute of Scientific and Technical Information of China (English)

    张竹红; 田亚平

    2013-01-01

    Objective To study the biological significance of lymphocyte cytosolic protein 1 (LCP1) expression in diffuse large B-cell lymphoma (DLBCL) cells and its effect on proliferation of DLBCL cells. Methods Expression of LCP1 in healthy human B lymphoblastoid cells and various DLBCL cells was detected by Western blot. Over-expressed LCP1 was silenced in DLBCL cell line OCI-LY19. Vitality of the cells was tested with a CCK8 kit. Effect of LCP1 on cell cycle of OCI-LY19 cells was observed with PI staining. Results The expression level of LCP1 was significantly higher in DLBCL cells than in healthy human B lymphoblastoid cells. The vitality of OCI-LY19 cells decreased and the progressive cell sycle of OCI-LY19 cells was inhibited after LCP1 was silenced. Conclusion LCP1 is closely related with the proliferation of DLBCL cells and is an important biological marker for DLBCL.%目的:探索弥漫性大B细胞淋巴瘤中淋巴细胞溶质蛋白1(lymphocyte cytosolic protein 1,LCP1)表达的生物学意义及对细胞增殖的影响。方法用Wstern Blot的方法观察LCP1在正常人B淋巴母细胞系和多种弥漫性大B细胞淋巴瘤细胞系中的表达情况;进而在高表达LCP1的弥漫性大B细胞淋巴瘤(diffuse large B-cell lymphom,DLBCL)细胞系OCI-LY19中将其沉默,使用CCK8试剂盒检测其对细胞活力的影响;并用PI染色的方法检测LCP1对OCI-LY19细胞的细胞周期的影响。结果 LCP1在DLBCL细胞中的表达量明显高于正常人B淋巴母细胞系,沉默LCP1后发现OCI-LY19细胞活力下降,且细胞周期进展明显被抑制。结论 LCP1与DLBCL细胞增殖密切相关,提示其是一个重要DLBCL生物标记。

  7. Interleukin-24 mediates apoptosis in human B-cells through early activation of cell cycle arrest followed by late induction of the mitochondrial apoptosis pathway.

    Science.gov (United States)

    Hadife, Nader; Nemos, Christophe; Frippiat, Jean-Pol; Hamadé, Tala; Perrot, Aurore; Dalloul, Ali

    2013-03-01

    Interleukin (IL)-24 has death-promoting effects on various proliferating cells including B-cells from chronic lymphocytic leukemia (CLL) and germinal center B-cells, but its molecular mechanisms are poorly understood. Using a B-cell differentiation model and mRNA profiling, we found that recombinant (r)IL-24 stimulated genes of the mitochondrial apoptotic pathway (Bax, Bid, Casp8, COX6C, COX7B) after 36 h, whereas the transcription of genes involved in DNA replication and metabolism was inhibited within 6 h. Unexpectedly, insulin-like growth factor 1 (IGF1), a hormone known to promote cell growth, was stimulated by IL-24. Activated B-cells express receptor for IGF1, to which they become sensitized and undergo apoptosis, a mechanism similar in this respect to IL-24-induced cell death. Furthermore, inhibition of the IGF1 pathway reversed the effects of IL-24. IL-24-mediated apoptosis was also antagonized by pifithrin-alpha, an inhibitor of p53 transactivation. Altogether, these results disclose sequential molecular signals generated by IL-24 in activated B-cells. PMID:22860893

  8. Dicer Gene Expression as a Prognostic Factor in Acute Lymphoblastic Leukemia and Chronic Lymphocytic Leukemia in Fars Province

    Science.gov (United States)

    Farzaneh, Mohamad Reza; Shahryari, Jahanbanoo; Safaei, Akbar; Valibeigi, Behnaz; Davani, Shahrbanou Karimi; Tabibi, Narjes

    2016-01-01

    Alterations in the expression of microRNAs (miRNAs) have been proposed to play a role in the pathogenesis of acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Dicer is one of the main regulators of miRNA biogenesis, and deregulation of its expression has been indicated as a possible cause of miRNA alterations observed in various cancers. Our aim was to analyze the expression of the Dicer protein and its relationship with ALL and CLL. This cross-sectional study was performed from 2010 to 2012 in Shahid Faghihi Hospital, Shiraz, Iran. In this study, 30 patients with CLL, 21 patients with ALL, 10 child healthy donors, and 19 adult healthy donors were recruited. The patients’ samples were checked via flow cytometry, immunohistochemistry, and immunocytochemistry. The controls’ samples were also examined in the hematology ward. Total RNA was extracted from the bone marrow and peripheral blood samples of the patients and controls. Then, reverse-transcription polymerase chain reaction was used to estimate the level of Dicer miRNA. The outcomes of the expression analysis of Dicer revealed statistically significant differences between the ALL patients/child healthy controls (mean±SD, 0.19±0.28 vs. 0.73±0.12; P<0.001) and the CLL patients/adult healthy controls (mean±SD, 0.24±0.25 vs. 0.41±0.28; P=0.033). This is the first piece of evidence showing that the expression of the Dicer gene greatly decreased in the patients with ALL in comparison to the child controls. The expression of the Dicer gene was also downregulated in the patients with CLL compared to the adult controls. Given the above findings, the expression of Dicer may play an important role in the progression and prognosis of these diseases.

  9. Molecular cloning of human T-cell lymphotrophic virus type I-like proviral genome from the peripheral lymphocyte DNA of a patient with chronic neurologic disorders

    International Nuclear Information System (INIS)

    Human T-cell lymphotropic virus type 1 (HTLV-I), the etiologic agent of human T-cell leukemia, has recently been shown to be associated with neurologic disorders such as tropical spastic paraparesis, HTLV-associated myelopathy, and possibly with multiple sclerosis. In this communication, the authors have examined one specific case of neurologic disorder that can be classified as multiple sclerosis or tropical spastic paraparesis. The patient suffering from chronic neurologic disorder was found to contain antibodies to HTLV-I envelope and gag proteins in his serum and cerebrospinal fluid. Lymphocytes from peripheral blood and cerebrospinal fluid of the patient were shown to express viral RNA sequences by in situ hybridization. Southern blot analysis of the patient lymphocyte DNA revealed the presence of HTLV-I-related sequences. Blot-hybridization analysis of the RNA from fresh peripheral lymphocytes stimulated with interleukin 2 revealed the presence of abundant amounts of genomic viral RNA with little or no subgenomic RNA. They have clones the proviral genome from the DNA of the peripheral lymphocytes and determined its restriction map. This analysis shows that this proviral genome is very similar if not identical to that of the prototype HTLV-I genome

  10. Augmentation of Recipient Adaptive Alloimmunity by Donor Passenger Lymphocytes within the Transplant

    Directory of Open Access Journals (Sweden)

    Ines G. Harper

    2016-05-01

    Full Text Available Chronic rejection of solid organ allografts remains the major cause of transplant failure. Donor-derived tissue-resident lymphocytes are transferred to the recipient during transplantation, but their impact on alloimmunity is unknown. Using mouse cardiac transplant models, we show that graft-versus-host recognition by passenger donor CD4 T cells markedly augments recipient cellular and humoral alloimmunity, resulting in more severe allograft vasculopathy and early graft failure. This augmentation is enhanced when donors were pre-sensitized to the recipient, is dependent upon avoidance of host NK cell recognition, and is partly due to provision of cognate help for allo-specific B cells from donor CD4 T cells recognizing B cell MHC class II in a peptide-degenerate manner. Passenger donor lymphocytes may therefore influence recipient alloimmune responses and represent a therapeutic target in solid organ transplantation.

  11. Induction of polyclonal B cell activation and differentiation by the AIDS retrovirus (HTLV-III/LAV)

    International Nuclear Information System (INIS)

    The immune systems of individuals infected with HTLV-III/LAV are characterized by a profound defect in cellular immunity together with paradoxical polyclonal B cell activation. The present study examined the direct effects of HTLV-III/LAV on B lymphocytes. Peripheral blood B cells from healthy donors were incubated with a variety of HTLV-III/LAV isolates for 1 h and 3H-thymidine incorporation was measured at multiple time points. Responses ranged from 9000-28,000 cpm and peaked on day 4. This B cell activation was not enhanced by the addition of interleukin-2 to culture, was not synergistic with Staphylococcus aureus Cowan I, was not modulated by the addition of T lymphocytes to culture, and was not associated with B cell transformation. Supernatant Ig could first be detected in virus-activated cultures at day 4, plateaued by day 8, and yielded a mean of 12,500 ng IgG+IgM/ml/50,000 B cells. Thus, HTLV-III/LAV is a potent T cell independent B cell mitogen capable of inducing B cell activation, proliferation, and differentiation comparable in magnitude to that of the most potent B cell activators. This biological property of HTLV-III/LAV may help explain the profound polyclonal B cell activation observed in patients with AIDS and may provide investigators with another probe for investigating the mechanisms of B cell activation

  12. CD20阳性淋巴细胞在慢性移植肾肾病组织中浸润的意义%Significance of CD20-positive lymphocytes infiltrating in renal allograft biopsies with chronic allograft nephropathy

    Institute of Scientific and Technical Information of China (English)

    胡建敏; 赵明; 郭颖; 陈桦; 李民

    2012-01-01

    CD20-positive rate.Immunohistochemical staining showed there were 12 cases (27.3%) with C4d linear deposition in peritubular capillary endothelial cells (PTC).C4d positive rate had no significant difference among the CAN classifications. There was no significant relationship between C4d deposition and CD20-positive lymphocytic infiltration.The average serum creatinine in CD20-negtive group and CD20-posigtive group was 140.8 ± 22.0 and 183.5 ± 25.5μmol/L before biopsy,and 165.6 ± 37.6 and 242.2 ± 59.1 μmol/L one year after biopsy.The average serum creatinine level in CD20-positive group was higher than in CD20-negtive group before and after biopsy.Conclusion Progressive chronic humoral immunity is high risk in the process of CAN. The CD20-positive lymphocyte infiltration has no relevance with CAN grade and C4d deposition in PTC,but is associated with circulating antibody PRA and allograft long-term outcome. Pathogenetic mechanism may not contribute to chronic humoral immune,but B cells presenting donor antigens,are recognized and activated by T cells as antigen-presenting cells.

  13. Quantification of B cells and T lymphocyte subsets in bovine leukemia virus infected dairy cowsQuantificação da população de linfócitos B e das subpopulações de linfócitos T em bovinos infectados pelo vírus da leucose enzoótica bovina

    Directory of Open Access Journals (Sweden)

    Claúdia Regina Stricagnolo

    2012-08-01

    , 15 animals were selected and divided uniformly in three groups (negative, AL, PL. The BLV infection was detected by agar gel immunodiffusion and enzyme-linked immunosorbent-assay. The lymphocytes subsets were evaluated using monoclonal antibodies by flow cytometry. The results of the present study pointed out to an increase in B lymphocytes, and also an augment in CD5+ and CD11b+ cells in animals showing PL. Consequently, it can be observed a decrease in the percentage of T cells subsets in these animals. Conversely, no significant alterations in the absolute number of the T lymphocytes, T CD4+ cells and T CD8+ lymphocytes were found in BLV-infected dairy cows with PL. Therefore, the correlation between the absolute numbers of B- and T cell subsets in the peripheral blood applied to each group showed a significant and positive strong correlation between numbers of B cells and T cells or T CD8+ cells in the PL animals, although the same cannot be predicted for T CD4+ lymphocytes. No such correlation was encountered for the AL and negative-control animals.

  14. Therapeutic strategies targeting B-cells in multiple sclerosis.

    Science.gov (United States)

    Milo, Ron

    2016-07-01

    Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) that traditionally has been considered to be mediated primarily by T-cells. Increasing evidence, however, suggests the fundamental role of B-cells in the pathogenesis of the disease. Recent strategies targeting B-cells in MS have demonstrated impressive and sometimes surprising results: B-cell depletion by monoclonal antibodies targeting the B-cell surface antigen CD20 (e.g. rituximab, ocrelizumab, ofatumumab) was shown to exert profound anti-inflammatory effect in MS with favorable risk-benefit ratio, with ocrelizumab demonstrating efficacy in both relapsing-remitting (RR) and primary-progressive (PP) MS in phase III clinical trials. Depletion of CD52 expressing T- and B-cells and monocytes by alemtuzumab resulted in impressive and durable suppression of disease activity in RRMS patients. On the other hand, strategies targeting B-cell cytokines such as atacicept resulted in increased disease activity. As our understanding of the biology of B-cells in MS is increasing, new compounds that target B-cells continue to be developed which promise to further expand the armamentarium of MS therapies and allow for more individualized therapy for patients with this complex disease. PMID:26970489

  15. Rational Design of a Multiepitope Vaccine Encoding T-Lymphocyte Epitopes for Treatment of Chronic Hepatitis B Virus Infections▿

    OpenAIRE

    Depla, Erik; Der Aa, Annegret Van; Livingston, Brian D.; Crimi, Claire; Allosery, Koen; De Brabandere, Veronique; Krakover, Jonathan; Murthy, Sidharta; Huang, Manley; Power, Scott; Babé, Lilia; Dahlberg, Carol; McKinney, Denise; Sette, Alessandro; Southwood, Scott

    2007-01-01

    Protein sequences from multiple hepatitis B virus (HBV) isolates were analyzed for the presence of amino acid motifs characteristic of cytotoxic T-lymphocyte (CTL) and helper T-lymphocyte (HTL) epitopes with the goal of identifying conserved epitopes suitable for use in a therapeutic vaccine. Specifically, sequences bearing HLA-A1, -A2, -A3, -A24, -B7, and -DR supertype binding motifs were identified, synthesized as peptides, and tested for binding to soluble HLA. The immunogenicity of peptid...

  16. Anatomy of a new B-cell-specific enhancer.

    OpenAIRE

    Koch, W; Benoist, C.; Mathis, D

    1989-01-01

    The major histocompatibility complex class II molecules, like the immunoglobulins, are prominent B-lymphocyte markers. Herein, we describe a B-cell-specific enhancer associated with the murine class II gene, Ek alpha. This enhancer has a complex anatomy that suggests interactions between remotely spaced elements. Of particular interest is the finding that two CCAAT boxes spaced one kilobase apart are important for enhancer activity. Somewhat surprisingly, the E alpha and immunoglobulin enhanc...

  17. Relationship Between Radiation-Induced Apoptosis of T Lymphocytes and Chronic Toxicity in Patients With Prostate Cancer Treated by Radiation Therapy: A Prospective Study

    International Nuclear Information System (INIS)

    Purpose: To assess the correlation of radiation-induced apoptosis in vitro of CD4 and CD8 T lymphocytes with late toxicity of prostate cancer patients treated with radiation therapy. Methods and Materials: 214 patients were prospectively included in the study. Peripheral blood was drawn from patients before treatment and irradiated with 8 Gy. The percentage of CD4+ and CD8+ T lymphocytes that underwent radiation-induced apoptosis was assessed by flow cytometry. Toxicity and mortality were correlated in 198 cases with pretreatment apoptosis and clinical and biological variables by use of a Cox proportional hazards model. Results: The mean percentage of CD4+ and CD8+ T lymphocyte radiation-induced apoptosis was 28.58% (±14.23) and 50.76% (±18.9), respectively. Genitourinary (GU) toxicity was experienced by 39.9% of patients, while gastrointestinal (GI) toxicity was experienced by 19.7%. The probability of development of GU toxicity was nearly doubled (hazard ratio [HR] 1.99, P=.014) in those patients in whom the percentage of in vitro radiation-induced apoptosis of CD4+ T-lymphocytes was ≤28.58%. It was also almost double in patients who received doses ≥50 Gy in 65% of the bladder volume (V65 ≥50) (HR 1.92, P=.048). No correlation was found between GI toxicity and any of the variables studied. The probability of death during follow-up, after adjustment for different variables, was 2.7 times higher in patients with a percentage of CD8+ T lymphocyte apoptosis ≤50.76% (P=.022). Conclusions: In conclusion, our study shows, in the largest prospective cohort of prostate cancer patients undergoing radiation therapy, that in vitro radiation-induced apoptosis of CD4+ T lymphocytes assessed before radiation therapy was associated with the probability of developing chronic GU toxicity. In addition, the radiation dose received in the urinary bladder (V65 ≥50) affected the occurrence of GU toxicity. Finally, we also demonstrate that radiation-induced apoptosis of

  18. Relationship Between Radiation-Induced Apoptosis of T Lymphocytes and Chronic Toxicity in Patients With Prostate Cancer Treated by Radiation Therapy: A Prospective Study

    Energy Technology Data Exchange (ETDEWEB)

    Foro, Palmira, E-mail: pforo@parcdesalutmar.cat [Department of Radiation Oncology, Parc de Salut Mar, Barcelona (Spain); Universitat Pompeu Fabra, Barcelona (Spain); Algara, Manuel [Department of Radiation Oncology, Parc de Salut Mar, Barcelona (Spain); Universitat Pompeu Fabra, Barcelona (Spain); Lozano, Joan [Department of Radiation Oncology, Parc de Salut Mar, Barcelona (Spain); Rodriguez, Nuria; Sanz, Xavier [Department of Radiation Oncology, Parc de Salut Mar, Barcelona (Spain); Universitat Pompeu Fabra, Barcelona (Spain); Torres, Erica [Pathology Department, Parc de Salut Mar, Barcelona (Spain); Carles, Joan [Universitat Autonoma de Barcelona, Barcelona (Spain); Department of Oncology, Hospital Vall d' Hebron, Barcelona (Spain); Reig, Anna; Membrive, Ismael [Department of Radiation Oncology, Parc de Salut Mar, Barcelona (Spain); Quera, Jaume [Department of Radiation Oncology, Parc de Salut Mar, Barcelona (Spain); Universitat Pompeu Fabra, Barcelona (Spain); Fernandez-Velilla, Enric; Pera, Oscar [Department of Radiation Oncology, Parc de Salut Mar, Barcelona (Spain); Lacruz, Marti [Universitat Pompeu Fabra, Barcelona (Spain); Radiation Protection Department, Parc de Salut Mar, Barcelona (Spain); Bellosillo, Beatriz [Universitat Pompeu Fabra, Barcelona (Spain); Pathology Department, Parc de Salut Mar, Barcelona (Spain)

    2014-04-01

    Purpose: To assess the correlation of radiation-induced apoptosis in vitro of CD4 and CD8 T lymphocytes with late toxicity of prostate cancer patients treated with radiation therapy. Methods and Materials: 214 patients were prospectively included in the study. Peripheral blood was drawn from patients before treatment and irradiated with 8 Gy. The percentage of CD4+ and CD8+ T lymphocytes that underwent radiation-induced apoptosis was assessed by flow cytometry. Toxicity and mortality were correlated in 198 cases with pretreatment apoptosis and clinical and biological variables by use of a Cox proportional hazards model. Results: The mean percentage of CD4+ and CD8+ T lymphocyte radiation-induced apoptosis was 28.58% (±14.23) and 50.76% (±18.9), respectively. Genitourinary (GU) toxicity was experienced by 39.9% of patients, while gastrointestinal (GI) toxicity was experienced by 19.7%. The probability of development of GU toxicity was nearly doubled (hazard ratio [HR] 1.99, P=.014) in those patients in whom the percentage of in vitro radiation-induced apoptosis of CD4+ T-lymphocytes was ≤28.58%. It was also almost double in patients who received doses ≥50 Gy in 65% of the bladder volume (V65 ≥50) (HR 1.92, P=.048). No correlation was found between GI toxicity and any of the variables studied. The probability of death during follow-up, after adjustment for different variables, was 2.7 times higher in patients with a percentage of CD8+ T lymphocyte apoptosis ≤50.76% (P=.022). Conclusions: In conclusion, our study shows, in the largest prospective cohort of prostate cancer patients undergoing radiation therapy, that in vitro radiation-induced apoptosis of CD4+ T lymphocytes assessed before radiation therapy was associated with the probability of developing chronic GU toxicity. In addition, the radiation dose received in the urinary bladder (V65 ≥50) affected the occurrence of GU toxicity. Finally, we also demonstrate that radiation-induced apoptosis of

  19. RPPA-based protein profiling reveals eIF4G overexpression and 4E-BP1 serine 65 phosphorylation as molecular events that correspond with a pro-survival phenotype in chronic lymphocytic leukemia.

    Science.gov (United States)

    Shull, Austin Y; Noonepalle, Satish K; Awan, Farrukh T; Liu, Jimei; Pei, Lirong; Bollag, Roni J; Salman, Huda; Ding, Zhiyong; Shi, Huidong

    2015-06-10

    Chronic lymphocytic leukemia (CLL), the most common adult leukemia, remains incurable despite advancements in treatment regimens over the past decade. Several expression profile studies have been pursued to better understand CLL pathogenesis. However, these large-scale studies only provide information at the transcriptional level. To better comprehend the differential protein changes that take place in CLL, we performed a reverse-phase protein array (RPPA) analysis using 167 different antibodies on B-cell lysates from 18 CLL patients and 6 normal donors. From our analysis, we discovered an enrichment of protein alterations involved with mRNA translation, specifically upregulation of the translation initiator eIF4G and phosphorylation of the cap-dependent translation inhibitor 4E-BP1 at serine 65. Interestingly, 4E-BP1 phosphorylation occurred independently of AKT phosphorylation, suggesting a disconnect between PI3K/AKT pathway activation and 4E-BP1 phosphorylation. Based on these results, we treated primary CLL samples with NVP-BEZ235, a PI3K/mTOR dual inhibitor, and compared its apoptotic-inducing potential against the BTK inhibitor Ibrutinib and the PI3Kδ inhibitor Idelalisib. We demonstrated that treatment with NVP-BEZ235 caused greater apoptosis, greater apoptotic cleavage of eIF4G, and greater dephosphorylation of 4E-BP1 in primary CLL cells. Taken together, these results highlight the potential dependence of eIF4G overexpression and 4E-BP1 phosphorylation in CLL survival. PMID:25999352

  20. Chronic Lymphocytic Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. ...

  1. Surface membrane antigen expression changes induced in vitro by exogenous growth factors in chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Vilpo, J; Hulkkonen, J; Hurme, M; Vilpo, L

    2002-09-01

    The factors determining the growth and survival of cells in B chronic lymphocytic leukemia (CLL) have remained poorly understood. We investigated the effects of optimal mitogen combinations (OMCs) on the expression of 26 surface membrane antigens among 33 CLL patients. The seven OMCs used were selected after pre-testing 14 combinations of (1) S. aureus Cowan I (SAC), (2) interleukin-2 (IL-2), (3) tumor necrosis factor alpha (TNF-alpha) and (4) 12-O-tetradecanoylphorbol 13-acetate (TPA; also known as phorbol 12-myristate 13-acetate or PMA). In flow cytometry we revealed that OMCs induced statistically highly significant upregulation of the expression of CD5, CD11c, CD19, CD22, CD23, CD25, CD38, CD40, CD45, CD45RO, CD95, CD126, CD130 and FMC7, and downregulation of CD20 and CD124 expression. Interestingly, the expression of CD27, CD45RA, CD79b, CD80, CD122 and that of the immunoglobulin gene superfamily members CD21, Ig-kappa, Ig-lambda, Ig-delta and Ig-micro were not significantly affected under similar conditions. The expression of several antigens was co-regulated, suggesting common regulatory pathways. These antigens include CD11c/CD5, CD11c/CD22, CD11c/CD126, CD11c/FMC7 as well as CD27/CD45, CD27/CD45RA and CD27/CD79b. Upregulation of surface antigen expression, induced by OMCs, should be applicable in antibody therapy in vitro and in vivo, and in negative stem cell selection for autotransplantation. Furthermore, the current strategy to enhance cell surface antigen expression may be a versatile tool to raise humoral and cell-mediated host defense against CLL cells. Upregulation of proteins mediating positive growth signals (eg CD25, CD40) and negative signals or apoptosis (eg CD95) may be used to sensitize cells to chemotherapy and programmed cell death. PMID:12200683

  2. OCA-B integrates B cell antigen receptor-, CD40L- and IL 4-mediated signals for the germinal center pathway of B cell development.

    OpenAIRE

    Qin, X F; Reichlin, A; Luo, Y.; Roeder, R. G.; Nussenzweig, M.C.

    1998-01-01

    Many of the key decisions in lymphocyte differentiation and activation are dependent on integration of antigen receptor and co-receptor signals. Although there is significant understanding of these receptors and their signaling pathways, little is known about the molecular requirements for signal integration at the level of activation of gene expression. Here we show that in primary B cells, expression of the B-cell specific transcription coactivator OCA-B (also known as OBF-1 or Bob-1) is re...

  3. S-phase induction by interleukin-6 followed by chemotherapy in patients with chronic lymphocytic leukemia and non-Hodgkin's lymphoma

    DEFF Research Database (Denmark)

    Brown, P D; Diamant, Marcus; Jensen, P O;

    1999-01-01

    Interleukin-6 (IL-6) has in vitro demonstrated growth regulatory effects on tumor cells from patients with chronic lymphocytic leukemia (CLL) and lymphoma. The proliferation rate of these cells is usually very low and this is thought to be one of the reasons for the lack of a curative potential of...... cytostatic chemotherapy in CLL and low grade NHL. Recombinant human (rh) IL-6 might increase the in vivo proliferation rate leading to a higher sensitivity for chemotherapy. We tested this hypothesis by administering rhIL-6 to 9 CLL patients and 3 NHL patients in doses of 2.5 micrograms/kg, 5 micrograms...

  4. A Systemic Capillary Leak Syndrome (Clarkson Syndrome in a Patient with Chronic Lymphocytic Leukemia: A Case Report in an Out-of-Hospital Setting

    Directory of Open Access Journals (Sweden)

    Manon Durand Bechu

    2016-01-01

    Full Text Available Systemic Capillary Leak Syndrome (SCLS is a rare disease with poor prognosis, characterized by the occurrence of mucocutaneous and visceral edema with hypotension, hemoconcentration, and unexpected hypoalbuminemia. The disease can be idiopathic (Clarkson syndrome or secondary to other diseases and treatments. We describe this syndrome in a prehospitalized, 63-year-old patient with chronic lymphocytic leukemia and an idiopathic form of SCLS manifesting as hypovolemic shock. Initial care is hospitalization in intensive care. In addition to etiological treatment if fluid replacement is necessary, treatment must be closely monitored for secondary overload complications. Catecholamine rather than arrhythmogenic support may be associated.

  5. A Systemic Capillary Leak Syndrome (Clarkson Syndrome) in a Patient with Chronic Lymphocytic Leukemia: A Case Report in an Out-of-Hospital Setting

    Science.gov (United States)

    Durand Bechu, Manon; Rouget, Antoine; Recher, Christian; Azoulay, Elie; Bounes, Vincent

    2016-01-01

    Systemic Capillary Leak Syndrome (SCLS) is a rare disease with poor prognosis, characterized by the occurrence of mucocutaneous and visceral edema with hypotension, hemoconcentration, and unexpected hypoalbuminemia. The disease can be idiopathic (Clarkson syndrome) or secondary to other diseases and treatments. We describe this syndrome in a prehospitalized, 63-year-old patient with chronic lymphocytic leukemia and an idiopathic form of SCLS manifesting as hypovolemic shock. Initial care is hospitalization in intensive care. In addition to etiological treatment if fluid replacement is necessary, treatment must be closely monitored for secondary overload complications. Catecholamine rather than arrhythmogenic support may be associated. PMID:27069700

  6. Peripheral blood and mesenteric lymph node lymphocytes in Crohn's disease.

    OpenAIRE

    Richens, E R; Thorp, C M; Bland, P W; Gough, K R

    1980-01-01

    Analysis of peripheral blood lymphocytes from 44 patients with Crohn's disease showed no difference in the proportions of T- and B-cells from those in 38 healthy controls. Analysis revealed no disturbances in relation to duration or to activity of disease or to drug treatment. Lymphocytes from 18 patients with rheumatoid arthritis also showed normal proportions of T- and B-cells. Lymphocytes taken from gut lymph nodes were studied in five patients with Crohn's disease. On comparison with peri...

  7. Double-Positive CD21+CD27+ B Cells Are Highly Proliferating Memory Cells and Their Distribution Differs in Mucosal and Peripheral Tissues

    OpenAIRE

    Das, Arpita; Xu, Huanbin; Wang, Xiaolei; Yau, Canddy L.; Veazey, Ronald S.; Pahar, Bapi

    2011-01-01

    Background Several B-cell defects arise in HIV infected patients, particularly in patients with chronic infection and high viral load. Loss of memory B cells (CD27+ B cells) in peripheral blood and lymphoid tissues is one of the major B cell dysfunctions in HIV and simian immunodeficiency virus (SIV) infection. Despite several studies, definitive identification of memory B cells based on CD27 surface expression has not been described. Similarly, the rates of cell turnover in different B cell ...

  8. Idelalisib for relapsed/refractory indolent B-cell non-Hodgkin's lymphoma: an overview of pharmacokinetics and clinical trial outcomes.

    Science.gov (United States)

    Davies, Andrew

    2015-10-01

    Indolent non-Hodgkin's lymphoma (iNHL) describes a group of B-cell lymphomas with a long median survival and a relapsing-remitting clinical course. Although existing treatments are initially effective, patients often relapse, demonstrating decreasing efficacy with successive treatment courses. Alternative treatments are needed. PI3Kδ plays an essential, non-redundant role in B-cell receptor signaling critical to the pathogenesis of iNHL. It is expressed predominantly in hematopoietic cells, making PI3Kδ an attractive therapeutic target. Idelalisib is an oral PI3Kδ inhibitor approved in 2014 in the USA and the EU as monotherapy in relapsed follicular lymphoma or relapsed small lymphocytic lymphoma previously treated with two or more prior systemic therapies, or as part of combination therapy with rituximab in patients with chronic lymphocytic leukemia, for whom rituximab monotherapy would be considered appropriate due to the presence of comorbidities. Herein, we review the available data for idelalisib, with an emphasis on relapsed/refractory B-cell iNHL. PMID:26343890

  9. T、B、NK细胞亚型与慢性荨麻疹发病机制的关系%T, B and NK lymphocyte subgroups in the pathogenesis of chronic urticaria

    Institute of Scientific and Technical Information of China (English)

    朱慧兰; 李润祥; 郭庆; 罗静英; 李振洁; 李嘉彦; 吴志华

    2008-01-01

    Objective To study the relationship of T, B and NK lymphocytes with the pathogenesis of chronic urticaria. Methods Flow cytometry was applied to assess the proportion of T, B and NK lymphocyte subgroups in the peripheral blood of 51 patients with chronic urticaria and 30 sex and age-matched human controls. The CD4:CD8 ratio was calculated. Moreover, the symptoms, disease course and response to antihistamines of these patients were evaluated by one physician. Results The percentage of CD8+ T and NK cells, CD4:CD8 ratio were (27.20±8.22)%, (21.20±10.84)% and 1.48±0.62, respectively, in these patients,(29.9±3.74)%, (17.5±3.56)%, 1.24±0.27, respectively, in the controls; the differences were significant between the two groups (all P<0.05). Decreased levels of CD3+ T cells, CD8+ T cells and B cells were noted in patients resistant to antihistamines compared with those responsive to antihistamines[(61.81±11.70)% vs (75.74±2.36)%, (24.00±7.79)% vs (34.22±9.30)%, (10.78±2.07)% vs (15.25±4.10)%, P<0.05, 0.01, 0.05, respectively)], while the CD4:CD8 ratio and percentage of NK cells were increased in antihistamine-resistant patients compared to those in antihistamine-sensitive patients [1.67±0.76 vs 1.17±0.41, (28.61±12.62)% vs (12.78±6.02)%, both P<0.01 ]. In these patients with chronic urticaria, the percentages of CD3+ T and CD8+ T cells were negatively correlated with the symptom scores (R = -0.31, -0.28, respectively, both P<0.05 ), while the percentage of B cells was positively correlated with the symptom scores and disease course (R = 0.53, 0.55, respectively, both P<0.01 ). Conclusions There is an abnormality in the proportion of T, B and NK lymphocyte subgroups in patients with chronic urticaria,which indicates that humoral immunity may be involved in the pathogenesis of chronic urticaria and the mechanism for responsiveness to antihistamine.%目的 探讨T、B、NK细胞亚型与慢性荨麻疹发病机制的关系.方法

  10. Proposals for the classification of chronic (mature) B and T lymphoid leukaemias. French-American-British (FAB) Cooperative Group.

    OpenAIRE

    Bennett, J M; Catovsky, D.; Daniel, M T; Flandrin, G; Galton, D A; Gralnick, H R; Sultan, C.

    1989-01-01

    Peripheral blood, bone marrow films, and bone marrow biopsy specimens from 110 patients, well characterised by clinical and laboratory studies, including electron microscopy, were reviewed, to determine proposals for the classification of chronic (mature) B and T cell leukaemias. On the basis of cytology and membrane phenotype the following disorders were defined: (i) B cell type: chronic lymphocytic leukaemia (CLL); CLL of mixed cell type, which includes cases with more than 10% and less tha...

  11. The PD-1/PD-L1 (B7-H1 Pathway in Chronic Infection-Induced Cytotoxic T Lymphocyte Exhaustion

    Directory of Open Access Journals (Sweden)

    Kimberly A. Hofmeyer

    2011-01-01

    Full Text Available Cytotoxic CD8 T lymphocytes (CTLs play a pivotal role in the control of infection. Activated CTLs, however, often lose effector function during chronic infection. PD-1 receptor and its ligand PD-L1 of the B7/CD28 family function as a T cell coinhibitory pathway and are emerging as major regulators converting effector CTLs into exhausted CTLs during chronic infection with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and other pathogens capable of establishing chronic infections. Importantly, blockade of the PD-1/PD-L1 pathway is able to restore functional capabilities to exhausted CTLs and early clinical trials have shown promise. Further research will reveal how chronic infection induces upregulation of PD-1 on CTLs and PD-L1 on antigen-presenting cells and other tissue cells and how the PD-1/PD-L1 interaction promotes CTLs exhaustion, which is crucial for developing effective prophylactic and therapeutic vaccination against chronic infections.

  12. Restitution of superoxide generation in autosomal cytochrome-negative chronic granulomatous disease (A22(0) CGD)-derived B lymphocyte cell lines by transfection with p22phax cDNA

    OpenAIRE

    1993-01-01

    The respiratory burst oxidase of phagocytes and B lymphocytes is a multicomponent enzyme that catalyzes the one-electron reduction of oxygen by NADPH. It is responsible for the O2-production that occurs when these cells are exposed to phorbol 12-myristate 13-acetate or physiologic stimuli, such as phagocytosis in phagocytes or cross- linking of surface immunoglobulin in B lymphocytes. The activity of this enzyme is greatly diminished or absent in patients with chronic granulomatous disease (C...

  13. Alisertib in Combination With Vorinostat in Treating Patients With Relapsed or Recurrent Hodgkin Lymphoma, B-Cell Non-Hodgkin Lymphoma, or Peripheral T-Cell Lymphoma

    Science.gov (United States)

    2016-07-12

    Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; T-Cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  14. Induction of novel CD8+ T-cell responses during chronic untreated HIV-1 infection by immunization with subdominant cytotoxic T-lymphocyte epitopes

    DEFF Research Database (Denmark)

    Kloverpris, Henrik; Karlsson, Ingrid; Bonde, Jesper;

    2009-01-01

    OBJECTIVE:: To investigate the potential to induce additional cytotoxic T-lymphocyte (CTL) immunity during chronic HIV-1 infection. DESIGN:: We selected infrequently targeted or subdominant but conserved HLA-A*0201-binding epitopes in Gag, Pol, Env, Vpu and Vif. These relatively immune silent epi...... lead to stronger and more durable cellular responses to selected epitopes with the potential to control viral replication and prevent disease in HIV-1-infected individuals.......OBJECTIVE:: To investigate the potential to induce additional cytotoxic T-lymphocyte (CTL) immunity during chronic HIV-1 infection. DESIGN:: We selected infrequently targeted or subdominant but conserved HLA-A*0201-binding epitopes in Gag, Pol, Env, Vpu and Vif. These relatively immune silent...... epitopes were modified as anchor-optimized peptides to improve immunogenicity and delivered on autologous monocyte-derived dendritic cells (MDDCs). METHODS:: Twelve treatment-naïve HLA-A*0201 HIV-1-infected Danish individuals received 1 x 10 MDDCs subcutaneously (s.c.) (weeks 0, 2, 4 and 8), pulsed with...

  15. Idelalisib- a PI3Kδ targeting agent for B-cell malignancies.

    Science.gov (United States)

    Hewett, Yvonne G; Uprety, Dipesh; Shah, Binay K

    2016-04-01

    Idelalisib, the first in-class phosphotidlyinositol 3-kinase delta (PI3Kδ) inhibitor, was approved by the US Food and Drug Administration in July 2014. It simultaneously received breakthrough therapy designation in combination with rituximab for the treatment of relapsed chronic lymphocytic leukemia (CLL) as well as accelerated approval as monotherapy for the treatment of relapsed follicular lymphoma and relapsed small lymphocytic lymphoma. In a pivotal phase III study of 220 patients with relapsed CLL, the overall response rate of patients who received rituximab plus idelalisib was 81%. The median progression-free survival (PFS) was 5 months with rituximab plus placebo group, but was not reached in the idelalisib arm. At 24 weeks, the PFS in patients receiving idelalisib was 93%. In a phase II trial of 125 patients with relapsed or refractory indolent non-Hodgkin lymphoma who received idelalisib 150 mg twice daily, the response rate was 57%. Complete response was seen in 6% of patients. The median duration of response was 12.5 months, and median PFS was 11 months. Idelalisib is a promising new therapy for relapsed indolent B-cell malignancies. PMID:25712626

  16. Effect of oxymatrine on specific cytotoxic T lymphocyte surface programmed death receptor-1 expression in patients with chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    GU Xi-bing; PEI Hao; YANG Xiao-juan; HUA Zhong; LU Zhong-hua; ZHANG Bo; ZHU Yin-fang; WU Hang-yuan; JIANG Yi-ming; CHEN Hao-kun

    2012-01-01

    Background Oxymatrine has certain antiviral effects in the treatment of chronic hepatitis B (CHB),but its exact mechanism is unclear.The objective of the present study was to explore oxymatrine's antiviral mechanism by studying its effect on the hepatitis B virus (HBV) specific cytotoxic T lymphocyte (CTL) surface programmed death receptor-1 (PD-1)expression in CHB patients.Methods Sixty-five CHB patients who had HBV DNA≥104 copies/ml,positive HBeAg,positive human leukocyte antigen (HLA)-A2,alanine aminotransferase (ALT) >2×upper limit of normal value (ULN) were randomly divided into two groups:treatment group (n=33),treated with an intravenous infusion of 600 mg oxymatrine in glucose solution once a day for a month,then with a 200 mg oxymatrine oral capsule three times a day,and a 200 mg silibin meglumine tablet three times a day; control group (n=32) patients were treated only with silibin meglumine tablet,method and dosage were the same as those of treatment group.Three months later,peripheral blood HBV-specific CTL surface PD-1 expression,HBV-specific CTL level,HBV DNA,HBeAg,and results of liver function tests were analyzed and compared.Results Three months post-treatment,in the treatment group,peripheral blood HBV-specific CTL surface PD-1 expression ((19.42±15.94)%) decreased significantly compared to the pretreatment level ((31.30±24.06)%; P <0.05),and decreased significantly compared to that of control group three months after treatment ((29.45±21.62)%; P <0.05).HBV-specific CTL level ((0.42±0.07)%) significantly increased compared with the pretreatment ((0.29±0.15)%; P <0.01),and the control group posttreatment level was (0.31±0.15)% (P <0.05).HBV DNA level in 11 cases became negative (HBV DNA<500 copies/ml,33.33%),which was higher than that of the control group after treatment (two cases,6.25%;x2=7.45,P <0.01),HBeAg of nine cases turned negative (27.27%),which was higher than that of the control group after

  17. Human circulating plasma DNA significantly decreases while lymphocyte DNA damage increases under chronic occupational exposure to low-dose gamma-neutron and tritium β-radiation

    Energy Technology Data Exchange (ETDEWEB)

    Korzeneva, Inna B., E-mail: inna.korzeneva@molgen.vniief.ru [Russian Federal Nuclear Center – All-Russian Research Institute of Experimental Physics (RFNC-VNIIEF) 607190, Sarov, 37 Mira ave., Nizhniy Novgorod Region (Russian Federation); Kostuyk, Svetlana V.; Ershova, Liza S. [Research Centre for Medical Genetics, Russian Academy of Medical Sciences, 115478 Moscow, 1 Moskvorechye str. (Russian Federation); Osipov, Andrian N. [Federal Medial and Biological Center named after Burnazyan of the Federal Medical and Biological Agency (FMBTz named after Burnazyan of FMBA), Moscow (Russian Federation); State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Zhivopisnaya, 46, Moscow, 123098 (Russian Federation); Zhuravleva, Veronika F.; Pankratova, Galina V. [Russian Federal Nuclear Center – All-Russian Research Institute of Experimental Physics (RFNC-VNIIEF) 607190, Sarov, 37 Mira ave., Nizhniy Novgorod Region (Russian Federation); Porokhovnik, Lev N.; Veiko, Natalia N. [Research Centre for Medical Genetics, Russian Academy of Medical Sciences, 115478 Moscow, 1 Moskvorechye str. (Russian Federation)

    2015-09-15

    Highlights: • The chronic exposure to low-dose IR induces DSBs in human lymphocytes (TM index). • Exposure to IR decreases the level of human circulating DNA (cfDNA index). • IR induces an increase of DNase1 activity (DNase1 index) in plasma. • IR induces an increase of the level of antibodies to DNA (Ab DNA index) in plasma. • The ratio cfDNA/(DNase 1 × Ab DNA × TM) is a potential marker of human exposure to IR. - Abstract: The blood plasma of healthy people contains cell-fee (circulating) DNA (cfDNA). Apoptotic cells are the main source of the cfDNA. The cfDNA concentration increases in case of the organism’s cell death rate increase, for example in case of exposure to high-dose ionizing radiation (IR). The objects of the present research are the blood plasma and blood lymphocytes of people, who contacted occupationally with the sources of external gamma/neutron radiation or internal β-radiation of tritium N = 176). As the controls (references), blood samples of people, who had never been occupationally subjected to the IR sources, were used (N = 109). With respect to the plasma samples of each donor there were defined: the cfDNA concentration (the cfDNA index), DNase1 activity (the DNase1 index) and titre of antibodies to DNA (the Ab DNA index). The general DNA damage in the cells was defined (using the Comet assay, the tail moment (TM) index). A chronic effect of the low-dose ionizing radiation on a human being is accompanied by the enhancement of the DNA damage in lymphocytes along with a considerable cfDNA content reduction, while the DNase1 content and concentration of antibodies to DNA (Ab DNA) increase. All the aforementioned changes were also observed in people, who had not worked with the IR sources for more than a year. The ratio cfDNA/(DNase1 × Ab DNA × TM) is proposed to be used as a marker of the chronic exposure of a person to the external low-dose IR. It was formulated the assumption that the joint analysis of the cfDNA, DNase1, Ab

  18. Human circulating plasma DNA significantly decreases while lymphocyte DNA damage increases under chronic occupational exposure to low-dose gamma-neutron and tritium β-radiation

    International Nuclear Information System (INIS)

    Highlights: • The chronic exposure to low-dose IR induces DSBs in human lymphocytes (TM index). • Exposure to IR decreases the level of human circulating DNA (cfDNA index). • IR induces an increase of DNase1 activity (DNase1 index) in plasma. • IR induces an increase of the level of antibodies to DNA (Ab DNA index) in plasma. • The ratio cfDNA/(DNase 1 × Ab DNA × TM) is a potential marker of human exposure to IR. - Abstract: The blood plasma of healthy people contains cell-fee (circulating) DNA (cfDNA). Apoptotic cells are the main source of the cfDNA. The cfDNA concentration increases in case of the organism’s cell death rate increase, for example in case of exposure to high-dose ionizing radiation (IR). The objects of the present research are the blood plasma and blood lymphocytes of people, who contacted occupationally with the sources of external gamma/neutron radiation or internal β-radiation of tritium N = 176). As the controls (references), blood samples of people, who had never been occupationally subjected to the IR sources, were used (N = 109). With respect to the plasma samples of each donor there were defined: the cfDNA concentration (the cfDNA index), DNase1 activity (the DNase1 index) and titre of antibodies to DNA (the Ab DNA index). The general DNA damage in the cells was defined (using the Comet assay, the tail moment (TM) index). A chronic effect of the low-dose ionizing radiation on a human being is accompanied by the enhancement of the DNA damage in lymphocytes along with a considerable cfDNA content reduction, while the DNase1 content and concentration of antibodies to DNA (Ab DNA) increase. All the aforementioned changes were also observed in people, who had not worked with the IR sources for more than a year. The ratio cfDNA/(DNase1 × Ab DNA × TM) is proposed to be used as a marker of the chronic exposure of a person to the external low-dose IR. It was formulated the assumption that the joint analysis of the cfDNA, DNase1, Ab

  19. Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+ Macrophage Function during Viral Infection

    OpenAIRE

    Xu, Haifeng C.; Huang, Jun; Khairnar, Vishal; Duhan, Vikas; Pandyra, Aleksandra A; Grusdat, Melanie; Shinde, Prashant; McIlwain, David R.; Maney, Sathish Kumar; Gommerman, Jennifer; Löhning, Max; Ohashi, Pamela S.; Mak, Tak W; Pieper, Kathrin; Sic, Heiko

    2015-01-01

    The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the gener...

  20. Chronic proliferative dermatitis in Sharpin null mice: development of an autoinflammatory disease in the absence of B and T lymphocytes and IL4/IL13 signaling.

    Directory of Open Access Journals (Sweden)

    Christopher S Potter

    Full Text Available SHARPIN is a key regulator of NFKB and integrin signaling. Mice lacking Sharpin develop a phenotype known as chronic proliferative dermatitis (CPDM, typified by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. Rag1(-/- mice, which lack mature B and T cells, were crossed with Sharpin(-/- mice to examine the role of lymphocytes in CDPM. Although inflammation in the lungs, liver, and joints was reduced in these double mutant mice, dermatitis was not reduced in the absence of functional lymphocytes, suggesting that lymphocytes are not primary drivers of the inflammation in the skin. Type 2 cytokine expression is increased in CPDM. In an attempt to reduce this aspect of the phenotype, Il4ra(-/- mice, unresponsive to both IL4 and IL13, were crossed with Sharpin(-/- mice. Double homozygous Sharpin(-/- , Il4ra(-/- mice developed an exacerbated granulocytic dermatitis, acute system inflammation, as well as hepatic necrosis and mineralization. High expression of CHI3L4, normally seen in CPDM skin, was abolished in Sharpin(-/- , Il4ra(-/- double mutant mice indicating the crucial role of IL4 and IL13 in the expression of this protein. Cutaneous eosinophilia persisted in Sharpin(-/- , Il4ra(-/- mice, although expression of Il5 mRNA was reduced and the expression of Ccl11 and Ccl24 was completely abolished. TSLP and IL33 were both increased in the skin of Sharpin(-/- mice and this was maintained in Sharpin(-/- , Il4ra(-/- mice suggesting a role for TSLP and IL33 in the eosinophilic dermatitis in SHARPIN-deficient mice. These studies indicate that cutaneous inflammation in SHARPIN-deficient mice is autoinflammatory in nature developing independently of B and T lymphocytes, while the systemic inflammation seen in CPDM has a strong lymphocyte-dependent component. Both the cutaneous and systemic inflammation is enhanced by loss of IL4 and IL13 signaling

  1. B-CELLS SPECIFIC FOR BROMELAIN-TREATED ERYTHROCYTES ORE NOT DERIVED FROM ADULT-RAT BONE-MARROW

    NARCIS (Netherlands)

    DEBOER, NK; MEEDENDORP, B; AMMERLAAN, WAM; DEBOER, T; NIEUWENHUIS, P; KROESE, FGM

    1994-01-01

    As part of an evolutionary layered hematopoietic system, the B lymphocyte compartment consists of different lineages of B lymphocytes, which evolve sequentially during ontogeny. In mice, there is ample evidence for the existence of at least two lineages, a layer of B-1 cells (Ly-1 B cells) and the e

  2. Inherited polymorphisms in hyaluronan synthase 1 predict risk of systemic B-cell malignancies but not of breast cancer.

    Directory of Open Access Journals (Sweden)

    Hemalatha Kuppusamy

    Full Text Available Genetic variations in the hyaluronan synthase 1 gene (HAS1 influence HAS1 aberrant splicing. HAS1 is aberrantly spliced in malignant cells from multiple myeloma (MM and Waldenstrom macroglobulinemia (WM, but not in their counterparts from healthy donors. The presence of aberrant HAS1 splice variants predicts for poor survival in multiple myeloma (MM. We evaluated the influence of inherited HAS1 single nucleotide polymorphisms (SNP on the risk of having a systemic B cell malignancy in 1414 individuals compromising 832 patients and 582 healthy controls, including familial analysis of an Icelandic kindred. We sequenced HAS1 gene segments from 181 patients with MM, 98 with monoclonal gammopathy of undetermined significance (MGUS, 72 with Waldenstrom macroglobulinemia (WM, 169 with chronic lymphocytic leukemia (CLL, as well as 34 members of a monoclonal gammopathy-prone Icelandic family, 212 age-matched healthy donors and a case-control cohort of 295 breast cancer patients with 353 healthy controls. Three linked single nucleotide polymorphisms (SNP in HAS1 intron3 are significantly associated with B-cell malignancies (range p = 0.007 to p = 10(-5, but not MGUS or breast cancer, and predict risk in a 34 member Icelandic family (p = 0.005, Odds Ratio = 5.8 (OR, a relatively homogeneous cohort. In contrast, exon3 SNPs were not significantly different among the study groups. Pooled analyses showed a strong association between the linked HAS1 intron3 SNPs and B-cell malignancies (OR = 1.78, but not for sporadic MGUS or for breast cancer (OR<1.0. The minor allele genotypes of HAS1 SNPs are significantly more frequent in MM, WM, CLL and in affected members of a monoclonal gammopathy-prone family than they are in breast cancer, sporadic MGUS or healthy donors. These inherited changes may increase the risk for systemic B-cell malignancies but not for solid tumors.

  3. Common infectious agents and monoclonal B-cell lymphocytosis: a cross-sectional epidemiological study among healthy adults.

    Directory of Open Access Journals (Sweden)

    Delphine Casabonne

    Full Text Available BACKGROUND: Risk factors associated with monoclonal B-cell lymphocytosis (MBL, a potential precursor of chronic lymphocytic leukaemia (CLL, remain unknown. METHODS: Using a cross-sectional study design, we investigated demographic, medical and behavioural risk factors associated with MBL. "Low-count" MBL (cases were defined as individuals with very low median absolute count of clonal B-cells, identified from screening of healthy individuals and the remainder classified as controls. 452 individuals completed a questionnaire with their general practitioner, both blind to the MBL status of the subject. Odds ratios (OR and 95% confidence interval (CI for MBL were estimated by means of unconditional logistic regression adjusted for confounding factors. RESULTS: MBL were detected in 72/452 subjects (16%. Increasing age was strongly associated with MBL (P-trend<0.001. MBL was significantly less common among individuals vaccinated against pneumococcal or influenza (OR 0.49, 95% confidence interval (CI: 0.25 to 0.95; P-value=0.03 and OR: 0.52, 95% CI: 0.29 to 0.93, P-value=0.03, respectively. Albeit based on small numbers, cases were more likely to report infectious diseases among their children, respiratory disease among their siblings and personal history of pneumonia and meningitis. No other distinguishing epidemiological features were identified except for family history of cancer and an inverse relationship with diabetes treatment. All associations described above were retained after restricting the analysis to CLL-like MBL. CONCLUSION: Overall, these findings suggest that exposure to infectious agents leading to serious clinical manifestations in the patient or its surroundings may trigger immune events leading to MBL. This exploratory study provides initial insights and directions for future research related to MBL, a potential precursor of chronic lymphocytic leukaemia. Further work is warranted to confirm these findings.

  4. Defective nonhomologous end joining blocks B-cell development in FLT3/ITD mice

    OpenAIRE

    Li, Li; Zhang, Li; Fan, Jinshui; Greenberg, Kathleen; Desiderio, Stephen; Rassool, Feyruz V.; Small, Donald

    2011-01-01

    We have generated an FLT3/ITD knock-in mouse model in which mice with an FLT3/ITD mutation develop myeloproliferative disease (MPD) and a block in early B-lymphocyte development. To elucidate the role of FLT3/ITD signaling in B-cell development, we studied VDJ recombination in the pro-B cells of FLT3/ITD mice and discovered an increased frequency of DNA double strand breaks (DSBs) introduced by the VDJ recombinase. Early pro-B cells from FLT3/ITD mice were found to have a lower efficiency and...

  5. Cutting Edge: Integrin α4 Is Required for Regulatory B Cell Control of Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Glatigny, Simon; Wagner, Catriona A; Bettelli, Estelle

    2016-05-01

    The neutralization of integrin α4 (Itga4) is currently used as treatment in multiple sclerosis. Although most studies have focused on its function on lymphocyte migration to the CNS, we have uncovered the importance of Itga4 for the generation of regulatory B cells in peripheral immune organs and their control of pathogenic T cell response and CNS pathology. Our study underscores the importance of looking at the dual role of B cells in CNS autoimmunity and provides important perspectives regarding the efficacy and side effects associated with Itga4 neutralization and other B cell-targeting therapies. PMID:27016608

  6. Evaluation of geriatric assessment in patients with chronic lymphocytic leukemia: Results of the CLL9 trial of the German CLL study group.

    Science.gov (United States)

    Goede, Valentin; Bahlo, Jasmin; Chataline, Viktoria; Eichhorst, Barbara; Dürig, Jan; Stilgenbauer, Stephan; Kolb, Gerald; Honecker, Friedemann; Wedding, Ulrich; Hallek, Michael

    2016-04-01

    Multidimensional geriatric assessment (GA) has been demonstrated to predict outcomes in older patients with cancer. This study evaluated GA in a cohort of older patients with chronic lymphocytic leukemia (CLL). Seventy-five of 97 subjects with CLL who were enrolled in a clinical trial of the German CLL Study Group underwent GA prior to the start of study treatment (low-dose chemotherapy with fludarabine). GA included cumulative illness rating scale (CIRS), timed-up-and-go (TUG) test, dementia detection (DEMTECT) test and instrumental activities of daily living (IADL) index. There was little correlation between CIRS, TUG, DEMTECT or IADL results and treatment toxicity, feasibility or efficacy in this study. CIRS and IADL had no statistically significant impact on overall prognosis. However, under-performance in TUG or DEMTECT test was strongly associated with poor survival. The latter findings provide a rationale to further investigate geriatric assessment in CLL and in the context with other CLL treatments. PMID:26377031

  7. Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin's lymphoma and chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Jóhannsson, Jakob; Specht, Lena; Mejer, Johannes;

    2002-01-01

    PURPOSE: Indolent non-Hodgkin's lymphoma (INHL) and chronic lymphocytic leukemia (CLL) are highly sensitive to radiotherapy (RT). Previous retrospective studies have shown high response rates after local palliative RT of 4 Gy in 2 fractions, which prompted this prospective Phase II trial of the...... estimated at 22 months. None of the patients had significant side effects from the treatment. CONCLUSION: Low-dose RT (4 Gy in 2 fractions) is a highly effective palliative treatment of localized lymphoma masses in patients with disseminated INHL and CLL. The treatment has minimal side effects....... palliation from localized lymphoma masses. The patients were treated to a total of 31 different sites. Seventeen patients had previously been treated with chemotherapy. The median observation time after the start of RT was 8 months (range 3-26). RESULTS: All patients and all irradiated sites were assessable...

  8. S-phase induction by interleukin-6 followed by chemotherapy in patients with chronic lymphocytic leukemia and non-Hodgkin's lymphoma

    DEFF Research Database (Denmark)

    Brown, P D; Diamant, Marcus; Jensen, P O;

    1999-01-01

    cytostatic chemotherapy in CLL and low grade NHL. Recombinant human (rh) IL-6 might increase the in vivo proliferation rate leading to a higher sensitivity for chemotherapy. We tested this hypothesis by administering rhIL-6 to 9 CLL patients and 3 NHL patients in doses of 2.5 micrograms/kg, 5 micrograms......Interleukin-6 (IL-6) has in vitro demonstrated growth regulatory effects on tumor cells from patients with chronic lymphocytic leukemia (CLL) and lymphoma. The proliferation rate of these cells is usually very low and this is thought to be one of the reasons for the lack of a curative potential of...... had progressive disease and the remaining patients demonstrated no change. Two patients, who received 10 micrograms/kg/day rhIL-6, demonstrated a significant increase in LI, one of these was first observed in the second treatment cycle. A significant decrease was seen in two patients receiving 2...

  9. Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia--a comparative study of four differently designed, high resolution microarray platforms

    DEFF Research Database (Denmark)

    Gunnarsson, R.; Staaf, J.; Jansson, M.;

    2008-01-01

    Screening for gene copy-number alterations (CNAs) has improved by applying genome-wide microarrays, where SNP arrays also allow analysis of loss of heterozygozity (LOH). We here analyzed 10 chronic lymphocytic leukemia (CLL) samples using four different high-resolution platforms: BAC arrays (32K...... of 32 additional regions present in 2-3 platforms illustrated a discrepancy in detection of small CNAs, which often involved reported copy-number variations. LOH analysis using dChip revealed concordance of mainly large regions, but showed numerous, small nonoverlapping regions and LOH escaping...... detection. Evaluation of baseline variation and copy-number ratio response showed the best performance for the Agilent platform and confirmed the robustness of BAC arrays. Accordingly, these platforms demonstrated a higher degree of platform-specific CNAs. The SNP arrays displayed higher technical variation...

  10. Single-institution long-term outcomes for patients receiving nonmyeloablative conditioning hematopoeitic cell transplantation for chronic lymphocytic leukemia and follicular lymphoma

    DEFF Research Database (Denmark)

    Mortensen, Bo K; Petersen, Søren; Kornblit, Brian; Andersen, Per Kragh; Braendstrup, Peter; Andersen, Niels S; Sengeløv, Henrik; Vindeløv, Lars

    2012-01-01

    Non-myeloablative conditioning hematopoietic cell transplantation (NMC-HCT) has improved the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). In a cohort of 85 patients (45 with CLL and 40 with FL), we observed 5-yr overall survival (OS) and progression-free survival...... (PFS) of 53% and 38% in the CLL group and 81% and 76% in the FL group. In the both the CLL group and the FL group, a strong trend toward better OS and PFS was observed among patients in complete remission (CR) at HCT. Within the FL group, sixteen patients had at one or more time points in their disease...... history had transformed FL. In contrast to the poor survival found in patients with transformed FL in previous studies, the 5-yr OS was almost identical in patients with transformed and non-transformed FL, 83% and 78%, respectively. In conclusion, our study supports that NMC-HCT is a safe and efficacious...

  11. Pharmacokinetics and pharmacokinetic/pharmacodynamic associations of ofatumumab, a human monoclonal CD20 antibody, in patients with relapsed or refractory chronic lymphocytic leukaemia: a phase 1-2 study

    DEFF Research Database (Denmark)

    Coiffier, Bertrand; Losic, Nedjad; Rønn, Birgitte Biilmann;

    2010-01-01

    The purpose of this phase 1-2 study was to investigate the association between the pharmacokinetic properties of ofatumumab, a human monoclonal CD20 antibody, and outcomes in 33 patients with relapsed/refractory chronic lymphocytic leukaemia receiving 4 weekly infusions of ofatumumab. The...

  12. Perioperative dynamic alterations in peripheral regulatory T and B cells in patients with hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Chen Tianxiang

    2012-01-01

    Full Text Available Abstract Background Intratumoral and circulating regulatory T cells (Tregs have been shown to be critical in the pathogenesis of hepatocellular carcinoma (HCC. However there is limited knowledge on the alterations of regulatory B cells (Bregs. We here investigated perioperative dynamic alterations of peripheral circulating Tregs and Bregs in HCC patients to reveal the relationship between regulatory lymphocytes and its clinical implications. Methods 36 patients with HCC, 6 with chronic hepatitis B infection and 10 healthy donors were enrolled for this study. Frequencies of peripheral Tregs and Bregs were measured by flow cytometry with antibodies against CD4, CD25, CD127, CD19 and IL-10 before, and after radical surgery. Then, clinical informatics of HCC patients was achieved through Digital Evaluation Score System (DESS for the assessment of disease severity. Finally, we analysed correlations between digitalized clinical features and kinetics of circulating regulatory lymphocytes. Results Level of circulating CD4+CD25+CD127- Tregs in HCC patients was significantly lower than that in healthy donors and patients with chronic hepatitis B infection before surgery, but was increased after surgery. Preoperative level of CD19+ IL-10+ Bregs in HCC patients was also significantly lower than the other groups. However it dramatically was elevated right after surgery and remained elevated compared to controls (about 7 days after surgery, P = 0.04. Frequency of circulating Tregs was correlated with circulating leukocytes, ferritin, and clinical features suggesting tumor aggressiveness including portal vein thrombosis, hepatic vein involvement and advanced clinical stages. Frequency of circulating Bregs was associated with Hepatitis B e Antigen (HBeAg and Hepatitis B virus (HBV DNA copy number. In addition, DESS was significantly and positively correlated with other staging systems. Conclusion Frequencies of peripheral Tregs and Bregs in HCC patients

  13. Lymphocyte migration studies in man

    International Nuclear Information System (INIS)

    In this paper the author outlines what is known of the migration and recirculation of the lymphocyte in man and animals. He then attempts to demonstrate how a better grasp of these phenomena may contribute to an understanding of the pathophysiology of human diseases such as chronic lymphocytic leukemia, non-Hodgkin's lymphomas, Hodgkin's, and other diseases

  14. Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B-cell subsets

    Science.gov (United States)

    Lundy, Steven K.; Wu, Qi; Wang, Qin; Dowling, Catherine A.; Taitano, Sophina H.; Mao, Guangmei

    2016-01-01

    Objective: To test the hypothesis that dimethyl fumarate (Tecfidera, BG-12) affects B-cell subsets in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Peripheral blood B cells were compared for surface marker expression in patients with RRMS prior to initiation of treatment, after 4–6 months, and at more than 1 year of treatment with BG-12. Production of interleukin (IL)–10 by RRMS patient B cells was also analyzed. Results: Total numbers of peripheral blood B lymphocytes declined after 4–6 months of BG-12 treatment, due to losses in both the CD27+ memory B cells and CD27neg B-cell subsets. Some interpatient variability was observed. In contrast, circulating CD24highCD38high (T2-MZP) B cells increased in percentage in the majority of patients with RRMS after 4–6 months and were present in higher numbers in all of the patients after 12 months of treatment. The CD43+CD27+ B-1 B cells also increased at the later time point in most patients but were unchanged at 4–6 months compared to pretreatment levels. Purified B cells from 7 of the 9 patients with RRMS tested after 4–6 months of treatment were able to produce IL-10 following CD40 ligand stimulation, and the amount corresponded with the combined levels of T2-MZP and B-1 B cells in the sample. None of the patients with RRMS in this study have had a relapse while taking BG-12. Conclusions: These data suggest that BG-12 differentially affects B-cell subsets in patients with RRMS, resulting in increased numbers of circulating B lymphocytes with regulatory capacity. PMID:27006972

  15. New helping friends for B cells.

    OpenAIRE

    Cerutti, Andrea; Puga, Irene; Cols, Montserrat

    2012-01-01

    Over the past decade, a growing recognition of the importance of neutralizing antibodies in host defense combined with the success of B-cell depletion therapies in treating autoimmune disorders has led to an increased focus on better understanding the pathways underpinning B-cell antibody production. In general, B cells require cognate interaction with T helper cells in the germinal center of lymphoid follicles to generate protective antibodies. However, recent evidence shows that B cells rec...

  16. Human circulating plasma DNA significantly decreases while lymphocyte DNA damage increases under chronic occupational exposure to low-dose gamma-neutron and tritium β-radiation.

    Science.gov (United States)

    Korzeneva, Inna B; Kostuyk, Svetlana V; Ershova, Liza S; Osipov, Andrian N; Zhuravleva, Veronika F; Pankratova, Galina V; Porokhovnik, Lev N; Veiko, Natalia N

    2015-09-01

    The blood plasma of healthy people contains cell-fee (circulating) DNA (cfDNA). Apoptotic cells are the main source of the cfDNA. The cfDNA concentration increases in case of the organism's cell death rate increase, for example in case of exposure to high-dose ionizing radiation (IR). The objects of the present research are the blood plasma and blood lymphocytes of people, who contacted occupationally with the sources of external gamma/neutron radiation or internal β-radiation of tritium N = 176). As the controls (references), blood samples of people, who had never been occupationally subjected to the IR sources, were used (N = 109). With respect to the plasma samples of each donor there were defined: the cfDNA concentration (the cfDNA index), DNase1 activity (the DNase1 index) and titre of antibodies to DNA (the Ab DNA index). The general DNA damage in the cells was defined (using the Comet assay, the tail moment (TM) index). A chronic effect of the low-dose ionizing radiation on a human being is accompanied by the enhancement of the DNA damage in lymphocytes along with a considerable cfDNA content reduction, while the DNase1 content and concentration of antibodies to DNA (Ab DNA) increase. All the aforementioned changes were also observed in people, who had not worked with the IR sources for more than a year. The ratio cfDNA/(DNase1×Ab DNA × TM) is proposed to be used as a marker of the chronic exposure of a person to the external low-dose IR. It was formulated the assumption that the joint analysis of the cfDNA, DNase1, Ab DNA and TM values may provide the information about the human organism's cell resistivity to chronic exposure to the low-dose IR and about the development of the adaptive response in the organism that is aimed, firstly, at the effective cfDNA elimination from the blood circulation, and, secondly - at survival of the cells, including the cells with the damaged DNA. PMID:26113293

  17. Effects of Exercise on Behavior and Peripheral Blood Lymphocyte Apoptosis in a Rat Model of Chronic Fatigue Syndrome

    Institute of Scientific and Technical Information of China (English)

    邹军; 苑建齐; 吕爽; 屠嘉衡

    2010-01-01

    This study examined the effects of exercise on behavior and peripheral blood leukocyte apoptosis in a rat model of chronic fatigue syndrome(CFS).Thirty-six healthy male Sprague-Dawley rats were equally randomized into 3 groups:the control group,CFS model group and the exercise group in terms of body weight.A total of 25 rats entered the final statistical analysis due to 11 deaths during the study.CFS model was established by subjecting the rats in CFS model group and exercise group to electric shock,chronic...

  18. HLA-G is a component of the chronic lymphocytic leukemia escape repertoire to generate immune suppression: impact of the HLA-G 14 base pair (rs66554220) polymorphism

    Science.gov (United States)

    Rizzo, Roberta; Audrito, Valentina; Vacca, Paola; Rossi, Davide; Brusa, Davide; Stignani, Marina; Bortolotti, Daria; D’Arena, Giovanni; Coscia, Marta; Laurenti, Luca; Forconi, Francesco; Gaidano, Gianluca; Mingari, Maria Cristina; Moretta, Lorenzo; Malavasi, Fabio; Deaglio, Silvia

    2014-01-01

    This work investigates the possibility that HLA-G, a molecule modulating innate and adaptive immunity, is part of an immune escape strategy of chronic lymphocytic leukemia cells. A 14 base pair insertion/deletion polymorphism (rs66554220) in the 3′-untranslated region of HLA-G influences mRNA stability and protein expression. The analysis of a cohort of patients with chronic lymphocytic leukemia confirmed that del/del individuals are characterized by higher levels of surface and soluble HLA-G than subjects with the other two genotypes. In line with its role in immunomodulation, the percentage of regulatory T lymphocytes is higher in del/del patients than in patients with the other genotypes and correlates with the amounts of surface or soluble HLA-G. Furthermore, addition of sHLA-G-rich plasma from patients with chronic lymphocytic leukemia induces natural killer cell apoptosis and impairs natural killer cell lysis, with effects proportional to the amount of soluble HLA-G added. Lastly, the presence of an HLA-G 14 base pair polymorphism is of prognostic value, with del/del patients showing reduced overall survival, as compared to those with other genotypes. These results suggest that: (i) the HLA-G 14 base pair polymorphism influences the levels of surface and soluble HLA-G expression, and (ii) the over-expression of HLA-G molecules contributes to creating tolerogenic conditions. PMID:24362551

  19. RelB is differentially regulated by IkappaB Kinase-alpha in B cells and mouse lung by cigarette smoke.

    Science.gov (United States)

    Yang, Se-Ran; Yao, Hongwei; Rajendrasozhan, Saravanan; Chung, Sangwoon; Edirisinghe, Indika; Valvo, Samantha; Fromm, George; McCabe, Michael J; Sime, Patricia J; Phipps, Richard P; Li, Jian-Dong; Bulger, Michael; Rahman, Irfan

    2009-02-01

    The activation of transcription factor NF-kappaB is controlled by two main pathways: the classical canonical (RelA/p65-p50)- and the alternative noncanonical (RelB/p52)-NF-kappaB pathways. RelB has been shown to play a protective role in RelA/p65-mediated proinflammatory cytokine release in immune-inflammatory lymphoid cells. Increased infiltration of macrophages and lymphoid cells occurs in lungs of patients with chronic obstructive pulmonary disease, leading to abnormal inflammation. We hypothesized that RelB, and its signaling pathway, is differentially regulated in macrophages and B cells and in lung cells, leading to differential regulation of proinflammatory cytokines in response to cigarette smoke (CS). CS exposure increased the levels of RelB and NF-kappaB-inducing kinase associated with recruitment of RelB on promoters of the IL-6 and macrophage inflammatory protein-2 genes in mouse lung. Treatment of macrophage cell line, MonoMac6, with CS extract showed activation of RelB. In contrast, RelB was degraded by a proteasome-dependent mechanism in B lymphocytes (human Ramos, mouse WEHI-231, and primary mouse spleen B cells), suggesting that RelB is differentially regulated in lung inflammatory and lymphoid cells in response to CS exposure. Transient transfection of dominant negative IkappaB-kinase-alpha and double mutants of NF-kappaB-inducing kinase partially attenuated the CS extract-mediated loss of RelB in B cells and normalized the increased RelB level in macrophages. Taken together, these data suggest that RelB is differentially regulated in response to CS exposure in macrophages, B cells, and in lung cells by IkappaB-kinase-alpha-dependent mechanism. Rapid degradation of RelB signals for RelA/p65 activation and loss of its protective ability to suppress the proinflammatory cytokine release in lymphoid B cells. PMID:18688039

  20. Bryostatin and Vincristine in B-Cell Malignancies

    Science.gov (United States)

    2013-01-10

    Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Stage III Multiple Myeloma