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Sample records for cell acute lymphoblastic

  1. PHF6 mutations in T-cell acute lymphoblastic leukemia

    NARCIS (Netherlands)

    P. van Vlierberghe (Pieter); T. Palomero (Teresa); H. Khiabanian (Hossein); J. van der Meulen (Joni); M. Castillo (Mireia); N. van Roy (Nadine); B. de Moerloose (Barbara); J. Philippé (Jan); S. González-García (Sara); M.L. Toribio (María); T. Taghon (Tom); L.C. Zuurbier (Linda); B. Cauwelier (Barbara); C.J. Harrison (Christine); C. Schwab (Claire); M. Pisecker (Markus); S. Strehl; A.W. Langerak (Anton); J. Gecz (Jozef); E. Sonneveld (Edwin); R. Pieters (Rob); E. Paietta (Elisabeth); J. Rowe (Jacob); P.H. Wiernik (Peter); Y. Benoit (Yves); J. Soulier (Jean); B. Poppe (Bruce); X. Yao (Xiaopan); C. Cordon-Cardo (Carlos); J.P.P. Meijerink (Jules); R. Rabadan (Raul); F. Speleman (Franki); A.A. Ferrando (Adolfo)

    2010-01-01

    textabstractTumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males. In this study, we report the identification of inactivating

  2. Acute T- cell lymphoblastic lymphoma - A case report | Sumba | East ...

    African Journals Online (AJOL)

    We highlight the case of a two year old female who presented with a two month history of left posterior auricular swelling. The swelling developed following trauma, was painless and progressively enlarging. After extensive evaluation the mass was noted to be an extramedullary presentation of Acute T cell lymphoblastic ...

  3. Bilateral proliferative retinopathy in B-cell acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Devesh Kumawat

    2018-01-01

    Full Text Available A 4-year-old child with B-cell acute lymphoblastic leukemia presented with vitreous hemorrhage due to proliferative retinopathy in both eyes. Pars plana vitrectomy was performed in both eyes to clear nonresolving vitreous hemorrhage after systemic stabilization. Visual recovery was limited by the disc drag in the right eye and subfoveal exudation in the left eye. Etiopathogenesis and management of proliferative retinopathy in acute leukemias are discussed.

  4. B cell markers in Ph1-positive acute lymphoblastic leukemia.

    Science.gov (United States)

    Alimena, G; De Rossi, G; Gastaldi, R; Guglielmi, C; Mandelli, F

    1980-01-01

    A case of acute lymphoblastic leukemia (ALL) where the blast cells had B cell markers and displayed the presence of a typical Ph1 chromosome, originated by a standard t (9;22) translocation, is reported. Cytological and clinical aspects during the entire course of the disease were consistent with the diagnosis of ALL. Evidence of differentiation along a well-defined lymphoid cell line in a Ph1-positive cell confirms the presence of the Ph1 chromosome in conditions other than chronic granulocytic leukemia and shows that it possibly does not occur in an exclusively undifferentiated totipotent stem cell.

  5. Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Bongiovanni, Deborah; Saccomani, Valentina

    2017-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and diffusion to the central nervous system. In the past decade, the genomic landscape of T-ALL has been the target of intense research. The identification of specific genomic alterations has contributed to identify strong oncogenic drivers and signaling pathways regulating leukemia growth. Notwithstanding, T-ALL patients are still treated with high-dose multiagent chemotherapy, potentially exposing these patients to considerable acute and long-term side effects. This review summarizes recent advances in our understanding of the signaling pathways relevant for the pathogenesis of T-ALL and the opportunities offered for targeted therapy. PMID:28872614

  6. Oral squamous cell carcinoma following treatment of acute lymphoblastic leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Waal, R.I.F. van der; Waal, I. van der [Univ. Hospital Vrije Univ., Dept. of Oral and Maxillofacial Surgery/Oral Pathology, Amsterdam (Netherlands); Veerman, A.J.P. [Univ. Hospital Vrije Univ., Dept. of Paediatric Oncology, Amsterdam (Netherlands); Snow, G.B. [Univ. Hospital Vrije Univ., Dept. of Otorhinolaryngology, Amsterdam (Netherlands)

    1997-02-01

    With substantially increased survival after most paediatric cancers over the past decades have come the late sequelae of treatment. Of all late complications of treatment, second malignancies are generally considered to be the most serious. We report on a 20-year-old man with an oral squamous cell carcinoma 17 years after initial chemotherapy and irradiation for acute lymphoblastic leukaemia. Although occurrence of the oral malignancy in this patient could have been treatment-related, one should keep in mind that the occurrence of second tumours may also be based on a shared genetic aetiology. (au) 9 refs.

  7. Oral squamous cell carcinoma following treatment of acute lymphoblastic leukaemia

    International Nuclear Information System (INIS)

    Waal, R.I.F. van der; Waal, I. van der; Veerman, A.J.P.; Snow, G.B.

    1997-01-01

    With substantially increased survival after most paediatric cancers over the past decades have come the late sequelae of treatment. Of all late complications of treatment, second malignancies are generally considered to be the most serious. We report on a 20-year-old man with an oral squamous cell carcinoma 17 years after initial chemotherapy and irradiation for acute lymphoblastic leukaemia. Although occurrence of the oral malignancy in this patient could have been treatment-related, one should keep in mind that the occurrence of second tumours may also be based on a shared genetic aetiology. (au) 9 refs

  8. Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

    Science.gov (United States)

    2017-03-27

    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); B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

  9. Increased regulatory T cells in acute lymphoblastic leukemia patients.

    Science.gov (United States)

    Idris, Siti-Zuleha; Hassan, Norfarazieda; Lee, Le-Jie; Md Noor, Sabariah; Osman, Raudhawati; Abdul-Jalil, Marsitah; Nordin, Abdul-Jalil; Abdullah, Maha

    2015-10-01

    Regulation in adaptive immune response balances a fine line that prevents instigation of self-damage or fall into unresponsiveness permitting abnormal cell growth. Mechanisms that keep this balance in check include regulatory T cells (Tregs). Tregs consist of a small but heterogeneous population which may be identified by the phenotype, CD3+CD4+CD25+CD127-. Role of Tregs in pathogenesis of cancers is thus far supported by evidence of increased Tregs in various cancers and may contribute to poorer prognosis. Tregs may also be important in acute leukemias. A review of the literature on Tregs in acute leukemias was conducted and Tregs were determined in B-cell acute lymphoblastic leukemias (ALLs). Studies on Tregs in B-cell ALL are few and controversial. We observed a significantly increased percentage of Tregs (mean ± SD, 9.72 ± 3.79% vs. 7.05 ± 1.74%; P = 0.047) in the bone marrow/peripheral blood of ALL (n = 17) compared to peripheral blood of normal controls (n = 35). A positive trend between Tregs and age (R = 0.474, P = 0.055, n = 17) implicates this factor of poor prognosis in B-cell ALL. Tregs in cancer are particularly significant in immunotherapy. The manipulation of the immune system to treat cancer has for a long time ignored regulatory mechanisms inducible or in place. In lymphoma studies tumor-specific mechanisms that are unlike conventional methods in the induction of Tregs have been hypothesized. In addition, tumor-infiltrating Tregs may present different profiles from peripheral blood pictures. Tregs will continue to be dissected to reveal their mysteries and their impact on clinical significance.

  10. Expression of HER2/Neu in B-Cell Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Rodriguez-Rodriguez, Sergio; Pomerantz, Alan; Demichelis-Gomez, Roberta; Barrera-Lumbreras, Georgina; Barrales-Benitez, Olga; Aguayo-Gonzalez, Alvaro

    2016-01-01

    The expression of HER2/neu in B-cell acute lymphoblastic leukemia has been reported in previous studies. The objective of this research was to study the expression of HER2/neu on the blasts of patients with acute leukemia from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. From June 2015 to February 2016, a HER2/neu monoclonal antibody was added to the panel of antibodies that we routinely use in patients with acute leukemia. An expression of ≥ 30% was considered positive. We studied 33 patients: 19 had de novo leukemia (57.6%), three (9.1%) were in relapse, and in 11 (33.3%) their status could not be specified. Seventeen patients (51.5%) were classified as B-cell acute lymphoblastic leukemia with a median expression of HER2/neu of 0.3% (range 0-90.2). Three patients with B-cell acute lymphoblastic leukemia were positive for HER2/neu: 89.4%, 90.9%, and 62.4%. The first and third patient had de novo B-cell acute lymphoblastic leukemia. The second patient was in second relapse after allogeneic stem cell transplant. All three patients were categorized as high-risk at the time of diagnosis. In the studied Mexican population, we found a positive expression of HER2/neu in 17% of the B-cell acute lymphoblastic leukemia patients, similar to previous studies in which the expression was found in 15-50%.

  11. CD19/CD22 Chimeric Antigen Receptor T Cells and Chemotherapy in Treating Children or Young Adults With Recurrent or Refractory CD19 Positive B Acute Lymphoblastic Leukemia

    Science.gov (United States)

    2017-11-20

    B Acute Lymphoblastic Leukemia; CD19 Positive; Minimal Residual Disease; Philadelphia Chromosome Positive; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Refractory Acute Lymphoblastic Leukemia

  12. Apoptosis induction by Maackia amurensis agglutinin in childhood acute lymphoblastic leukemic cells

    DEFF Research Database (Denmark)

    Kapoor, Sarika; Marwaha, Ram; Majumdar, Siddhartha

    2007-01-01

    acute lymphoblastic leukemia (ALL) as compared to cells from children with non-hematological disorders ("Controls"). MAA recognized a 66 kDa sialoglycoprotein present in membrane fraction of ALL cells. Moreover, MAA induced apoptosis in ALL cells was found to be reduced significantly in presence of GM2...

  13. TLX1 and NOTCH coregulate transcription in T cell acute lymphoblastic leukemia cells

    OpenAIRE

    Riz, Irene; Hawley, Teresa S; Luu, Truong V; Lee, Norman H; Hawley, Robert G

    2010-01-01

    Abstract Background The homeobox gene TLX1 (for T-cell leukemia homeobox 1, previously known as HOX11) is inappropriately expressed in a major subgroup of T cell acute lymphoblastic leukemia (T-ALL) where it is strongly associated with activating NOTCH1 mutations. Despite the recognition that these genetic lesions cooperate in leukemogenesis, there have been no mechanistic studies addressing how TLX1 and NOTCH1 functionally interact to promote the leukemic phenotype. Results Global gene expre...

  14. Leukemia-Initiating Cells in T-Cell Acute Lymphoblastic Leukemia

    OpenAIRE

    Tan, Shi Hao; Bertulfo, Fatima Carla; Sanda, Takaomi

    2017-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy characterized by the clonal proliferation of immature T-cell precursors. T-ALL has many similar pathophysiological features to acute myeloid leukemia, which has been extensively studied in the establishment of the cancer stem cell (CSC) theory, but the CSC concept in T-ALL is still debatable. Although leukemia-initiating cells (LICs), which can generate leukemia in a xenograft setting, have been found in both human T-AL...

  15. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Shah, S.; Schrader, K.A.; Waanders, E.; Timms, A.E.; Vijai, J.; Miething, C.; Wechsler, J.; Yang, J.; Hayes, J.; Klein, R.J.; Zhang, J.; Wei, L.; Wu, G.; Rusch, M.; Nagahawatte, P.; Ma, J; Chen, S.C.; Song, G.; Cheng, J.; Meyers, P.; Bhojwani, D.; Jhanwar, S.; Maslak, P.; Fleisher, M.; Littman, J.; Offit, L.; Rau-Murthy, R.; Fleischut, M.H.; Corines, M.; Murali, R.; Gao, X.; Manschreck, C.; Kitzing, T.; Murty, V.V.; Raimondi, S.C.; Kuiper, R.P.; Simons, A.; Schiffman, J.D.; Onel, K.; Plon, S.E.; Wheeler, D.A.; Ritter, D.; Ziegler, D.S.; Tucker, K.; Sutton, R.; Chenevix-Trench, G.; Li, J.; Huntsman, D.G.; Hansford, S.; Senz, J.; Walsh, T.; Lee (Helen Dowling Instituut), M. van der; Hahn, C.N.; Roberts, K.G.; King, M.C.; Lo, S.M.; Levine, R.L.; Viale, A.; Socci, N.D.; Nathanson, K.L.; Scott, H.S.; Daly, M.; Lipkin, S.M.; Lowe, S.W.; Downing, J.R.; Altshuler, D.; Sandlund, J.T.; Horwitz, M.S.; Mullighan, C.G.; Offit, K.

    2013-01-01

    Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL), but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A

  16. TAL1/SCL is downregulated upon histone deacetylase inhibition in T-cell acute lymphoblastic leukemia cells

    NARCIS (Netherlands)

    Cardoso, B. A.; de Almeida, S. F.; Laranjeira, A. B. A.; Carmo-Fonseca, M.; Yunes, J. A.; Coffer, P. J.; Barata, J. T.

    2011-01-01

    The transcription factor T-cell acute lymphocytic leukemia (TAL)-1 is a major T-cell oncogene associated with poor prognosis in T-cell acute lymphoblastic leukemia (T-ALL). TAL1 binds histone deacetylase 1 and incubation with histone deacetylase inhibitors (HDACis) promotes apoptosis of leukemia

  17. Chimeric Antigen Receptor T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Ciprian Tomuleasa

    2018-02-01

    Full Text Available Chimeric antigen receptor (CAR T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check. In this article, we present the possible advantages of using CAR T-cells in treating acute lymphoblastic leukemia, presenting the technology and the current knowledge in their preclinical and early clinical trial use. Thus, this article first presents the main present-day knowledge on the standard of care for acute lymphoblastic leukemia. Afterward, current knowledge is presented about the use of CAR T-cells in cancer immunotherapy, describing their design, the molecular constructs, and the preclinical data on murine models to properly explain the background for their clinical use. Last, but certainly not least, this article presents the use of CAR T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia, describing both their potential clinical advantages and the possible side effects.

  18. Childhood Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Pui, Ching-Hon; Yang, Jun J; Hunger, Stephen P

    2015-01-01

    PURPOSE: To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. METHODS: A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article...

  19. Leukemia-Initiating Cells in T-Cell Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Tan, Shi Hao; Bertulfo, Fatima Carla; Sanda, Takaomi

    2017-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy characterized by the clonal proliferation of immature T-cell precursors. T-ALL has many similar pathophysiological features to acute myeloid leukemia, which has been extensively studied in the establishment of the cancer stem cell (CSC) theory, but the CSC concept in T-ALL is still debatable. Although leukemia-initiating cells (LICs), which can generate leukemia in a xenograft setting, have been found in both human T-ALL patients and animal models, the nature and origin of LICs are largely unknown. In this review, we discuss recent studies on LICs in T-ALL and the potential mechanisms of LIC emergence in this disease. We focus on the oncogenic transcription factors TAL1, LMO2 , and NOTCH1 and highlight the significance of the transcriptional regulatory programs in normal hematopoietic stem cells and T-ALL.

  20. Leukemia-Initiating Cells in T-Cell Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Shi Hao Tan

    2017-09-01

    Full Text Available T-cell acute lymphoblastic leukemia (T-ALL is a hematological malignancy characterized by the clonal proliferation of immature T-cell precursors. T-ALL has many similar pathophysiological features to acute myeloid leukemia, which has been extensively studied in the establishment of the cancer stem cell (CSC theory, but the CSC concept in T-ALL is still debatable. Although leukemia-initiating cells (LICs, which can generate leukemia in a xenograft setting, have been found in both human T-ALL patients and animal models, the nature and origin of LICs are largely unknown. In this review, we discuss recent studies on LICs in T-ALL and the potential mechanisms of LIC emergence in this disease. We focus on the oncogenic transcription factors TAL1, LMO2, and NOTCH1 and highlight the significance of the transcriptional regulatory programs in normal hematopoietic stem cells and T-ALL.

  1. Epigenetic inactivation of TWIST2 in acute lymphoblastic leukemia modulates proliferation, cell survival and chemosensitivity

    Science.gov (United States)

    Thathia, Shabnam H.; Ferguson, Stuart; Gautrey, Hannah E.; van Otterdijk, Sanne D.; Hili, Michela; Rand, Vikki; Moorman, Anthony V.; Meyer, Stefan; Brown, Robert; Strathdee, Gordon

    2012-01-01

    Background Altered regulation of many transcription factors has been shown to be important in the development of leukemia. TWIST2 modulates the activity of a number of important transcription factors and is known to be a regulator of hematopoietic differentiation. Here, we investigated the significance of epigenetic regulation of TWIST2 in the control of cell growth and survival and in response to cytotoxic agents in acute lymphoblastic leukemia. Design and Methods TWIST2 promoter methylation status was assessed quantitatively, by combined bisulfite and restriction analysis (COBRA) and pyrosequencing assays, in multiple types of leukemia and TWIST2 expression was determined by quantitative reverse transcriptase polymerase chain reaction analysis. The functional role of TWIST2 in cell proliferation, survival and response to chemotherapy was assessed in transient and stable expression systems. Results We found that TWIST2 was inactivated in more than 50% of cases of childhood and adult acute lymphoblastic leukemia through promoter hypermethylation and that this epigenetic regulation was especially prevalent in RUNX1-ETV6-driven cases. Re-expression of TWIST2 in cell lines resulted in a dramatic reduction in cell growth and induction of apoptosis in the Reh cell line. Furthermore, re-expression of TWIST2 resulted in increased sensitivity to the chemotherapeutic agents etoposide, daunorubicin and dexamethasone and TWIST2 hypermethylation was almost invariably found in relapsed adult acute lymphoblastic leukemia (91% of samples hypermethylated). Conclusions This study suggests a dual role for epigenetic inactivation of TWIST2 in acute lymphoblastic leukemia, initially through altering cell growth and survival properties and subsequently by increasing resistance to chemotherapy. PMID:22058208

  2. Sulforaphane induces cell cycle arrest and apoptosis in acute lymphoblastic leukemia cells.

    Directory of Open Access Journals (Sweden)

    Koramit Suppipat

    Full Text Available Acute lymphoblastic leukemia (ALL is the most common hematological cancer in children. Although risk-adaptive therapy, CNS-directed chemotherapy, and supportive care have improved the survival of ALL patients, disease relapse is still the leading cause of cancer-related death in children. Therefore, new drugs are needed as frontline treatments in high-risk disease and as salvage agents in relapsed ALL. In this study, we report that purified sulforaphane, a natural isothiocyanate found in cruciferous vegetables, has anti-leukemic properties in a broad range of ALL cell lines and primary lymphoblasts from pediatric T-ALL and pre-B ALL patients. The treatment of ALL leukemic cells with sulforaphane resulted in dose-dependent apoptosis and G2/M cell cycle arrest, which was associated with the activation of caspases (3, 8, and 9, inactivation of PARP, p53-independent upregulation of p21(CIP1/WAF1, and inhibition of the Cdc2/Cyclin B1 complex. Interestingly, sulforaphane also inhibited the AKT and mTOR survival pathways in most of the tested cell lines by lowering the levels of both total and phosphorylated proteins. Finally, the administration of sulforaphane to the ALL xenograft models resulted in a reduction of tumor burden, particularly following oral administration, suggesting a potential role as an adjunctive agent to improve the therapeutic response in high-risk ALL patients with activated AKT signaling.

  3. Tumefactive intracranial presentation of precursor B-cell acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Forester, Craig M.; Braunreiter, Chi L.; Yaish, Hasan; Afify, Zeinab; Hedlund, Gary L.

    2009-01-01

    In children, leukemia is the most common malignancy, and approximately 75% of leukemias are acute lymphoblastic leukemia (ALL). Central nervous system leukemia is found at diagnosis in fewer than 5% of children with ALL. Leukemic intracranial masses have been described with acute myeloid leukemia, but ALL presenting as a mass lesion is rare. We describe a unique case of an intracranial confirmed precursor B cell (pre-B) ALL mass in a 13-year-old girl that was diagnosed by brain CT, MRI and cerebral angiography, and confirmed by biopsy. This report details pertinent history and distinguishing imaging features of an intracranial ALL tumefaction. (orig.)

  4. Tumefactive intracranial presentation of precursor B-cell acute lymphoblastic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Forester, Craig M. [University of Utah, Salt Lake City, UT (United States); Braunreiter, Chi L. [University of Utah, Division of Pediatric Hematology Oncology, Primary Children' s Medical Center, Salt Lake City, UT (United States); Helen DeVos Children' s Hospital, Department of Pediatric Hematology Oncology, Grand Rapids, MI (United States); Yaish, Hasan; Afify, Zeinab [University of Utah, Division of Pediatric Hematology Oncology, Primary Children' s Medical Center, Salt Lake City, UT (United States); Hedlund, Gary L. [Primary Children' s Medical Center, Department of Pediatric Radiology, Salt Lake City, UT (United States)

    2009-11-15

    In children, leukemia is the most common malignancy, and approximately 75% of leukemias are acute lymphoblastic leukemia (ALL). Central nervous system leukemia is found at diagnosis in fewer than 5% of children with ALL. Leukemic intracranial masses have been described with acute myeloid leukemia, but ALL presenting as a mass lesion is rare. We describe a unique case of an intracranial confirmed precursor B cell (pre-B) ALL mass in a 13-year-old girl that was diagnosed by brain CT, MRI and cerebral angiography, and confirmed by biopsy. This report details pertinent history and distinguishing imaging features of an intracranial ALL tumefaction. (orig.)

  5. Trigeminal nerve involvement in T-cell acute lymphoblastic leukemia: value of MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Karadag, Demet; Karaguelle, Ayse Tuba; Erden, Ilhan; Erden, Ayse E-mail: erden@ada.net.tr

    2002-10-01

    A 30-year-old male with T-cell acute lymphoblastic leukemia presented with facial numbness. Neurological examination revealed paresthesia of the left trigeminal nerve. Cerebrospinal fluid (CSF) cytology showed no atypical cells. Gadolinium-enhanced magnetic resonance (MR) imaging demonstrated enlargement and enhancement of intracranial portions of the left trigeminal nerve. The abnormal MR imaging findings almost completely resolved after the chemotherapy. Gadolinium-enhanced MR imaging is not only a useful procedure for the early diagnosis of cranial nerve invasion by leukemia but it might be helpful to follow the changes after the treatment.

  6. Successful Treatment of Fanconi Anemia and T-Cell Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Terrie Flatt

    2012-01-01

    Full Text Available Fanconi anemia is associated with an increased risk of malignancy. Patients are sensitive to the toxic effects of chemotherapy. We report the case of a patient with Fanconi anemia who developed T-cell acute lymphoblastic leukemia. He experienced chemotherapy-related complications including prolonged neutropenia, grade IV vincristine neuropathy, and disseminated aspergillosis. He was successfully treated with modified dosing of cytarabine and intrathecal methotrexate followed by allogeneic bone marrow transplant. The aspergillosis was treated with systemic antifungal treatment and surgical resection. Now 30 months after bone marrow transplant the patient is without evidence of aspergillosis or leukemia.

  7. Transcriptional regulatory networks downstream of TAL1/SCL in T-cell acute lymphoblastic leukemia

    OpenAIRE

    Palomero, Teresa; Odom, Duncan T.; O'Neil, Jennifer; Ferrando, Adolfo A.; Margolin, Adam; Neuberg, Donna S.; Winter, Stuart S.; Larson, Richard S.; Li, Wei; Liu, X. Shirley; Young, Richard A.; Look, A. Thomas

    2006-01-01

    Aberrant expression of 1 or more transcription factor oncogenes is a critical component of the molecular pathogenesis of human T-cell acute lymphoblastic leukemia (T-ALL); however, oncogenic transcriptional programs downstream of T-ALL oncogenes are mostly unknown. TAL1/SCL is a basic helix-loop-helix (bHLH) transcription factor oncogene aberrantly expressed in 60% of human T-ALLs. We used chromatin immunoprecipitation (ChIP) on chip to identify 71 direct transcriptional targets of TAL1/SCL. ...

  8. Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    La Starza, Roberta; Barba, Gianluca; Demeyer, Sofie; Pierini, Valentina; Di Giacomo, Danika; Gianfelici, Valentina; Schwab, Claire; Matteucci, Caterina; Vicente, Carmen; Cools, Jan; Messina, Monica; Crescenzi, Barbara; Chiaretti, Sabina; Foà, Robin; Basso, Giuseppe; Harrison, Christine J; Mecucci, Cristina

    2016-08-01

    Recurrent deletions of the long arm of chromosome 5 were detected in 23/200 cases of T-cell acute lymphoblastic leukemia. Genomic studies identified two types of deletions: interstitial and terminal. Interstitial 5q deletions, found in five cases, were present in both adults and children with a female predominance (chi-square, P=0.012). Interestingly, these cases resembled immature/early T-cell precursor acute lymphoblastic leukemia showing significant down-regulation of five out of the ten top differentially expressed genes in this leukemia group, including TCF7 which maps within the 5q31 common deleted region. Mutations of genes known to be associated with immature/early T-cell precursor acute lymphoblastic leukemia, i.e. WT1, ETV6, JAK1, JAK3, and RUNX1, were present, while CDKN2A/B deletions/mutations were never detected. All patients had relapsed/resistant disease and blasts showed an early differentiation arrest with expression of myeloid markers. Terminal 5q deletions, found in 18 of patients, were more prevalent in adults (chi-square, P=0.010) and defined a subgroup of HOXA-positive T-cell acute lymphoblastic leukemia characterized by 130 up- and 197 down-regulated genes. Down-regulated genes included TRIM41, ZFP62, MAPK9, MGAT1, and CNOT6, all mapping within the 1.4 Mb common deleted region at 5q35.3. Of interest, besides CNOT6 down-regulation, these cases also showed low BTG1 expression and a high incidence of CNOT3 mutations, suggesting that the CCR4-NOT complex plays a crucial role in the pathogenesis of HOXA-positive T-cell acute lymphoblastic leukemia with terminal 5q deletions. In conclusion, interstitial and terminal 5q deletions are recurrent genomic losses identifying distinct subtypes of T-cell acute lymphoblastic leukemia. Copyright© Ferrata Storti Foundation.

  9. Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells

    NARCIS (Netherlands)

    Hulleman, Esther; Kazemier, Karin M.; Holleman, Amy; VanderWeele, David J.; Rudin, Charles M.; Broekhuis, Mathilde J. C.; Evans, William E.; Pieters, Rob; Den Boer, Monique L.

    2009-01-01

    Treatment failure in pediatric acute lymphoblastic leukemia (ALL) is related to cellular resistance to glucocorticoids (eg, prednisolone). Recently, we demonstrated that genes associated with glucose metabolism are differentially expressed between prednisolone-sensitive and prednisolone-resistant

  10. Recognition of acute lymphoblastic leukemia cells in microscopic images using k-means clustering and support vector machine classifier.

    Science.gov (United States)

    Amin, Morteza Moradi; Kermani, Saeed; Talebi, Ardeshir; Oghli, Mostafa Ghelich

    2015-01-01

    Acute lymphoblastic leukemia is the most common form of pediatric cancer which is categorized into three L1, L2, and L3 and could be detected through screening of blood and bone marrow smears by pathologists. Due to being time-consuming and tediousness of the procedure, a computer-based system is acquired for convenient detection of Acute lymphoblastic leukemia. Microscopic images are acquired from blood and bone marrow smears of patients with Acute lymphoblastic leukemia and normal cases. After applying image preprocessing, cells nuclei are segmented by k-means algorithm. Then geometric and statistical features are extracted from nuclei and finally these cells are classified to cancerous and noncancerous cells by means of support vector machine classifier with 10-fold cross validation. These cells are also classified into their sub-types by multi-Support vector machine classifier. Classifier is evaluated by these parameters: Sensitivity, specificity, and accuracy which values for cancerous and noncancerous cells 98%, 95%, and 97%, respectively. These parameters are also used for evaluation of cell sub-types which values in mean 84.3%, 97.3%, and 95.6%, respectively. The results show that proposed algorithm could achieve an acceptable performance for the diagnosis of Acute lymphoblastic leukemia and its sub-types and can be used as an assistant diagnostic tool for pathologists.

  11. Precursor T-cell acute lymphoblastic leukemia presenting with bone marrow necrosis: a case report

    Directory of Open Access Journals (Sweden)

    Khoshnaw Najmaddin SH

    2012-10-01

    Full Text Available Abstract Introduction Bone marrow necrosis is a clinicopathological condition diagnosed most often at postmortem examination, but it is also seen during the course of malignancy and is not always associated with a poor prognosis. The morphological features of bone marrow necrosis are disruption of the normal marrow architecture and necrosis of myeloid tissue and medullary stroma. Non-malignant conditions associated with bone marrow necrosis are sickle cell anemia, infections, drugs (sulfasalazine, interferon α, all-trans retinoic acid, granulocyte colony-stimulating factor and fludarabine, disseminated intravascular coagulation, antiphospholipid antibody syndrome and acute graft versus host diseases. The malignant causes are leukemia, lymphoma and metastatic carcinomas. Herein we report the case of a patient with precursor T-cell acute lymphoblastic leukemia and bone marrow necrosis at initial presentation. Case presentation A 10-year-old Kurdish boy was presented with generalized bone pain and fever of 1 month’s duration which was associated with sweating, easy fatigability, nose bleeding, breathlessness and severe weight loss. On examination, we observed pallor, tachypnea, tachycardia, low blood pressure, fever, petechial hemorrhage, ecchymoses, tortuous dilated veins over the chest and upper part of abdomen, multiple small cervical lymph node enlargements, mildly enlarged spleen, palpable liver and gross abdominal distention. Blood analysis revealed pancytopenia and elevated lactate dehydrogenase and erythrocyte sedimentation rate. Imaging results showed mediastinal widening on a planar chest X-ray and diffuse focal infiltration of the axial bone marrow on magnetic resonance imaging of the lumbosacral vertebrae. Bone marrow aspiration and biopsy examination showed extensive bone marrow necrosis. Immunophenotyping analysis of the bone marrow biopsy confirmed T-cell acute lymphoblastic leukemia, as CD3 and terminal deoxynucleotidyl

  12. Risk-Based Classification System of Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

    Science.gov (United States)

    2018-02-22

    Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Childhood B Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  13. Potential for bispecific T-cell engagers: role of blinatumomab in acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Le Jeune C

    2016-02-01

    Full Text Available Caroline Le Jeune, Xavier Thomas Hospices Civils de Lyon, Hematology Department, Lyon-Sud Hospital, Pierre Bénite, France Abstract: Patients with relapsed/refractory (R/R B-precursor acute lymphoblastic leukemia (ALL and patients whose minimal residual disease persists during treatment have a poor leukemia-free survival. Despite improvements in front-line therapy, the outcome in these patients remains poor, especially after relapse. As there are no standard chemotherapeutic regimens for the treatment of patients with R/R B-precursor ALL, T-cell-based therapeutic approaches have recently come to the forefront in ALL therapy. Recently, monoclonal antibodies have been developed to target specific antigens expressed in B-lineage blast cells. In this setting, CD19 is of great interest as this antigen is expressed in B-lineage cells. Therefore, it has been selected as the target antigen for blinatumomab, a new bi-specific T-cell engager antibody. This sophisticated antibody binds sites for both CD19 and CD3, leading to T-cell proliferation and activation and B-cell apoptosis. Owing to its short serum half-life, blinatumomab has been administrated by continuous intravenous infusion with a favorable safety profile. The most significant toxicities were central nervous system events and the cytokine release syndrome. This new therapeutic approach using blinatumomab has been shown to be effective in patients with positive minimal residual disease and in patients with R/R B-precursor ALL leading to a recent approval by the US Food and Drug Administration after an accelerated review process. This review focuses on the profile of blinatumomab and its efficacy and safety. Keywords: B-cell lineage acute lymphoblastic leukemia, relapsed/refractory, minimal residual disease, BiTE monoclonal antibodies, blinatumomab

  14. CAR-T cells and allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Liu, Jun; Zhang, Xi; Zhong, Jiang F; Zhang, Cheng

    2017-10-01

    Relapsed/refractory acute lymphoblastic leukemia (ALL) has a low remission rate after chemotherapy, a high relapse rate and poor long-term survival even when allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed. Chimeric antigen receptors redirected T cells (CAR-T cells) can enhance disease remission with a favorable outcome for relapsed/refractory ALL, though some cases quickly relapsed after CAR-T cell treatment. Thus, treatment with CAR-T cells followed by allo-HSCT may be the best way to treat relapsed/refractory ALL. In this review, we first discuss the different types of CAR-T cells. We then discuss the treatment of relapsed/refractory ALL using only CAR-T cells. Finally, we discuss the use of CAR-T cells, followed by allo-HSCT, for the treatment of relapsed/refractory ALL.

  15. IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study

    NARCIS (Netherlands)

    Y. Li (Yan); J.G.C.A.M. Buijs-Gladdines (Jessica); K. Canté-Barrett (Kirsten); A. Stubbs (Andrew); E.M. Vroegindeweij (Eric); W.K. Smits; R. van Marion (Ronald); W.N.M. Dinjens (Winand); M.A. Horstmann (Martin); R. Kuiper (Ruud); R.C. Buijsman; G.J.R. Zaman; P.J. van der Spek (Peter); R. Pieters (Rob); J.P.P. Meijerink (Jules)

    2016-01-01

    textabstractBackground: Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with

  16. Acute Lymphoblastic Leukemia (ALL) (For Parents)

    Science.gov (United States)

    ... Staying Safe Videos for Educators Search English Español Acute Lymphoblastic Leukemia (ALL) KidsHealth / For Parents / Acute Lymphoblastic Leukemia (ALL) What's in this article? About Leukemia Causes ...

  17. The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia

    Science.gov (United States)

    Zuurbier, Linda; Petricoin, Emanuel F.; Vuerhard, Maartje J.; Calvert, Valerie; Kooi, Clarissa; Buijs-Gladdines, Jessica G.C.A.M.; Smits, Willem K.; Sonneveld, Edwin; Veerman, Anjo J.P.; Kamps, Willem A.; Horstmann, Martin; Pieters, Rob; Meijerink, Jules P.P.

    2012-01-01

    Background PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to γ-secretase inhibitors. Design and Methods The impact of PTEN, PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols. Results PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN-splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKT mutations were especially abundant in TAL- or LMO-rearranged leukemia but nearly absent in TLX3-rearranged patients (P=0.03), the opposite to that observed for NOTCH1-activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations (P=0.006) or had weak NOTCH1-activating mutations (P=0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients (P=0.005). Conclusions PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors. PMID:22491738

  18. Profound radiosensitivity in leukemic T-cell lines and T-cell-type acute lymphoblastic leukemia demonstrated by sodium [51Cr]chromate labeling

    International Nuclear Information System (INIS)

    Nakazawa, S.; Minowada, J.; Tsubota, T.; Sinks, L.F.

    1978-01-01

    Radiation sensitivity was determined by measuring spontaneous release from 51 Cr-labeled cells in various lymphoid cell populations. Among six leukemia T-cell lines originating from acute lymphoblastic leukemia, four such lines were found to be highly radiosensitive. In contrast, two of the leukemic T-cell lines and four normal control B-cell lines were not radiosensitive. Thymocytes from six patients and leukemia T-cell blasts from three patients with T-cell leukemia were likewise found to be highly radiosensitive, whereas leukemic blasts from six patients with null-cell (non-T, non-B-cell) acute lymphoblastic leukemia were not radiosensitive. Normal peripheral blood lymphocytes and mitogen-induced normal lymphoblasts were found not to be radiosensitive. The results indicate that measurement of the radiation sensitivity of acute leukemic blasts may have a therapeutic significance in coping with the heterogeneous nature of individual leukemia cases

  19. Rearrangements and amplification of the ABL1 gene as an example of kinase activation in T-cell acute lymphoblastic

    OpenAIRE

    Graux, Carlos

    2008-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is a neoplastic disorder that develops from a single hematopoietic T-cell precursor that acquired oncogenic anomalies. T-ALL is a heterogeneous disease comprising several clinico-biological entities characterized by distinct underlying genetic defects. In the first part of this work, we attempted to correlate those numerous anomalies with the role of the corresponding non mutated genes or pathways in normal T-cell development. Mutations targeting se...

  20. TLX1 and NOTCH coregulate transcription in T cell acute lymphoblastic leukemia cells

    Directory of Open Access Journals (Sweden)

    Lee Norman H

    2010-07-01

    Full Text Available Abstract Background The homeobox gene TLX1 (for T-cell leukemia homeobox 1, previously known as HOX11 is inappropriately expressed in a major subgroup of T cell acute lymphoblastic leukemia (T-ALL where it is strongly associated with activating NOTCH1 mutations. Despite the recognition that these genetic lesions cooperate in leukemogenesis, there have been no mechanistic studies addressing how TLX1 and NOTCH1 functionally interact to promote the leukemic phenotype. Results Global gene expression profiling after downregulation of TLX1 and inhibition of the NOTCH pathway in ALL-SIL cells revealed that TLX1 synergistically regulated more than 60% of the NOTCH-responsive genes. Structure-function analysis demonstrated that TLX1 binding to Groucho-related TLE corepressors was necessary for maximal transcriptional regulation of the NOTCH-responsive genes tested, implicating TLX1 modulation of the NOTCH-TLE regulatory network. Comparison of the dataset to publicly available biological databases indicated that the TLX1/NOTCH-coregulated genes are frequently targeted by MYC. Gain- and loss-of-function experiments confirmed that MYC was an essential mediator of TLX1/NOTCH transcriptional output and growth promotion in ALL-SIL cells, with TLX1 contributing to the NOTCH-MYC regulatory axis by posttranscriptional enhancement of MYC protein levels. Functional classification of the TLX1/NOTCH-coregulated targets also showed enrichment for genes associated with other human cancers as well as those involved in developmental processes. In particular, we found that TLX1, NOTCH and MYC coregulate CD1B and RAG1, characteristic markers of early cortical thymocytes, and that concerted downregulation of the TLX1 and NOTCH pathways resulted in their irreversible repression. Conclusions We found that TLX1 and NOTCH synergistically regulate transcription in T-ALL, at least in part via the sharing of a TLE corepressor and by augmenting expression of MYC. We conclude that

  1. Purification and characterization of fetal hematopoietic cells that express the common acute lymphoblastic leukemia antigen (CALLA)

    DEFF Research Database (Denmark)

    Hokland, P; Rosenthal, P; Griffin, J D

    1983-01-01

    lymphoblastic leukemia cell with respect to surface marker phenotype. A population of CALLA- cells devoid of mature erythroid and myeloid surface markers was found to contain higher numbers of TdT+ cells but lower numbers of cyto-mu, B1, and Ia+ cells than the CALLA+ subset. In vitro analysis of normal...

  2. 6-Thioguanine Reactivates Epigenetically Silenced Genes in Acute Lymphoblastic Leukemia Cells by Facilitating Proteasome-mediated Degradation of DNMT1

    OpenAIRE

    Yuan, Bifeng; Zhang, Jing; Wang, Hongxia; Xiong, Lei; Cai, Qian; Wang, Tina; Jacobsen, Steven; Pradhan, Sriharsa; Wang, Yinsheng

    2011-01-01

    Thiopurines including 6-thioguanine (SG), 6-mercaptopurine and azathioprine are effective anticancer agents with remarkable success in clinical practice, especially in effective treatment of acute lymphoblastic leukemia (ALL). SG is understood to act as a DNA hypomethylating agent in ALL cells, however, the underlying mechanism leading to global cytosine demethylation remains unclear. Here we report that SG treatment results in reactivation of epigenetically silenced genes in T leukemia cells...

  3. [Effects of PCI-32765 and Dasatinib on the Acute Lymphoblastic Leukemic Cells and Their Mechanisms].

    Science.gov (United States)

    Deng, Yuan; Tao, Shan-Dong; Zhang, Xin; Ma, Jing-Jing; He, Zheng-Mei; Chen, Yue; Deng, Zhi-Kui; Yu, Liang

    2017-02-01

    To investigate the effects of Btk inhibitor (PCI-32765) and BCR-ABL tyrosine kinase inhibitor (Dasatinib) on proliferation and apoptosis of acute lymphoblastic leukemia (ALL) cell lines (Sup-B15, RS4;11) and the possible mechanism. RS4;11 and Sup-B15 cells were treated with PCI-32765 and Dasatinib, the cell proliferation and apoptosis were detected by CCK-8, the Btk and other apoptotic proteins were detected by Western blot. PCI-32765 could inhibit the proliferation of RS4;11 and Sup-B15 cells in a dose-dependent manner, Sup-B15 cells were more sensitive to PCI-32765 than RS4;11 cells, their IC 50 were 3 µmol/L and 8 µmol/L respectively, the difference between them was statistically significant (PPCI-32765(PPCI-32765 or Dasatinib alone group and the combination group at the different time-point (8, 12, 24, 36, 48 and 72 h), the 2 drugs showed a synergistic effect on cells in a time-dependent manner. After being treated with PCI-32765 and Dasatinib, the RS4;11 and Sup-B15 cells showed that cell shrinkage, increase of cytoplasmic density, nuclear pyknosis, deviation and karyorrhexis, and increase of the apoptotic cells in the combination group, while the promotive effect of low dosage dasatinib on apoptosis of RS4;11 cells was not strong. PCI-32765 and Dasatinib could decrease the expression and activity of BCR-ABL, Btk, Lyn, Src in Sup-B15 and RS4;11 cells. PCI-32765 or Dasatinib can inhibit the proliferation and induce the apoptosis of Sup-B15 and RS4;11 cells, PCI-32765 and Dasatinib displayed the synergistic effects. The possible mechanism may be related with the blocking of B cell receptor(BCR) signal pathway, thereby inhibiting the cell proliferation and promoting the cell apoptosis.

  4. MicroRNA-101 regulates T-cell acute lymphoblastic leukemia progression and chemotherapeutic sensitivity by targeting Notch1.

    Science.gov (United States)

    Qian, Lu; Zhang, Wanggang; Lei, Bo; He, Aili; Ye, Lianhong; Li, Xingzhou; Dong, Xin

    2016-11-01

    The present study aimed to investigate the role of microRNA (miR)-101 in acute lymphoblastic leukemia progression and chemoresistance. Furthermore, a novel target gene of miR-101 was identified. Here, we confirmed that miR-101 was significantly downregulated in the blood samples of patients with T-cell acute lymphoblastic leukemia (T-ALL) compared with the healthy controls, as determined by reverse transcription quantitative polymerase chain reaction (RTqPCR) analysis. The in vitro experiments demonstrated that miR-101 significantly repressed the proliferation and invasion, and induced potent apoptosis in Jurkat cells, as determined by CCK-8, flow cytometer and cell invasion assays. Luciferase assay confirmed that Notch1 was a target gene of miR-101, and western blotting showed that miR-101 suppressed the expression of Notch1 at the protein level. Moreover, functional restoration assays revealed that Notch1 mediates the effects of miR-101 on Jurkat cell proliferation, apoptosis and invasion. miR-101 enhanced the sensitivity of Jurkat cells to the chemotherapeutic agent adriamycin. Taken together, our results show for the first time that miR-101 acts as a tumor suppressor in T-cell acute lymphoblastic leukaemia and it could enhance chemotherapeutic sensitivity. Furthermore, Notch1 was identified to be a novel target of miR-101. This study indicates that miR-101 may represent a potential therapeutic target for T-cell acute lymphoblastic leukemia intervention.

  5. Thromboembolism in Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Rank, Cecilie Utke; Toft, Nina; Tuckuviene, Ruta

    2018-01-01

    Thromboembolism frequently occurs during acute lymphoblastic leukemia (ALL) therapy. We prospectively registered thromboembolic events during treatment of 1772 consecutive Nordic/Baltic ALL patients 1-45years treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL...

  6. Mosaic Down syndrome and acute lymphoblastic B cell-leukemia. Case report

    Directory of Open Access Journals (Sweden)

    Parra-Baltazar, Isabel Mónica

    2016-10-01

    Full Text Available Down syndrome (DS or trisomy 21 is a constitutional chromosomal abnormality, which may be mosaic in 1 % to 4 % of cases. DS mosaic diagnosis is difficult because most patients have a normal phenotype and show no significant clinical abnormalities. Patients with DS have a higher risk of developing acute leukemia such as acute lymphoblastic leukemia (ALL. We report the case of a 19-year old woman with mosaic trisomy 21 and ALL.

  7. SET-NUP214 fusion in acute myeloid leukemia- and T-cell acute lymphoblastic leukemia-derived cell lines

    Directory of Open Access Journals (Sweden)

    Zaborski Margarete

    2009-01-01

    Full Text Available Abstract Background SET-NUP214 fusion resulting from a recurrent cryptic deletion, del(9(q34.11q34.13 has recently been described in T-cell acute lymphoblastic leukemia (T-ALL and in one case of acute myeloid leukemia (AML. The fusion protein appears to promote elevated expression of HOXA cluster genes in T-ALL and may contribute to the pathogenesis of the disease. We screened a panel of ALL and AML cell lines for SET-NUP214 expression to find model systems that might help to elucidate the cellular function of this fusion gene. Results Of 141 human leukemia/lymphoma cell lines tested, only the T-ALL cell line LOUCY and the AML cell line MEGAL expressed the SET(TAF-Iβ-NUP214 fusion gene transcript. RT-PCR analysis specifically recognizing the alternative first exons of the two TAF-I isoforms revealed that the cell lines also expressed TAF-Iα-NUP214 mRNA. Results of fluorescence in situ hybridization (FISH and array-based copy number analysis were both consistent with del(9(q34.11q34.13 as described. Quantitative genomic PCR also confirmed loss of genomic material between SET and NUP214 in both cell lines. Genomic sequencing localized the breakpoints of the SET gene to regions downstream of the stop codon and to NUP214 intron 17/18 in both LOUCY and MEGAL cells. Both cell lines expressed the 140 kDa SET-NUP214 fusion protein. Conclusion Cell lines LOUCY and MEGAL express the recently described SET-NUP214 fusion gene. Of special note is that the formation of the SET exon 7/NUP214 exon 18 gene transcript requires alternative splicing as the SET breakpoint is located downstream of the stop codon in exon 8. The cell lines are promising model systems for SET-NUP214 studies and should facilitate investigating cellular functions of the the SET-NUP214 protein.

  8. Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Ng, O H; Erbilgin, Y; Firtina, S; Celkan, T; Karakas, Z; Aydogan, G; Turkkan, E; Yildirmak, Y; Timur, C; Zengin, E; Dongen, J J M van; Staal, F J T; Ozbek, U; Sayitoglu, M

    2014-01-01

    WNT signaling has been implicated in the regulation of hematopoietic stem cells and plays an important role during T-cell development in thymus. Here we investigated WNT pathway activation in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. To evaluate the potential role of WNT signaling in T-cell leukomogenesis, we performed expression analysis of key components of WNT pathway. More than 85% of the childhood T-ALL patients showed upregulated β-catenin expression at the protein level compared with normal human thymocytes. The impact of this upregulation was reflected in high expression of known target genes (AXIN2, c-MYC, TCF1 and LEF). Especially AXIN2, the universal target gene of WNT pathway, was upregulated at both mRNA and protein levels in ∼40% of the patients. When β-CATENIN gene was silenced by small interfering RNA, the cancer cells showed higher rates of apoptosis. These results demonstrate that abnormal WNT signaling activation occurs in a significant fraction of human T-ALL cases independent of known T-ALL risk factors. We conclude that deregulated WNT signaling is a novel oncogenic event in childhood T-ALL

  9. Role of low density lipoprotein-bound cholesterol esters in acute lymphoblastic leukemia cells

    International Nuclear Information System (INIS)

    Cutts, J.L.; Madden, E.A.; Melnykovych, G.

    1986-01-01

    The glucocorticoid sensitive CEM-C7 T-cell line was derived from human acute lymphoblastic leukemia cells by Norman and Thompson. Madden et al. have demonstrated that this growth inhibitory effect is due in part to a glucocorticoid-mediated inhibition of cholesterol synthesis and can be partially reversed by cholesterol dispersions. To further delineate the role of cholesterol in this growth inhibition, they have examined the ability of low density lipoprotein (LDL)-bound [ 3 H]cholesterol linoleate to reverse the growth inhibitory effect of 1 μM dexamethasone (Dex) on the CEM-C7 cells. LDL-bound cholesterol linoleate was unable to reverse the Dex-mediated growth inhibition, although incorporation of [ 14 C] acetate into free cholesterol was inhibited by 29%, following the Brown and Goldstein model. The presence of Dex further inhibited acetate incorporation into free cholesterol in the LDL-treated cells. Under all conditions, more than 99% of the acetate incorporated into cholesterol was present as free cholesterol, while over 87% of the LDL-bound cholesterol linoleate taken up remained in the ester compartment. These results indicate that CEM-C7 cells are unable to utilize LDL-bound cholesterol esters as a source of free cholesterol and rely on endogenous synthesis for their free cholesterol requirements

  10. In vitro toxicity assay of cisplatin on mouse acute lymphoblastic leukaemia and spermatogonial stem cells.

    Science.gov (United States)

    Shabani, R; Ashtari, K; Behnam, B; Izadyar, F; Asgari, H; Asghari Jafarabadi, M; Ashjari, M; Asadi, E; Koruji, M

    2016-06-01

    Testicular cancer is the most common cancer affecting men in reproductive age, and cisplatin is one of the major helpful chemotherapeutic agents for treatment of this cancer. In addition, exposure of testes cancer cells to cisplatin could potentially eliminate tumour cells from germ cells in patients. The aim of this study was to evaluate the effect of cisplatin on viability of mouse acute lymphoblastic leukaemia cell line (EL-4) and neonatal mouse spermatogonial cells in vitro. In this study, the isolated spermatogonial stem cells (SSC) and EL-4 were divided into six groups including control (received medium), sham (received DMSO in medium) and experimental groups which received different doses of cisplatin (0.5, 5, 10 and 15 μg ml(-1) ). Cells viability was evaluated with MTT assay. The identity of the cultured cells was confirmed by the expression of specific markers. Our finding showed that viability of both SSC and EL-4 cells was reduced with the dose of 15 μg/ml when compared to the control group (P ≤ 0.05). Also, the differences between the IC50 in doses 10 and 15 μg/ml at different time were significant (P ≤ 0.05). The number of TUNEL-positive cells was increased, and the BAX and caspase-3 expressions were upregulated in EL4 cells for group that received an effective dose of cisplatin). In conclusion, despite the dramatic effects of cisplatin on both cells, spermatogonial stem cells could form colony in culture. © 2015 Blackwell Verlag GmbH.

  11. Regulation of cancer stem cell properties by CD9 in human B-acute lymphoblastic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Yamazaki, Hiroto [Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Wilson Xu, C. [Drug Development Program, Nevada Cancer Institute, Las Vegas, NV (United States); Naito, Motohiko [Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Nishida, Hiroko [Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo (Japan); Okamoto, Toshihiro; Ghani, Farhana Ishrat; Iwata, Satoshi [Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Inukai, Takeshi; Sugita, Kanji [Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi (Japan); Morimoto, Chikao, E-mail: morimoto@ims.u-tokyo.ac.jp [Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Drug Development Program, Nevada Cancer Institute, Las Vegas, NV (United States)

    2011-05-27

    Highlights: {yields} We performed more detailed analysis of CD9 function for CSC properties in B-ALL. {yields} Leukemogenic fusion/Src family proteins were markedly regulated in the CD9{sup +} cells. {yields} Proliferation of B-ALL cells was inhibited by anti-CD9 monoclonal antibody. {yields} Knockdown of CD9 by RNAi remarkably reduced the leukemogenic potential. {yields} CD9-knockdown affected the expression and phosphorylation of Src family and USP22. -- Abstract: Although the prognosis of acute lymphoblastic leukemia (ALL) has improved considerably in recent years, some of the cases still exhibit therapy-resistant. We have previously reported that CD9 was expressed heterogeneously in B-ALL cell lines and CD9{sup +} cells exhibited an asymmetric cell division with greater tumorigenic potential than CD9{sup -} cells. CD9{sup +} cells were also serially transplantable in immunodeficient mice, indicating that CD9{sup +} cell possess self-renewal capacity. In the current study, we performed more detailed analysis of CD9 function for the cancer stem cell (CSC) properties. In patient sample, CD9 was expressed in the most cases of B-ALL cells with significant correlation of CD34-expression. Gene expression analysis revealed that leukemogenic fusion proteins and Src family proteins were significantly regulated in the CD9{sup +} population. Moreover, CD9{sup +} cells exhibited drug-resistance, but proliferation of bulk cells was inhibited by anti-CD9 monoclonal antibody. Knockdown of CD9 remarkably reduced the leukemogenic potential. Furthermore, gene ablation of CD9 affected the expression and tyrosine-phosphorylation of Src family proteins and reduced the expression of histone-deubiquitinase USP22. Taken together, our results suggest that CD9 links to several signaling pathways and epigenetic modification for regulating the CSC properties of B-ALL.

  12. Cell proliferation and DNA dependent DNA polymerase estimation in acute lymphoblastic leukaemia during treatment with prednisone and vincristine

    Energy Technology Data Exchange (ETDEWEB)

    Lange Wantzin, G [Rigshospitalet, Copenhagen (Denmark)

    1979-01-01

    The presence of DNA polymerase and primer-template DNA in lymphoblast nuclei by measuring the in vitro incorporation of /sup 3/H-thymidine-5'-triphosphate (/sup 3/H-TTP) was studied in 10 patients with acute lymphoblastic leukemia. Protein synthesis and various other cytokinetic parameters were also studied. After prednisone (P) administration a marked decrease in /sup 3/H-TTP labelling index (/sup 3/H-TTP LI) was apparent together with an inhibition of /sup 3/H-leucine incorporation (/sup 3/H-LEU LI) into lymphoblasts. A moderate decrease in /sup 3/H-TDR labelling index (/sup 3/H-TDR LI) and a later decrease in mitotic index (MI) were seen. Single cell DNA measurements showed a depletion of /sup 3/H-TDR labelled lymphoblasts in early part of S-phase apparent at 24 h lasting up to 54 h after P administration. Vincristine given as a flash injection later in the study period caused an immediate rise of the MI, at the same time the P induced decline in /sup 3/H-TTP LI, /sup 3/H-TDR LI and /sup 3/H-LEU LI were continued in most patients. P is thought to damage the cells both in and outside the cell cycle. In the cell cycle the effect of P is an arresting effect in G/sub 1/.

  13. Cell proliferation and DNA dependent DNA polymerase estimation in acute lymphoblastic leukaemia during treatment with prednisone and vincristine

    International Nuclear Information System (INIS)

    Lange Wantzin, G.

    1979-01-01

    The presence of DNA polymerase and primer-template DNA in lymphoblast nuclei by measuring the in vitro incorporation of 3 H-thymidine-5'-triphosphate ( 3 H-TTP) was studied in 10 patients with acute lymphoblastic leukemia. Protein synthesis and various other cytokinetic parameters were also studied. After prednisone (P) administration a marked decrease in 3 H-TTP labelling index ( 3 H-TTP LI) was apparent together with an inhibition of 3 H-leucine incorporation ( 3 H-LEU LI) into lymphoblasts. A moderate decrease in 3 H-TDR labelling index ( 3 H-TDR LI) and a later decrease in mitotic index (MI) were seen. Single cell DNA measurements showed a depletion of 3 H-TDR labelled lymphoblasts in early part of S-phase apparent at 24 h lasting up to 54 h after P administration. Vincristine given as a flash injection later in the study period caused an immediate rise of the MI, at the same time the P induced decline in 3 H-TTP LI, 3 H-TDR LI and 3 H-LEU LI were continued in most patients. P is thought to damage the cells both in and outside the cell cycle. In the cell cycle the effect of P is an arresting effect in G 1 . (author)

  14. Proteomic changes in a childhood acute lymphoblastic leukemia cell line during the adaptation to vincristine.

    Science.gov (United States)

    Guzmán-Ortiz, Ana Laura; Aparicio-Ozores, Gerardo; Valle-Rios, Ricardo; Medina-Contreras, Oscar; Patiño-López, Genaro; Quezada, Héctor

    Relapse occurs in approximately 20% of Mexican patients with childhood acute lymphoblastic leukemia (ALL). In this group, chemoresistance may be one of the biggest challenges. An overview of complex cellular processes like drug tolerance can be achieved with proteomic studies. The B-lineage pediatric ALL cell line CCRF-SB was gradually exposed to the chemotherapeutic vincristine until proliferation was observed at 6nM, control cells were cultured in the absence of vincristine. The proteome from each group was analyzed by nanoHPLC coupled to an ESI-ion trap mass spectrometer. The identified proteins were grouped into overrepresented functional categories with the PANTHER classification system. We found 135 proteins exclusively expressed in the presence of vincristine. The most represented functional categories were: Toll receptor signaling pathway, Ras Pathway, B and T cell activation, CCKR signaling map, cytokine-mediated signaling pathway, and oxidative phosphorylation. Our study indicates that signal transduction and mitochondrial ATP production are essential during adaptation of leukemic cells to vincristine, these processes represent potential therapeutic targets. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

  15. JAK2 aberrations in childhood B-cell precursor acute lymphoblastic leukemia

    Science.gov (United States)

    de Goffau-Nobel, Willemieke; Hoogkamer, Alex Q.; Boer, Judith M.; Boeree, Aurélie; van de Ven, Cesca; Koudijs, Marco J.; Besselink, Nicolle J.M.; de Groot-Kruseman, Hester A.; Zwaan, Christian Michel; Horstmann, Martin A.; Pieters, Rob; den Boer, Monique L.

    2017-01-01

    JAK2 abnormalities may serve as target for precision medicines in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In the current study we performed a screening for JAK2 mutations and translocations, analyzed the clinical outcome and studied the efficacy of two JAK inhibitors in primary BCP-ALL cells. Importantly, we identify a number of limitations of JAK inhibitor therapy. JAK2 mutations mainly occurred in the poor prognostic subtypes BCR-ABL1-like and non- BCR-ABL1-like B-other (negative for sentinel cytogenetic lesions). JAK2 translocations were restricted to BCR-ABL1-like cases. Momelotinib and ruxolitinib were cytotoxic in both JAK2 translocated and JAK2 mutated cells, although efficacy in JAK2 mutated cells highly depended on cytokine receptor activation by TSLP. However, our data also suggest that the effect of JAK inhibition may be compromised by mutations in alternative survival pathways and microenvironment-induced resistance. Furthermore, inhibitors induced accumulation of phosphorylated JAK2Y1007, which resulted in a profound re-activation of JAK2 signaling upon release of the inhibitors. This preclinical evidence implies that further optimization and evaluation of JAK inhibitor treatment is necessary prior to its clinical integration in pediatric BCP-ALL. PMID:29163799

  16. Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Yuan-Fang Liu

    2016-06-01

    Full Text Available Genomic landscapes of 92 adult and 111 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL were investigated using next-generation sequencing and copy number alteration analysis. Recurrent gene mutations and fusions were tested in an additional 87 adult and 93 pediatric patients. Among the 29 newly identified in-frame gene fusions, those involving MEF2D and ZNF384 were clinically relevant and were demonstrated to perturb B-cell differentiation, with EP300-ZNF384 inducing leukemia in mice. Eight gene expression subgroups associated with characteristic genetic abnormalities were identified, including leukemia with MEF2D and ZNF384 fusions in two distinct clusters. In subgroup G4 which was characterized by ERG deletion, DUX4-IGH fusion was detected in most cases. This comprehensive dataset allowed us to compare the features of molecular pathogenesis between adult and pediatric B-ALL and to identify signatures possibly related to the inferior outcome of adults to that of children. We found that, besides the known discrepancies in frequencies of prognostic markers, adult patients had more cooperative mutations and greater enrichment for alterations of epigenetic modifiers and genes linked to B-cell development, suggesting difference in the target cells of transformation between adult and pediatric patients and may explain in part the disparity in their responses to treatment.

  17. IKAROS Gene Deleted B-Cell Acute Lymphoblastic Leukemia in Mexican Mestizos: Observations in Seven Patients and a Short Review of the Literature.

    Science.gov (United States)

    Ruiz-Delgado, Guillermo José; Cantero-Fortiz, Yahveth; León-Peña, Andrés Aurelio; León-González, Mónica; Nuñez-Cortés, Ana Karen; Ruiz-Argüelles, Guillermo José

    2016-01-01

    In B-cell acute lymphoblastic leukemia, one of the most frequent cytogenetic alterations is the presence of the Philadelphia chromosome. Recently, newly identified genetic alterations have been studied, among them the IKZF1 deletion. IKZF1 encodes IKAROS, a zinc finger protein that plays an important role in hematopoiesis involving the regulation process of adhesion, cellular migration, and as a tumor suppressor. We aimed to study the impact of IKAROS deletion in the evolution and prognosis of B-cell acute lymphoblastic leukemia. At a single center we prospectively studied patients diagnosed with B-cell acute lymphoblastic leukemia and screened for IKZF1 deletion using the multiplex ligation-dependent probe amplification method. We did a descriptive analysis of patients positive for the IKZF1 deletion to determine its impact on the evolution of the disease and survival rate. Between 2010 and 2015, 16 Mexican mestizo patients with B-cell acute lymphoblastic leukemia were prospectively screened for IKZF1 deletion; seven (43%) were positive and were included for further analysis. The age range of patients was 13-60 years; six were males and one female. All cases had type B acute lymphoblastic leukemia. Of the seven patients, two died, three were lost to follow-up, and two continue in complete remission with treatment. Results are worse than those in a group of patients with non-mutated IKAROS B-cell acute lymphoblastic leukemia previously studied in our center. Although this is a small sample, the presence of IKAROS deletion in acute lymphoblastic leukemia patients could represent a poor-prognosis marker and was probably related to therapy failure. It is also possible that this variant of leukemia may be more prevalent in Mexico. More studies are needed to define the role of IKZF1 deletion in acute lymphoblastic leukemia and the real prevalence of the disease in different populations.

  18. Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy.

    Science.gov (United States)

    Sandri, Sara; De Sanctis, Francesco; Lamolinara, Alessia; Boschi, Federico; Poffe, Ornella; Trovato, Rosalinda; Fiore, Alessandra; Sartori, Sara; Sbarbati, Andrea; Bondanza, Attilio; Cesaro, Simone; Krampera, Mauro; Scupoli, Maria T; Nishimura, Michael I; Iezzi, Manuela; Sartoris, Silvia; Bronte, Vincenzo; Ugel, Stefano

    2017-10-20

    Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment.

  19. Epigenetic inactivation of Notch-Hes pathway in human B-cell acute lymphoblastic leukemia.

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    Shao-Qing Kuang

    Full Text Available The Notch pathway can have both oncogenic and tumor suppressor roles, depending on cell context. For example, Notch signaling promotes T cell differentiation and is leukemogenic in T cells, whereas it inhibits early B cell differentiation and acts as a tumor suppressor in B cell leukemia where it induces growth arrest and apoptosis. The regulatory mechanisms that contribute to these opposing roles are not understood. Aberrant promoter DNA methylation and histone modifications are associated with silencing of tumor suppressor genes and have been implicated in leukemogenesis. Using methylated CpG island amplification (MCA/DNA promoter microarray, we identified Notch3 and Hes5 as hypermethylated in human B cell acute lymphoblastic leukemia (ALL. We investigated the methylation status of other Notch pathway genes by bisulfite pyrosequencing. Notch3, JAG1, Hes2, Hes4 and Hes5 were frequently hypermethylated in B leukemia cell lines and primary B-ALL, in contrast to T-ALL cell lines and patient samples. Aberrant methylation of Notch3 and Hes5 in B-ALL was associated with gene silencing and was accompanied by decrease of H3K4 trimethylation and H3K9 acetylation and gain of H3K9 trimethylation and H3K27 trimethylation. 5-aza-2'-deoxycytidine treatment restored Hes5 expression and decreased promoter hypermethylation in most leukemia cell lines and primary B-ALL samples. Restoration of Hes5 expression by lentiviral transduction resulted in growth arrest and apoptosis in Hes5 negative B-ALL cells but not in Hes5 expressing T-ALL cells. These data suggest that epigenetic modifications are implicated in silencing of tumor suppressor of Notch/Hes pathway in B-ALL.

  20. Epigenetic inactivation of Notch-Hes pathway in human B-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Kuang, Shao-Qing; Fang, Zhihong; Zweidler-McKay, Patrick A; Yang, Hui; Wei, Yue; Gonzalez-Cervantes, Emilio A; Boumber, Yanis; Garcia-Manero, Guillermo

    2013-01-01

    The Notch pathway can have both oncogenic and tumor suppressor roles, depending on cell context. For example, Notch signaling promotes T cell differentiation and is leukemogenic in T cells, whereas it inhibits early B cell differentiation and acts as a tumor suppressor in B cell leukemia where it induces growth arrest and apoptosis. The regulatory mechanisms that contribute to these opposing roles are not understood. Aberrant promoter DNA methylation and histone modifications are associated with silencing of tumor suppressor genes and have been implicated in leukemogenesis. Using methylated CpG island amplification (MCA)/DNA promoter microarray, we identified Notch3 and Hes5 as hypermethylated in human B cell acute lymphoblastic leukemia (ALL). We investigated the methylation status of other Notch pathway genes by bisulfite pyrosequencing. Notch3, JAG1, Hes2, Hes4 and Hes5 were frequently hypermethylated in B leukemia cell lines and primary B-ALL, in contrast to T-ALL cell lines and patient samples. Aberrant methylation of Notch3 and Hes5 in B-ALL was associated with gene silencing and was accompanied by decrease of H3K4 trimethylation and H3K9 acetylation and gain of H3K9 trimethylation and H3K27 trimethylation. 5-aza-2'-deoxycytidine treatment restored Hes5 expression and decreased promoter hypermethylation in most leukemia cell lines and primary B-ALL samples. Restoration of Hes5 expression by lentiviral transduction resulted in growth arrest and apoptosis in Hes5 negative B-ALL cells but not in Hes5 expressing T-ALL cells. These data suggest that epigenetic modifications are implicated in silencing of tumor suppressor of Notch/Hes pathway in B-ALL.

  1. An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study.

    Science.gov (United States)

    Bond, Jonathan; Marchand, Tony; Touzart, Aurore; Cieslak, Agata; Trinquand, Amélie; Sutton, Laurent; Radford-Weiss, Isabelle; Lhermitte, Ludovic; Spicuglia, Salvatore; Dombret, Hervé; Macintyre, Elizabeth; Ifrah, Norbert; Hamel, Jean-François; Asnafi, Vahid

    2016-06-01

    Gene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA-positive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently

  2. Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features

    Science.gov (United States)

    Schwab, Claire J.; Chilton, Lucy; Morrison, Heather; Jones, Lisa; Al-Shehhi, Halima; Erhorn, Amy; Russell, Lisa J.; Moorman, Anthony V.; Harrison, Christine J.

    2013-01-01

    In childhood B-cell precursor acute lymphoblastic leukemia, cytogenetics is important in diagnosis and as an indicator of response to therapy, thus playing a key role in risk stratification of patients for treatment. Little is known of the relationship between different cytogenetic subtypes in B-cell precursor acute lymphoblastic leukemia and the recently reported copy number abnormalities affecting significant leukemia associated genes. In a consecutive series of 1427 childhood B-cell precursor acute lymphoblastic leukemia patients, we have determined the incidence and type of copy number abnormalities using multiplex ligation-dependent probe amplification. We have shown strong links between certain deletions and cytogenetic subtypes, including the novel association between RB1 deletions and intrachromosomal amplification of chromosome 21. In this study, we characterized the different copy number abnormalities and show heterogeneity of PAX5 and IKZF1 deletions and the recurrent nature of RB1 deletions. Whole gene losses are often indicative of larger deletions, visible by conventional cytogenetics. An increased number of copy number abnormalities is associated with NCI high risk, specifically deletions of IKZF1 and CDKN2A/B, which occur more frequently among these patients. IKZF1 deletions and rearrangements of CRLF2 among patients with undefined karyotypes may point to the poor risk BCR-ABL1-like group. In conclusion, this study has demonstrated in a large representative cohort of children with B-cell precursor acute lymphoblastic leukemia that the pattern of copy number abnormalities is highly variable according to the primary genetic abnormality. PMID:23508010

  3. Morphological and immunological criteria of minimal residual disease detection in children with B-cell precursors acute lymphoblastic leukemia

    Science.gov (United States)

    Beznos, O. A.; Grivtsova, L. Yu; Popa, A. V.; Shervashidze, M. A.; Serebtyakova, I. N.; Tupitsyn, N. N.; Selchuk, V. U.; Grebennikova, O. P.; Titova, G. V.

    2018-01-01

    One of the key factors of prognosis and risk stratification in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is minimal residual disease (MRD). Identification of MRD on the day 15th is one of the most significant in prognosis of the disease. We compared data of a morphological and flow cytometry results of assessment of a bone marrow (BM) at the day 15th of induction chemotherapy in children with BCP-ALL.

  4. Shedding of CD9 antigen into cerebrospinal fluid by acute lymphoblastic leukemia cells.

    Science.gov (United States)

    Komada, Y; Ochiai, H; Shimizu, K; Azuma, E; Kamiya, H; Sakurai, M

    1990-07-01

    The accurate identification of small numbers of leukemic cells in the cerebrospinal fluid (CSF) presents a diagnostic problem in the treatment of acute lymphoblastic leukemia (ALL). We demonstrated that soluble CD9 antigen was shed into CSF obtained from children with ALL, using enzyme-linked immunosorbent assay (ELISA), which used the activity of CD9 antigen to bind the Ricinus communis agglutinin (RCA1) and a monoclonal antibody, SJ-9A4, simultaneously. Using RCA1/SJ-9A4 ELISA, CD9 antigen was detectable in CSF but not in plasma from 12 cases of CD9+ ALL in central nervous system (CNS) relapse. However, CD9 antigen was not released into CSF from 11 cases of CD9- ALL with CNS involvement, 136 cases of CD9+ ALL in complete remission (CR), 29 cases of CD9- ALL in CR, or 21 cases of aseptic meningitis. Interestingly, the levels of CD9 antigen were elevated in CSF from 7 of 10 CD9+ ALL patients without cytologically proven CNS involvement at diagnosis, with subsequent return to undetectable levels after initial induction chemotherapy was begun. In addition, sequential analysis of CSF from a 5-year-old boy with CD9+ ALL in CNS relapse showed that levels of CD9 antigen correlated well with the number of leukemic cells in CSF. Serial quantitative analysis of CD9 antigen in CSF could be useful to detect the proliferation of residual leukemic cells before the clinical manifestation.

  5. RUNX1 promotes cell growth in human T-cell acute lymphoblastic leukemia by transcriptional regulation of key target genes.

    Science.gov (United States)

    Jenkins, Catherine E; Gusscott, Samuel; Wong, Rachel J; Shevchuk, Olena O; Rana, Gurneet; Giambra, Vincenzo; Tyshchenko, Kateryna; Islam, Rashedul; Hirst, Martin; Weng, Andrew P

    2018-05-04

    RUNX1 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). The spectrum of RUNX1 mutations has led to the notion that it acts as a tumor suppressor in this context; however, other studies have placed RUNX1 along with transcription factors TAL1 and NOTCH1 as core drivers of an oncogenic transcriptional program. To reconcile these divergent roles, we knocked down RUNX1 in human T-ALL cell lines and deleted Runx1 or Cbfb in primary mouse T-cell leukemias. RUNX1 depletion consistently resulted in reduced cell proliferation and increased apoptosis. RUNX1 upregulated variable sets of target genes in each cell line, but consistently included a core set of oncogenic effectors including IGF1R and NRAS. Our results support the conclusion that RUNX1 has a net positive effect on cell growth in the context of established T-ALL. Copyright © 2018. Published by Elsevier Inc.

  6. Migration of acute lymphoblastic leukemia cells into human bone marrow stroma.

    Science.gov (United States)

    Makrynikola, V; Bianchi, A; Bradstock, K; Gottlieb, D; Hewson, J

    1994-10-01

    Most cases of acute lymphoblastic leukemia (ALL) arise from malignant transformation of B-cell precursors in the bone marrow. Recent studies have shown that normal and leukemic B-cell precursors bind to bone marrow stromal cells through the beta-1 integrins VLA-4 and VLA-5, thereby exposing early lymphoid cells to regulatory cytokines. It has been recently reported that the pre-B cell line NALM-6 is capable of migrating under layers of murine stromal cells in vitro (Miyake et al. J Cell Biol 1992;119:653-662). We have further analyzed leukemic cell motility using human bone marrow fibroblasts (BMF) as a stromal layer. The precursor-B ALL cell line NALM-6 rapidly adhered to BMF, and underwent migration or tunneling into BMF layers within 5 h, as demonstrated by light and electron microscopy, and confirmed by a chromium-labeling assay. Migration was also observed with the precursor-B ALL lines Reh and KM-3, with a T leukemia line RPMI-8402, the monocytic line U937, and the mature B line Daudi. In contrast, mature B (Raji), myeloid (K562, HL-60), and T lines (CCRF-CEM, MOLT-4) did not migrate. When cases of leukemia were analyzed, BMF migration was largely confined to precursor-B ALL, occurring in eight of 13 cases tested. Of other types of leukemia, migration was observed in one of four cases of T-ALL, but no evidence was seen in six acute myeloid leukemias and two patients with chronic lymphocytic leukemia. Only minimal migration into BMF was observed with purified sorted CD10+ CD19+ early B cells from normal adult marrow, while normal mature B lymphocytes from peripheral blood did not migrate. ALL migration was inhibited by monoclonal antibodies to the beta sub-unit of the VLA integrin family, and by a combination of antibodies to VLA-4 and VLA-5. Partial inhibition was also observed when leukemic cells were incubated with antibodies to VLA-4, VLA-5, or VLA-6 alone. In contrast, treatment of stromal cells with antibodies to vascular cell adhesion molecule or

  7. Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors

    Science.gov (United States)

    Zuurbier, Linda; Gutierrez, Alejandro; Mullighan, Charles G.; Canté-Barrett, Kirsten; Gevaert, A. Olivier; de Rooi, Johan; Li, Yunlei; Smits, Willem K.; Buijs-Gladdines, Jessica G.C.A.M.; Sonneveld, Edwin; Look, A. Thomas; Horstmann, Martin; Pieters, Rob; Meijerink, Jules P.P.

    2014-01-01

    Three distinct immature T-cell acute lymphoblastic leukemia entities have been described including cases that express an early T-cell precursor immunophenotype or expression profile, immature MEF2C-dysregulated T-cell acute lymphoblastic leukemia cluster cases based on gene expression analysis (immature cluster) and cases that retain non-rearranged TRG@ loci. Early T-cell precursor acute lymphoblastic leukemia cases exclusively overlap with immature cluster samples based on the expression of early T-cell precursor acute lymphoblastic leukemia signature genes, indicating that both are featuring a single disease entity. Patients lacking TRG@ rearrangements represent only 40% of immature cluster cases, but no further evidence was found to suggest that cases with absence of bi-allelic TRG@ deletions reflect a distinct and even more immature disease entity. Immature cluster/early T-cell precursor acute lymphoblastic leukemia cases are strongly enriched for genes expressed in hematopoietic stem cells as well as genes expressed in normal early thymocyte progenitor or double negative-2A T-cell subsets. Identification of early T-cell precursor acute lymphoblastic leukemia cases solely by defined immunophenotypic criteria strongly underestimates the number of cases that have a corresponding gene signature. However, early T-cell precursor acute lymphoblastic leukemia samples correlate best with a CD1 negative, CD4 and CD8 double negative immunophenotype with expression of CD34 and/or myeloid markers CD13 or CD33. Unlike various other studies, immature cluster/early T-cell precursor acute lymphoblastic leukemia patients treated on the COALL-97 protocol did not have an overall inferior outcome, and demonstrated equal sensitivity levels to most conventional therapeutic drugs compared to other pediatric T-cell acute lymphoblastic leukemia patients. PMID:23975177

  8. Changes in the transport of leucine-14C across the red cell membrane in children with acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Stepniewski, M.; Cyklis, R.; Szafran, Z.; Armata, J.; Nawrocka-Kanska, B.

    1981-01-01

    Distribution of leucine- 14 C between intracellular water of red blood cells and incubation medium was significantly higher in 13 children with acute lymphoblastic leukemia than in 22 healthy children. The distribution ratio of leucine- 14 C was significantly lower when measured in the group of 6 children in the period of remission, as compared with children in the acute phase of the disease and only slightly higher than in the control group. The results of this study indicate the existence of structural changes in leukemic red cell membrane responsible for the observed disturbances of leucine transport. (author)

  9. Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Serafin, Valentina; Capuzzo, Giorgia; Milani, Gloria; Minuzzo, Sonia Anna; Pinazza, Marica; Bortolozzi, Roberta; Bresolin, Silvia; Porcù, Elena; Frasson, Chiara; Indraccolo, Stefano; Basso, Giuseppe; Accordi, Benedetta

    2017-12-21

    Pediatric T-acute lymphoblastic leukemia (T-ALL) patients often display resistance to glucocorticoid (GC) treatment. These patients, classified as prednisone poor responders (PPR), have poorer outcome than do the other pediatric T-ALL patients receiving a high-risk adapted therapy. Because glucocorticoids are administered to ALL patients during all the different phases of therapy, GC resistance represents an important challenge to improving the outcome for these patients. Mechanisms underlying resistance are not yet fully unraveled; thus our research focused on the identification of deregulated signaling pathways to point out new targeted approaches. We first identified, by reverse-phase protein arrays, the lymphocyte cell-specific protein-tyrosine kinase (LCK) as aberrantly activated in PPR patients. We showed that LCK inhibitors, such as dasatinib, bosutinib, nintedanib, and WH-4-023, are able to induce cell death in GC-resistant T-ALL cells, and remarkably, cotreatment with dexamethasone is able to reverse GC resistance, even at therapeutic drug concentrations. This was confirmed by specific LCK gene silencing and ex vivo combined treatment of cells from PPR patient-derived xenografts. Moreover, we observed that LCK hyperactivation in PPR patients upregulates the calcineurin/nuclear factor of activated T cells signaling triggering to interleukin-4 ( IL-4 ) overexpression. GC-sensitive cells cultured with IL-4 display an increased resistance to dexamethasone, whereas the inhibition of IL-4 signaling could increase GC-induced apoptosis in resistant cells. Treatment with dexamethasone and dasatinib also impaired engraftment of leukemia cells in vivo. Our results suggest a quickly actionable approach to supporting conventional therapies and overcoming GC resistance in pediatric T-ALL patients. © 2017 by The American Society of Hematology.

  10. A novel 2,6-diisopropylphenyl-docosahexaenoamide conjugate induces apoptosis in T cell acute lymphoblastic leukemia cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Altenburg, Jeffrey D.; Harvey, Kevin A.; McCray, Sharon; Xu, Zhidong [Cellular Biochemistry Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, IN (United States); Siddiqui, Rafat A., E-mail: rsiddiqu@iuhealth.org [Cellular Biochemistry Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, IN (United States); Department of Biology, Indiana University-Purdue University, Indianapolis, IN (United States); Department of Medicine, Indiana University School of Medicine, Indianapolis, IN (United States)

    2011-07-29

    Highlights: {yields} 2,6-Diisopropylphenyl-docosahexaenoamide conjugates (DIP-DHA) inhibits the proliferation of T-cell leukemic cell lines. {yields} DIP-DHA resulted in increased activation of caspase-3, and caspase-7. {yields} DIP-DHA significantly downregulated CXCR4 surface expression. -- Abstract: We have previously characterized the effects of 2,6-diisopropylphenyl-docosahexaenoamide (DIP-DHA) conjugates and their analogs on the proliferation and progression of breast cancer cell lines. For this study, we investigated the effects of the DIP-DHA conjugate on 2 representative T cell acute lymphoblastic leukemia (T-ALL) cell lines: CEM and Jurkat. Treatment of both cell lines with DIP-DHA resulted in significantly greater inhibition of proliferation and induction of apoptosis than that of parent compounds, 2,6-diisopropylphenol (DIP) or docosahexaenoate (DHA). Treatment of the cells with DIP-DHA resulted in increased activation of caspase-3, and caspase-7. Furthermore, induction of apoptosis in both cell lines was reversed in the presence of a caspase family inhibitor. Treatment with DIP-DHA reduced mitochondrial membrane potential. These observations suggest that the effects are driven by intrinsic apoptotic pathways. DIP-DHA treatment also downregulated surface CXCR4 expression, an important chemokine receptor involved in cancer metastasis that is highly expressed in both CEM and Jurkat cells. In conclusion, our data suggest that the DIP-DHA conjugate exhibits significantly more potent effects on CEM and Jurkat cells than that of DIP or DHA alone. These conjugates have potential use for treatment of patients with T cell acute lymphoblastic leukemia.

  11. A novel 2,6-diisopropylphenyl-docosahexaenoamide conjugate induces apoptosis in T cell acute lymphoblastic leukemia cell lines

    International Nuclear Information System (INIS)

    Altenburg, Jeffrey D.; Harvey, Kevin A.; McCray, Sharon; Xu, Zhidong; Siddiqui, Rafat A.

    2011-01-01

    Highlights: → 2,6-Diisopropylphenyl-docosahexaenoamide conjugates (DIP-DHA) inhibits the proliferation of T-cell leukemic cell lines. → DIP-DHA resulted in increased activation of caspase-3, and caspase-7. → DIP-DHA significantly downregulated CXCR4 surface expression. -- Abstract: We have previously characterized the effects of 2,6-diisopropylphenyl-docosahexaenoamide (DIP-DHA) conjugates and their analogs on the proliferation and progression of breast cancer cell lines. For this study, we investigated the effects of the DIP-DHA conjugate on 2 representative T cell acute lymphoblastic leukemia (T-ALL) cell lines: CEM and Jurkat. Treatment of both cell lines with DIP-DHA resulted in significantly greater inhibition of proliferation and induction of apoptosis than that of parent compounds, 2,6-diisopropylphenol (DIP) or docosahexaenoate (DHA). Treatment of the cells with DIP-DHA resulted in increased activation of caspase-3, and caspase-7. Furthermore, induction of apoptosis in both cell lines was reversed in the presence of a caspase family inhibitor. Treatment with DIP-DHA reduced mitochondrial membrane potential. These observations suggest that the effects are driven by intrinsic apoptotic pathways. DIP-DHA treatment also downregulated surface CXCR4 expression, an important chemokine receptor involved in cancer metastasis that is highly expressed in both CEM and Jurkat cells. In conclusion, our data suggest that the DIP-DHA conjugate exhibits significantly more potent effects on CEM and Jurkat cells than that of DIP or DHA alone. These conjugates have potential use for treatment of patients with T cell acute lymphoblastic leukemia.

  12. Effects of Malnutrition on Neutrophil/Mononuclear Cell Apoptotic Functions in Children with Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Cakir, Fatma Betul; Berrak, Su Gülsün; Aydogan, Gonul; Tulunay, Aysin; Timur, Cetin; Canpolat, Cengiz; Eksioglu Demiralp, Emel

    2017-04-01

    Recent studies claim that apoptosis may explain immune dysfunction observed in malnutrition. The objective of this study was to determine the effect of malnutrition on apoptotic functions of phagocytic cells in acute lymphoblastic leukemia (ALL). Twenty-eight ALL patients (13 with malnutrition) and thirty controls were enrolled. Neutrophil and mononuclear cell apoptosis of ALL patients and the control group were studied on admission before chemotherapy and repeated at a minimum of three months after induction of chemotherapy or when the nutritional status of leukemic children improved. The apoptotic functions of both ALL groups on admission were significantly lower than those of the control group. The apoptotic functions were lower in ALL patients with malnutrition than those in ALL patients without malnutrition, but this was not statistically significant. The repeated apoptotic functions of both ALL groups were increased to similar values with the control group. This increase was found to be statistically significant. The apoptotic functions in ALL patients were not found to be affected by malnutrition. However, after dietary intervention, increased apoptotic functions in both ALL patient groups deserve mentioning. Dietary intervention should always be recommended as malnutrition or cachexia leads to multiple complications. Enhanced apoptosis might originate also from remission state of cancer.

  13. Leydig cell function in boys following treatment for testicular relapse of acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Blatt, J.; Sherins, R.J.; Niebrugge, D.; Bleyer, W.A.; Poplack, D.G.

    1985-01-01

    Current practice for achieving local control of testicular relapse in males with acute lymphoblastic leukemia (ALL) includes the use of 2,400-rad testicular radiation. Although this therapy is known to cause germ cell depletion, it has been assumed that it does not alter testicular secretion of testosterone. To test this assumption, the authors measured gonadotropin and testosterone levels in seven boys with ALL who had been treated with radiation for clinically apparent testicular relapse. In four of seven boys, testicular relapse was bilateral with overt involvement of one testicle and microscopic involvement of the other. Three of these four boys demonstrated delayed sexual maturation, and in addition to elevated follicle-stimulating hormone (FSH) concentrations, testosterone levels were low and luteinizing hormone levels were elevated compared with controls. These data indicate that boys with overt testicular leukemia who are treated with 2,400-rad testicular radiation are at risk for Leydig cell dysfunction. However, the relative contributions of radiation, prior chemotherapy, and leukemic infiltration to this dysfunction remain to be clarified

  14. Elucidation and modulation of glucocorticoid-induced apoptosis in acute lymphoblastic leukemia cells

    International Nuclear Information System (INIS)

    Eberhart, K.

    2011-01-01

    This thesis deals with the elucidation of the synergistic effect of the glucocorticoid dexamethasone and the metabolic modulator 2-deoxyglucose on apoptosis induction in two in vitro model systems of childhood acute lymphoblastic leukemia. 2-deoxyglucose accelerated the kinetics of, and increased the sensitivity to, glucocorticoid-induced apoptosis in two leukemia cell lines. In primary lymphocytes from healthy donors, in contrast, 2-deoxyglucose and dexamethasone did not act synergistically on apoptosis induction. To elucidate the molecular basis of the synergistic effect, glycolysis by means of glucose uptake, lactate production, ATP levels, glucose transporter and hexokinase expression and mitochondrial oxygen consumption was analyzed in treated vs. untreated cells. The study revealed a downregulation of gene expression of the glucose transporter GLUT1 and hexokinase 2 (HK2), release of HK2 from the outer mitochondrial membrane, as well as reduced glycolysis and mitochondrial respiration. Moreover, the analysis of the mitochondrial proteome by 2 dimensional differential gel electrophoresis after treatment with 2-deoxyglucose and dexamethasone revealed the regulation of several interesting candidate proteins involved in treatment related apoptosis. (author)

  15. Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Magnus Borssén

    Full Text Available BACKGROUND: Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL has improved, but there is a considerable fraction of patients experiencing a poor outcome. There is a need for better prognostic markers and aberrant DNA methylation is a candidate in other malignancies, but its potential prognostic significance in T-ALL is hitherto undecided. DESIGN AND METHODS: Genome wide promoter DNA methylation analysis was performed in pediatric T-ALL samples (n = 43 using arrays covering >27000 CpG sites. Clinical outcome was evaluated in relation to methylation status and compared with a contemporary T-ALL group not tested for methylation (n = 32. RESULTS: Based on CpG island methylator phenotype (CIMP, T-ALL samples were subgrouped as CIMP+ (high methylation and CIMP- (low methylation. CIMP- T-ALL patients had significantly worse overall and event free survival (p = 0.02 and p = 0.001, respectively compared to CIMP+ cases. CIMP status was an independent factor for survival in multivariate analysis including age, gender and white blood cell count. Analysis of differently methylated genes in the CIMP subgroups showed an overrepresentation of transcription factors, ligands and polycomb target genes. CONCLUSIONS: We identified global promoter methylation profiling as being of relevance for subgrouping and prognostication of pediatric T-ALL.

  16. Hematopoietic stem cell transplantation for isolated extramedullary relapse of acute lymphoblastic leukemia in children.

    Science.gov (United States)

    Gabelli, Maria; Zecca, Marco; Messina, Chiara; Carraro, Elisa; Buldini, Barbara; Rovelli, Attilio Maria; Fagioli, Franca; Bertaina, Alice; Lanino, Edoardo; Favre, Claudio; Rabusin, Marco; Prete, Arcangelo; Ripaldi, Mimmo; Barberi, Walter; Porta, Fulvio; Caniglia, Maurizio; Santarone, Stella; D'Angelo, Paolo; Basso, Giuseppe; Locatelli, Franco

    2018-06-13

    Relapse of acute lymphoblastic leukemia (ALL) may occur in extramedullary sites, mainly central nervous system (CNS) and testis. Optimal post-remissional treatment for isolated extramedullary relapse (IEMR) is still controversial. We collected data of children treated with hematopoietic stem cell transplantation (HSCT) for ALL IEMR from 1990 to 2015 in Italy. Among 281 patients, 167 had a relapse confined to CNS, 73 to testis, 14 to mediastinum, and 27 to other organs. Ninety-seven patients underwent autologous HSCT, 79 received allogeneic HSCT from a matched family donor, 75 from a matched unrelated donor, and 30 from an HLA-haploidentical donor. The 10-year overall survival was 56% and was not influenced by gender, ALL blast immune-phenotype, age, site of relapse, duration of first remission, and type of HSCT. In multivariable analysis, the only prognostic factors were disease status at HSCT and year of transplantation. Patients transplanted in third or subsequent complete remission (CR) had a risk of death 2.3 times greater than those in CR2. Children treated after 2000 had half the risk of death than those treated before that year. Our results suggest that both autologous and allogeneic HSCT may be considered for the treatment of pediatric ALL IEMR after the achievement of CR2.

  17. Fatal Candidemia in a Patient with Acute Lymphoblastic Leukemia

    Science.gov (United States)

    2018-02-16

    Profoosionaf 7 ,0 Fatal Candidemia in a Patient with Acute Lymphoblastic Leukemia Brittany Lenz, MD, Arturo Dominguez, MD, Adnan Mir, MD, PhD Objectives...with pre-B cell acute lymphoblastic leukemia was admitted for presumed septic shock secondary to an unknown infectious etiology. The patient was...NOTES 14. ABSTRACT Fatal Candidcn1ia in a Patient \\\\ith Acute Lympboblastic Leukemia Brittany Lenz. MD. Arturo Dominguez.. MD. Adnan J’vlir. MD, PhD

  18. Redirecting T cells to eradicate B-cell acute lymphoblastic leukemia: bispecific T-cell engagers and chimeric antigen receptors.

    Science.gov (United States)

    Aldoss, I; Bargou, R C; Nagorsen, D; Friberg, G R; Baeuerle, P A; Forman, S J

    2017-04-01

    Recent advances in antibody technology to harness T cells for cancer immunotherapy, particularly in the difficult-to-treat setting of relapsed/refractory acute lymphoblastic leukemia (r/r ALL), have led to innovative methods for directing cytotoxic T cells to specific surface antigens on cancer cells. One approach involves administration of soluble bispecific (or dual-affinity) antibody-based constructs that temporarily bridge T cells and cancer cells. Another approach infuses ex vivo-engineered T cells that express a surface plasma membrane-inserted antibody construct called a chimeric antigen receptor (CAR). Both bispecific antibodies and CARs circumvent natural target cell recognition by creating a physical connection between cytotoxic T cells and target cancer cells to activate a cytolysis signaling pathway; this connection allows essentially all cytotoxic T cells in a patient to be engaged because typical tumor cell resistance mechanisms (such as T-cell receptor specificity, antigen processing and presentation, and major histocompatibility complex context) are bypassed. Both the bispecific T-cell engager (BiTE) antibody construct blinatumomab and CD19-CARs are immunotherapies that have yielded encouraging remission rates in CD19-positive r/r ALL, suggesting that they might serve as definitive treatments or bridging therapies to allogeneic hematopoietic cell transplantation. With the introduction of these immunotherapies, new challenges arise related to unique toxicities and distinctive pathways of resistance. An increasing body of knowledge is being accumulated on how to predict, prevent, and manage such toxicities, which will help to better stratify patient risk and tailor treatments to minimize severe adverse events. A deeper understanding of the precise mechanisms of action and immune resistance, interaction with other novel agents in potential combinations, and optimization in the manufacturing process will help to advance immunotherapy outcomes in the r

  19. Troglitazone inhibits cell growth and induces apoptosis of B-cell acute lymphoblastic leukemia cells with t(14;18).

    Science.gov (United States)

    Takenokuchi, M; Saigo, K; Nakamachi, Y; Kawano, S; Hashimoto, M; Fujioka, T; Koizumi, T; Tatsumi, E; Kumagai, S

    2006-01-01

    Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, has been detected in several human leukemia cells. Recent studies reported that PPARgamma ligands inhibit cell proliferation and induce apoptosis in both normal and malignant B-lineage cells. We investigated the expression of PPARgamma and the effects of PPARgamma ligands on UTree-O2, Bay91 and 380, three B-cell acute lymphoblastic leukemia (B-ALL) cell lines with t(14;18), which show a poor prognosis, accompanying c-myc abnormality. Western blot analysis identified expression of PPARgamma protein and real-time PCR that of PPARgamma mRNA on the three cell lines. Troglitazone (TGZ), a synthetic PPARgamma ligand, inhibited cell growth in these cell lines in a dose-dependent manner, which was associated with G(1) cell cycle arrest and apoptosis. We also found this effect PPARgamma independent since PPARgamma antagonists failed to reverse this effect. We assessed the expression of c-myc, an apoptosis-regulatory gene, since c-myc abnormality was detected in most B-ALL cells with t(14;18). TGZ was found to dose-dependently downregulate the expression of c-myc mRNA and c-myc protein in the three cell lines. These results suggest that TGZ inhibits cell growth via induction of G(1) cell cycle arrest and apoptosis in these cell lines and that TGZ-induced apoptosis, at least in part, may be related to the downregulation of c-myc expression. Moreover, the downregulation of c-myc expression by TGZ may depend on a PPARgamma-independent mechanism. Further studies indicate that PPARgamma ligands may serve as a therapeutic agent in B-ALL with t(14;18).

  20. NF-κB in T-cell Acute Lymphoblastic Leukemia: Oncogenic Functions in Leukemic and in Microenvironmental Cells

    International Nuclear Information System (INIS)

    Santos, Nuno R. dos; Ghezzo, Marinella N.; Silva, Ricardo C. da; Fernandes, Mónica T.

    2010-01-01

    Two main NF-κB signaling pathways, canonical and noncanonical, performing distinct functions in organisms have been characterized. Identification of mutations in genes encoding components of these NF-κB signaling pathways in lymphoid malignancies confirmed their key role in leukemogenesis. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes that despite significant therapeutic advances can still be fatal. Although mutations in NF-κB genes have not been reported in T-ALL, NF-κB constitutive activation in human T-ALL and in acute T-cell leukemia mouse models has been observed. Although these studies revealed activation of members of both canonical and noncanonical NF-κB pathways in acute T-cell leukemia, only inhibition of canonical NF-κB signaling was shown to impair leukemic T cell growth. Besides playing an important pro-oncogenic role in leukemic T cells, NF-κB signaling also appears to modulate T-cell leukemogenesis through its action in microenvironmental stromal cells. This article reviews recent data on the role of these transcription factors in T-ALL and pinpoints further research crucial to determine the value of NF-κB inhibition as a means to treat T-ALL

  1. NF-κB in T-cell Acute Lymphoblastic Leukemia: Oncogenic Functions in Leukemic and in Microenvironmental Cells

    Energy Technology Data Exchange (ETDEWEB)

    Santos, Nuno R. dos, E-mail: nrsantos@ualg.pt; Ghezzo, Marinella N.; Silva, Ricardo C. da; Fernandes, Mónica T. [IBB-Institute for Biotechnology and Bioengineering, Centre for Molecular and Structural Biomedicine (CBME), University of Algarve, Campus de Gambelas, 8005-139 Faro (Portugal)

    2010-11-05

    Two main NF-κB signaling pathways, canonical and noncanonical, performing distinct functions in organisms have been characterized. Identification of mutations in genes encoding components of these NF-κB signaling pathways in lymphoid malignancies confirmed their key role in leukemogenesis. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes that despite significant therapeutic advances can still be fatal. Although mutations in NF-κB genes have not been reported in T-ALL, NF-κB constitutive activation in human T-ALL and in acute T-cell leukemia mouse models has been observed. Although these studies revealed activation of members of both canonical and noncanonical NF-κB pathways in acute T-cell leukemia, only inhibition of canonical NF-κB signaling was shown to impair leukemic T cell growth. Besides playing an important pro-oncogenic role in leukemic T cells, NF-κB signaling also appears to modulate T-cell leukemogenesis through its action in microenvironmental stromal cells. This article reviews recent data on the role of these transcription factors in T-ALL and pinpoints further research crucial to determine the value of NF-κB inhibition as a means to treat T-ALL.

  2. Hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Matsuyama, Takaharu; Kato, Koji

    2002-01-01

    A multicenter comparative study was carried out to investigate the efficacy and safety of hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia. One hundred twenty three patients at a variety of remission stages were eligible for study participation. Eighty-nine were transplanted with allogeneic grafts and 34 patients with autologous grafts (23 cases with bone marrow and 11 cases with peripheral blood stem cells). Conditioning regimens used were as follows: melphalan and busulfan for 40 patients, melphalan, busulfan and TBI for 44 patients, other regimens for 39 patients. To accelerate engraftment G-CSF (lenograstim) was administered as a 1-hour or 24-hour drip infusion daily at 5 μg/kg from day 5 until hematological recovery. The five year disease free survival (DFS) was 63% for 42 patients at CR1, 41% for 41 patients at CR2 and 33% for 40 patients at other stages. There was no significant difference in the DFS between allogeneic-transplantation and autologous-transplantation in all disease stages. In patients at remission stage for CR1 and CR2, the 5-year DFS by conditioning regimen was 63% for regimen with melphalan and busulfan, 54% for regimen with melphalan, busulfan and TBI and 54% for regimens with melphalan and TBI. There was no significant difference in the DFS between the groups. Serious complications such as renal failure were observed in 11%, veno-occlusive disease in 9%, and interstitial pneumonia in 9%. The most dominating cause of death was relapse in the disease (48% of deaths) which was most commonly observed in autologous transplantation. Contrary to that, treatment related toxic death was the most frequent cause of deaths in allogeneic-transplantation. (author)

  3. Hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Matsuyama, Takaharu; Kato, Koji [Nagoya First Red Cross Hospital (Japan). Children' s Medical Center; Hanada, Ryoji [Saitama Children' s Medical Center, Iwatsuki (Japan)] [and others

    2002-07-01

    A multicenter comparative study was carried out to investigate the efficacy and safety of hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia. One hundred twenty three patients at a variety of remission stages were eligible for study participation. Eighty-nine were transplanted with allogeneic grafts and 34 patients with autologous grafts (23 cases with bone marrow and 11 cases with peripheral blood stem cells). Conditioning regimens used were as follows: melphalan and busulfan for 40 patients, melphalan, busulfan and TBI for 44 patients, other regimens for 39 patients. To accelerate engraftment G-CSF (lenograstim) was administered as a 1-hour or 24-hour drip infusion daily at 5 {mu}g/kg from day 5 until hematological recovery. The five year disease free survival (DFS) was 63% for 42 patients at CR1, 41% for 41 patients at CR2 and 33% for 40 patients at other stages. There was no significant difference in the DFS between allogeneic-transplantation and autologous-transplantation in all disease stages. In patients at remission stage for CR1 and CR2, the 5-year DFS by conditioning regimen was 63% for regimen with melphalan and busulfan, 54% for regimen with melphalan, busulfan and TBI and 54% for regimens with melphalan and TBI. There was no significant difference in the DFS between the groups. Serious complications such as renal failure were observed in 11%, veno-occlusive disease in 9%, and interstitial pneumonia in 9%. The most dominating cause of death was relapse in the disease (48% of deaths) which was most commonly observed in autologous transplantation. Contrary to that, treatment related toxic death was the most frequent cause of deaths in allogeneic-transplantation. (author)

  4. Immunophenotype and increased presence of CD4+CD25+ regulatory T cells in patients with acute lymphoblastic leukemia

    OpenAIRE

    WU, CUI-PING; QING, XI; WU, CUI-YUN; ZHU, HONG; ZHOU, HAI-YAN

    2011-01-01

    Acute lymphoblastic leukemia (ALL), cancer of the white blood cells, is a heterogeneous disease that mainly occurs due to the malignant cloning of original and naive lymphocytes. The aim of this study was to explore the immunophenotype, the percentage of CD4+CD25+ regulatory T cells (Tregs) and the expression of cytokines interleukin (IL)-2, IL-10 and TGF-β in patients with ALL. The immunophenotype and levels of CD4+CD25+ Tregs were detected using flow cytometry in the peripheral blood of 35 ...

  5. SB225002 Induces Cell Death and Cell Cycle Arrest in Acute Lymphoblastic Leukemia Cells through the Activation of GLIPR1

    Science.gov (United States)

    Leal, Paulo C.; Bhasin, Manoj K.; Zenatti, Priscila Pini; Nunes, Ricardo J.; Yunes, Rosendo A.; Nowill, Alexandre E.; Libermann, Towia A.; Zerbini, Luiz Fernando; Yunes, José Andrés

    2015-01-01

    Acute Lymphoblastic Leukemia (ALL) is the most frequent childhood malignancy. In the effort to find new anti-leukemic agents, we evaluated the small drug SB225002 (N-(2-hydroxy-4-nitrophenyl)-N’-(2-bromophenyl)urea). Although initially described as a selective antagonist of CXCR2, later studies have identified other cellular targets for SB225002, with potential medicinal use in cancer. We found that SB225002 has a significant pro-apoptotic effect against both B- and T-ALL cell lines. Cell cycle analysis demonstrated that treatment with SB225002 induces G2-M cell cycle arrest. Transcriptional profiling revealed that SB225002-mediated apoptosis triggered a transcriptional program typical of tubulin binding agents. Network analysis revealed the activation of genes linked to the JUN and p53 pathways and inhibition of genes linked to the TNF pathway. Early cellular effects activated by SB225002 included the up-regulation of GLIPR1, a p53-target gene shown to have pro-apoptotic activities in prostate and bladder cancer. Silencing of GLIPR1 in B- and T-ALL cell lines resulted in increased resistance to SB225002. Although SB225002 promoted ROS increase in ALL cells, antioxidant N-Acetyl Cysteine pre-treatment only modestly attenuated cell death, implying that the pro-apoptotic effects of SB225002 are not exclusively mediated by ROS. Moreover, GLIPR1 silencing resulted in increased ROS levels both in untreated and SB225002-treated cells. In conclusion, SB225002 induces cell cycle arrest and apoptosis in different B- and T-ALL cell lines. Inhibition of tubulin function with concurrent activation of the p53 pathway, in particular, its downstream target GLIPR1, seems to underlie the anti-leukemic effect of SB225002. PMID:26302043

  6. Antigen Expression on Blast Cells and Hematological Parameters at Presentation in Acute Lymphoblastic Leukemia Patients

    International Nuclear Information System (INIS)

    Naeem, S.; Bukhari, M. H.

    2015-01-01

    Objective: To analyze the expression of various antigens on the leukemic blasts and to determine the hematological parameters, in Acute Lymphoblastic Leukemia (ALL) patients at presentation. Study Design: Observational study. Place and Duration of Study: King Edward Medical University, Lahore and Hameed Latif Hospital, Lahore, from February 2013 to March 2014. Methodology: A total of 50 newly diagnosed and untreated patients of ALL were selected from Mayo Hospital and Hameed Latif Hospital. These patients included both genders and all age groups. Hemoglobin, total leukocyte count and platelet count were determined on hematology analyser-Sysmex-Kx-2I. Blast cell percentage was estimated on Giemsa stained blood smears. Immuno phenotyping was done on bone marrow samples by 5 colour flow cytometery on Beckman Counter Navious Flow cytometer. An acute leukemia panel of 23 antibodies was used. The data was entered and analyzed in SPSS version 22. Results: Of the 50 ALL patients, 36 (72 percentage) were B-ALL and 14 (28 percentage) T-ALL. There were 18 (36 percentage) children and 32 (64 percentage) adults. T-ALL included 22 percentage of the childhood and 31 percentage of the adult cases. Immuno phenotypic analysis showed that CD19, CD79a and CD20 were B-lineage specific markers whereas cCD3, CD3 and CD5 were T-lineage specific. CD10 was the most sensitive marker for B-ALL and CD7 was the most sensitive marker of T-ALL. TdT was expressed in 92 percentage B-ALL and 71 percentage T-ALL cases, CD34 in 58 percentage and 43 percentage cases and CD45 in 83 percentage and 100 percentage respectively. High leukocyte count (> 50 x 109/L) was present in 58 percentage cases. Hemoglobin was < 10 g/dl in 74 percentage patients and platelet count was below 20 x 109/Lin 12 percentage patients. Leukocyte count, hemoglobin, platelet count and blast cell percentage did not show a significant difference in the two ALL immuno types. Conclusion: The frequency of T-ALL is higher in childhood

  7. Children with acute lymphoblastic leukemia show high numbers of CD4+ and CD8+ T-cells which are reduced by conventional chemotherapy

    OpenAIRE

    Mohamed Labib Salem; Mohamed Ramadan El-Shanshory; Nabila Ibrahim El-Desouki; Said Hammad Abdou; Mohamed Attia Attia; Abdel-Aziz Awad Zidan; Shymaa Sobhy Mourad

    2015-01-01

    Background: Acute lymphoblastic leukemia (ALL) is considered as one of the most common cancer in pediatric malignancies. Among ALL, B-cell Acute Lymphoblastic Leukemia (B-ALL) represents 80% to 85% of the childhood ALL. Problem: Although anti B-ALL chemotherapy kill B-ALL, it associates with alteration in the numbers of CD4+ and CD8+ T-cells, and thus impacts the overall immunity. Aim: To evaluate the impact of anti B-ALL on the numbers of CD4+ and CD8+ T-cells in correlation to the n...

  8. Core Transcriptional Regulatory Circuit Controlled by the TAL1 Complex in Human T Cell Acute Lymphoblastic Leukemia

    OpenAIRE

    Sanda, Takaomi; Lawton, Lee N.; Barrasa, M. Inmaculada; Fan, Zi Peng; Kohlhammer, Holger; Gutierrez, Alejandro; Ma, Wenxue; Tatarek, Jessica; Ahn, Yebin; Kelliher, Michelle A.; Jamieson, Catriona H.M.; Staudt, Louis M.; Young, Richard A.; Look, A. Thomas

    2012-01-01

    The oncogenic transcription factor TAL1/SCL is aberrantly expressed in over 40% of cases of human T-cell acute lymphoblastic leukemia (T-ALL), emphasizing its importance in the molecular pathogenesis of T-ALL. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3 and RUNX1. We show that TAL1 forms a positive interconnected auto-regulatory loop with GATA3 and RUNX1, and that the TAL1 complex directly activates the MY...

  9. Transient Responses to NOTCH and TLX1/HOX11 Inhibition in T-Cell Acute Lymphoblastic Leukemia/Lymphoma

    OpenAIRE

    Rakowski, Lesley A.; Lehotzky, Erica A.; Chiang, Mark Y.

    2011-01-01

    To improve the treatment strategies of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), further efforts are needed to identify therapeutic targets. Dysregulated expression of HOX-type transcription factors occurs in 30-40% of cases of T-ALL. TLX1/HOX11 is the prototypical HOX-type transcription factor. TLX1 may be an attractive therapeutic target because mice that are deficient in TLX1 are healthy. To test this possibility, we developed a conditional doxycycline-regulated mouse model of ...

  10. Prognostic impact of IKZF1 deletion in adults with common B-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Yao, Qiu-Mei; Liu, Kai-Yan; Gale, Robert Peter; Jiang, Bin; Liu, Yan-Rong; Jiang, Qian; Jiang, Hao; Zhang, Xiao-Hui; Zhang, Mei-Jie; Chen, Shan-Shan; Huang, Xiao-Jun; Xu, Lan-Ping; Ruan, Guo-Rui

    2016-04-11

    Interrogate the impact of IKZF1 deletion on therapy-outcomes of adults with common B-cell acute lymphoblastic leukemia. One hundred sixty-five consecutive adults with common B-cell ALL were tested for IKZF1 deletion and for BCR/ABL. Deletions in IKZF1 were detected using multiplex RQ-PCR, multiplex fluorescent PCR, sequence analysis and multiplex ligation-dependent probe amplification (MLPA). BCR/ABL was detected using RQ-PCR. All subjects received chemotherapy and some also received an allotransplant and tyrosine kinase-inhibitors. Multivariate analyses were done to identify associations between IKZF1 deletion and other variables on non-relapse mortality (NRM), cumulative incidence of relapse (CIR), leukemia-free survival (LFS) and survival. Amongst subjects achieving complete remission those with IKZF1 deletion had similar 5-year non-relapse mortality (NRM) (11% [2-20%] vs. 16% [4-28%]; P = 0.736), a higher 5-year cumulative incidence of relapse (CIR) (55% [35-76%] vs. 25% [12-38%]; P = 0.004), and worse 5-year leukemia-free survival (LFS) (33% [16-52%] vs. 59% [42-73%]; P = 0.012) and survival (48% [33-62%] vs. 75% [57-86%]; P = 0.002). In multivariate analyses IKZF1 deletion was associated with an increased relapse (relative risk [RR] =2.7, [1.4-5.2]; P = 0.002), a higher risk of treatment-failure (inverse of LFS; RR = 2.1, [1.2-3.6]; P = 0.007) and a higher risk of death (RR = 2.8, [1.5-5.5]; P = 0.002). The adverse impact of IKZF1 deletion on outcomes was stronger in subjects without vs. with BCR-ABL1 and in subjects receiving chemotherapy-only vs. an allotransplant. IKZF1 deletion was independently-associated with a higher relapse risk and worse LFS and survival in adults with common B-cell ALL after adjusting for other prognostic variables and differences in therapies. These data suggest IKZF1 deletion may be a useful prognostic variable in adults with common B-cell ALL, especially in persons without BCR-ABL1 and those receiving chemotherapy

  11. Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients.

    Science.gov (United States)

    Scheijen, Blanca; Boer, Judith M; Marke, René; Tijchon, Esther; van Ingen Schenau, Dorette; Waanders, Esmé; van Emst, Liesbeth; van der Meer, Laurens T; Pieters, Rob; Escherich, Gabriele; Horstmann, Martin A; Sonneveld, Edwin; Venn, Nicola; Sutton, Rosemary; Dalla-Pozza, Luciano; Kuiper, Roland P; Hoogerbrugge, Peter M; den Boer, Monique L; van Leeuwen, Frank N

    2017-03-01

    Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of IKZF1 deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of BTG1 were significantly enriched in IKZF1 -deleted B-cell precursor acute lymphoblastic leukemia ( P =0.007). While BTG1 deletions alone had no impact on prognosis, the combined presence of BTG1 and IKZF1 deletions was associated with a significantly lower 5-year event-free survival ( P =0.0003) and a higher 5-year cumulative incidence of relapse ( P =0.005), when compared with IKZF1 -deleted cases without BTG1 aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as CDKN2A/B, PAX5, EBF1 or RB1 , did not affect the outcome of IKZF1 -deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, Btg1 -deficient mice were crossed onto an Ikzf1 heterozygous background. We observed that loss of Btg1 increased the tumor incidence of Ikzf1 +/- mice in a dose-dependent manner. Moreover, murine B cells deficient for Btg1 and Ikzf1 +/- displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify BTG1 as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in IKZF1 -deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function. Copyright© Ferrata Storti Foundation.

  12. Hematopoietic stem cells can be separated from leukemic cells in a subgroup of adult acute lymphoblastic leukemia patients.

    Science.gov (United States)

    Wang, Wenwen; Foerner, Elena; Buss, Eike; Jauch, Anna; Eckstein, Volker; Wuchter, Patrick; Ho, Anthony D; Lutz, Christoph

    2017-06-01

    In B-cell acute lymphoblastic leukemia (B-ALL) separation of normal hematopoietic stem cells (HSC) has so far been limited to a subgroup of patients. As aldehyde dehydrogenase (ALDH)-activity is enriched in various stem cells we investigated its value for HSC isolation in adult B-ALL. Based on ALDH-activity patients could be stratified in ALDH-numerous (≥1.9% ALDH +  cells) and ALDH-rare (cells) cases. In ALDH-rare B-ALL clonal-marker negative HSC could be separated by the CD34 + CD38 - ALDH +  phenotype, whereas this separation was not possible in ALDH-numerous B-ALL. Functional analysis confirmed the HSC-potential of isolated cells, which were uniformly CD19-negative. However, addition of ALDH-activity further improved HSC-purity. In summary, we provide a method to separate functionally normal HSC from leukemic cells in a subgroup of B-ALL patients that can be identified prospectively. This protocol thereby facilitates comparative analyses of matched HSC and leukemic cells in order to improve our understanding of leukemia evolution.

  13. CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Davila, Marco L; Brentjens, Renier J

    2016-10-01

    Immunotherapy has demonstrated significant potential for the treatment of patients with chemotherapy-resistant hematologic malignancies and solid tumors. One type of immunotherapy involves the adoptive transfer of T cells that have been genetically modified with a chimeric antigen receptor (CAR) to target a tumor. These hybrid proteins are composed of the antigen-binding domains of an antibody fused to T-cell receptor signaling machinery. CAR T cells that target CD19 recently have made the jump from the laboratory to the clinic, and the results have been remarkable. CD19-targeted CAR T cells have induced complete remissions of disease in up to 90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), who have an expected complete response rate of 30% in response to chemotherapy. The high efficacy of CAR T cells in B-ALL suggests that regulatory approval of this therapy for this routinely fatal leukemia is on the horizon. We review the preclinical development of CAR T cells and their early clinical application for lymphoma. We also provide a comprehensive analysis of the use of CAR T cells in patients with B-ALL. In addition, we discuss the unique toxicities associated with this therapy and the management schemes that have been developed.

  14. CD90 and CD110 correlate with cancer stem cell potentials in human T-acute lymphoblastic leukemia cells

    International Nuclear Information System (INIS)

    Yamazaki, Hiroto; Nishida, Hiroko; Iwata, Satoshi; Dang, Nam H.; Morimoto, Chikao

    2009-01-01

    Although cancer stem cells (CSCs) have been recently identified in myeloid leukemia, published data on lymphoid malignancy have been sparse. T-acute lymphoblastic leukemia (T-ALL) is characterized by the abnormal proliferation of T-cell precursors and is generally aggressive. As CD34 is the only positive-selection marker for CSCs in T-ALL, we performed extensive analysis of CD markers in T-ALL cell lines. We found that some of the tested lines consisted of heterogeneous populations of cells with various levels of surface marker expression. In particular, a small subpopulation of CD90 (Thy-1) and CD110 (c-Mpl) were shown to correlate with stem cell properties both in vitro and in transplantation experiments. As these markers are expressed on hematopoietic stem cells, our results suggest that stem cell-like population are enriched in CD90+/CD110+ fraction and they are useful positive-selection markers for the isolation of CSCs in some cases of T-ALL.

  15. CD90 and CD110 correlate with cancer stem cell potentials in human T-acute lymphoblastic leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Yamazaki, Hiroto; Nishida, Hiroko; Iwata, Satoshi [Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639 (Japan); Dang, Nam H. [Department of Hematologic Malignancies, Nevada Cancer Institute, Las Vegas, NV (United States); Morimoto, Chikao, E-mail: morimoto@ims.u-tokyo.ac.jp [Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639 (Japan)

    2009-05-29

    Although cancer stem cells (CSCs) have been recently identified in myeloid leukemia, published data on lymphoid malignancy have been sparse. T-acute lymphoblastic leukemia (T-ALL) is characterized by the abnormal proliferation of T-cell precursors and is generally aggressive. As CD34 is the only positive-selection marker for CSCs in T-ALL, we performed extensive analysis of CD markers in T-ALL cell lines. We found that some of the tested lines consisted of heterogeneous populations of cells with various levels of surface marker expression. In particular, a small subpopulation of CD90 (Thy-1) and CD110 (c-Mpl) were shown to correlate with stem cell properties both in vitro and in transplantation experiments. As these markers are expressed on hematopoietic stem cells, our results suggest that stem cell-like population are enriched in CD90+/CD110+ fraction and they are useful positive-selection markers for the isolation of CSCs in some cases of T-ALL.

  16. Carfilzomib and Hyper-CVAD in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoma

    Science.gov (United States)

    2018-03-01

    Contiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia

  17. Plumbagin exerts an immunosuppressive effect on human T-cell acute lymphoblastic leukemia MOLT-4 cells

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Kyoung Jun; Lee, Yura [Department of Biomedical Laboratory Science, Daejeon 34824 (Korea, Republic of); Kim, Soon Ae [Department of Pharmacology, School of Medicine, Daejeon 34824 (Korea, Republic of); Kim, Jiyeon, E-mail: yeon@eulji.ac.kr [Department of Biomedical Laboratory Science, Daejeon 34824 (Korea, Republic of)

    2016-04-22

    Of the hematological disorders typified by poor prognoses and survival rates, T-cell acute lymphoblastic leukemia (T-ALL) is one of the most commonly diagnosed. Despite the development of new therapeutic agents, the treatment options for this cancer remain limited. In this manuscript, we investigated the anti-proliferative effects of plumbagin, mediated by the activation of mitogen-activated protein kinase (MAPK) pathways, and inhibition of NF-κB signaling; the human T-ALL MOLT-4 cell line was used as our experimental system. Plumbagin is a natural, plant derived compound, which exerts an anti-proliferative activity against many types of human cancer. Our experiments confirm that plumbagin induces a caspase-dependent apoptosis of MOLT-4 cells, with no significant cytotoxicity seen for normal peripheral blood mononuclear cells (PBMCs). Plumbagin also inhibited LPS-induced phosphorylation of p65, and the transcription of NF-κB target genes. Our results now show that plumbagin is a potent inhibitor of the NF-κB signaling pathway, and suppressor of T-ALL cell proliferation. - Highlights: • Plumbagin induces caspase-dependent apoptosis in T-ALL MOLT-4 cells. • Plumbagin activates phosphorylation of stress-activated protein kinase (SAPK) JNK and p38. • Plumbagin inhibits LPS-mediated NF-κB signaling cascade. • Plumbagin inhibits LPS-mediated transcriptional activity of pro-inflammatory cytokines.

  18. Pharmacogenetics in Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Cheok, Meyling H.; Pottier, Nicolas; Kager, Leo

    2009-01-01

    Progress in the treatment of acute leukemia in children has been remarkable, from a disease being lethal four decades ago to current cure rates exceeding 80%. This exemplary progress is largely due to the optimization of existing treatment modalities rather than the discovery of new antileukemic agents. However, despite these high cure rates, the annual number of children whose leukemia relapses after their initial therapy remains greater than that of new cases of most types of childhood cancers. The aim of pharmacogenetics is to develop strategies to personalize treatment and tailor therapy to individual patients, with the goal of optimizing efficacy and safety through better understanding of human genome variability and its influence on drug response. In this review, we summarize recent pharmacogenomic studies related to the treatment of pediatric acute lymphoblastic leukemia. These studies illustrate the promise of pharmacogenomics to further advance the treatment of human cancers, with childhood leukemia serving as a paradigm. PMID:19100367

  19. IKZF1 DELETIONS ARE INDEPENDENT PROGNOSTIC FACTOR IN PEDIATRIC B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    G. A. Tsaur

    2016-01-01

    Full Text Available We assessed the prognostic significance of IKZF1 gene deletions in 141 pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL  on Russian multicenter trial in pediatric clinics of Ekaterinburg and Orenburg. IKZF1 deletions were estimated by multiplex ligation-dependent probe amplification. IKZF1 deletions were revealed in 15 (10.6 % patients. IKZF1 deletions were associated with age older than 10 years (p = 0.007, initial white blood cell count higher than 30 × 109/l (p = 0.003, t(9;22(q34.q11 (p = 0.003 and delayed blast clearance: М3 status of bone marrow at day 15 of remission induction (p = 0.003, lack of hematological remission at day 36 (p < 0.001 and high levels of minimal residual disease at days 15, 36 and 85 (p = 0.014; p < 0.001; p = 0.001 correspondingly. Patients with IKZF1 deletions had significantly lower event-free survival (EFS (0.30 ± 0.15 vs 0.89 ± 0.03; p < 0.001 and overall survival (OS (0.44 ± 0.19 vs 0.93 ± 0.02; p < 0.001, while cumulative incidence of relapse was higher (0.67 ± 0.18 vs 0.07 ± 0.02; p < 0.001. In the multivariate analysis IKZF1 deletions were associated with decreased EFS (hazard ratio (HR 4.755; 95 % confidence interval (CI 1.856–12.185; p = 0.001, and OS (HR 4.208; 95 % CI 1.322–13.393; p = 0.015, but increased relapse risk (HR 9,083; 95 % CI 3.119–26.451; p < 0.001. IKZF1 deletions retained their prognostic significance in the intermediate risk group patients (p < 0.001, but not in standard or high-risk groups. Majority of IKZF1 deletions – 12 (80 % of 15 – were revealed in the “B-other” group (n = 83. In this cohort of patients IKZF1 deletions led to inferior EFS (HR 6.172; 95 % CI 1.834–20.767; p = 0.003 and higher relapse rate (HR 16.303; 95 % CI 3.324–79.965; p = 0.015. Thus, our results showed that IKZF1 deletions are independent risk factor in BCP-ALL patients.

  20. 3D/4D multiscale imaging in acute lymphoblastic leukemia cells: visualizing dynamics of cell death

    Science.gov (United States)

    Sarangapani, Sreelatha; Mohan, Rosmin Elsa; Patil, Ajeetkumar; Lang, Matthew J.; Asundi, Anand

    2017-06-01

    Quantitative phase detection is a new methodology that provides quantitative information on cellular morphology to monitor the cell status, drug response and toxicity. In this paper the morphological changes in acute leukemia cells treated with chitosan were detected using d'Bioimager a robust imaging system. Quantitative phase image of the cells was obtained with numerical analysis. Results show that the average area and optical volume of the chitosan treated cells is significantly reduced when compared with the control cells, which reveals the effect of chitosan on the cancer cells. From the results it can be attributed that d'Bioimager can be used as a non-invasive imaging alternative to measure the morphological changes of the living cells in real time.

  1. Age-related clinical and biological features of PTEN abnormalities in T-cell acute lymphoblastic leukaemia.

    Science.gov (United States)

    Tesio, M; Trinquand, A; Ballerini, P; Hypolite, G; Lhermitte, L; Petit, A; Ifrah, N; Baruchel, A; Dombret, H; Macintyre, E; Asnafi, V

    2017-12-01

    The tumour suppressor gene PTEN is commonly altered in T-cell acute lymphoblastic leukaemia but its prognostic impact is still debated. We screened a cohort of 573 fully characterised adult and paediatric T-cell acute lymphoblastic leukaemia (T-ALL) patients for genomic PTEN abnormalities. PTEN-inactivating mutations and/or deletions were identified in 91 cases (16%), including 18% of paediatric (49/277) and 14% of adult cases (42/296). Thirty-four patients harboured only mutations, 12 cases demonstrated only large deletions and 9 only microdeletions. About 36 patients had combined alterations. Different mechanisms of PTEN inactivation predicted differences in the clinical outcome for both adult and paediatric patients treated according to the GRAALL03/05 and FRALLE2000 protocols. Whereas large deletions predicted lower 5-year overall survival (P=0.0053 in adults, P=0.001 in children) and disease-free survival (P=0.0009 in adults, P=0.0002 in children), mutations were not associated with a worse prognosis. The prognostic impact of PTEN loss is therefore linked to the underlying type of genomic abnormality, both in adult and paediatric T-ALLs, demonstrating that detailed analysis of the type of abnormality type would be useful to refine risk stratification.

  2. Helios expression in regulatory T cells promotes immunosuppression, angiogenesis and the growth of leukemia cells in pediatric acute lymphoblastic leukemia.

    Science.gov (United States)

    Li, Xue; Li, Dong; Huang, Xiaoyang; Zhou, Panpan; Shi, Qing; Zhang, Bing; Ju, Xiuli

    2018-04-01

    Regulatory T cells (Tregs) characterized by the transcription factor forkhead box P3 (FoxP3) are crucial for maintaining immune tolerance and preventing autoimmunity. However, FoxP3 does not function alone and Helios is considered a potential candidate for defining Treg subsets. In this study, we investigated the expression and function of Helios for identifying Tregs in childhood precursor B-cell acute lymphoblastic leukemia (pre-B ALL). Our results demonstrated that patients with pre-B ALL had a higher percentage of Helios + FoxP3 + CD4 + Tregs. And there was a positive correlation between the expression of Helios and the suppressive function of Tregs, the risk gradation of ALL. Helios in combination with CD4 and FoxP3 may be an effective way to detect functional Tregs in pre-B ALL by promoting the secretion of transforming growth factor (TGF)-β1. Furthermore, Helios + Tregs could regulate angiogenesis in the BM niche of pre-B ALL via the VEGFA/VEGFR2 pathway. We also found Helios + Tregs decreased apoptosis rate of nalm-6 cells by up-regulating the expression of anti-apoptosis protein Bcl-2. In summary, these data strongly imply the physiological importance of Helios expression in Tregs, and suggest that the manipulation of Helios may serve as a novel strategy for cancer immunotherapy. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. Resveratrol given intraperitoneally does not inhibit growth of high-risk t(4;11) acute lymphoblastic leukemia cells in NOD/SCID mouse model

    Science.gov (United States)

    The efficacy of the phytochemical resveratrol as a preventive agent against the growth of t(4;11) acute lymphoblastic leukemia (ALL) was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) ALL line SEM. SEM cells were injected into the tail vein and engraftment was monitored by ...

  4. Solanine induced apoptosis and increased chemosensitivity to Adriamycin in T-cell acute lymphoblastic leukemia cells.

    Science.gov (United States)

    Yi, Ying-Jie; Jia, Xiu-Hong; Wang, Jian-Yong; Chen, Jie-Ru; Wang, Hong; Li, You-Jie

    2018-05-01

    Solanine is an alkaloid and is the main extract of the traditional Chinese herb, Solanum nigrum Linn . It has been reported that Solanine has anti-inflammatory and antitumor properties. The present study aimed to investigate the antitumor effect of Solanine in Jurkat cells and demonstrate the molecular mechanism of antitumor activity of Solanine. A Cell Counting Kit-8 assay demonstrated that Solanine inhibited the proliferation of Jurkat cells in a dose-and time-dependent manner. Cell apoptosis was measured by flow cytometry. Flow cytometry revealed that Solanine induced apoptosis in a dose-dependent manner in Jurkat cells. Reverse transcription-quantitative polymerase chain reaction demonstrated that Solanine modulated the mRNA levels of B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). Additionally, Bcl-2 and Bax expression was measured using western blot analysis. Western blot analysis revealed a significant increase in the expression of Bax and decrease in the expression of Bcl-2. Solanine increased the chemosensitivity of Jurkat cells to Adriamycin. In summary, the present results indicated that the antitumor activity of Solanine was associated with inhibition of cell proliferation, induction of apoptosis and increasing cytotoxicity of Adriamycin. Therefore, Solanine may have potential as a novel agent for the treatment of acute lymphocytic leukemia.

  5. Nanomedicine approaches in acute lymphoblastic leukemia.

    Science.gov (United States)

    Tatar, Andra-Sorina; Nagy-Simon, Timea; Tomuleasa, Ciprian; Boca, Sanda; Astilean, Simion

    2016-09-28

    Acute lymphoblastic leukemia (ALL) is the malignancy with the highest incidence amongst children (26% of all cancer cases), being surpassed only by the cancers of the brain and of the nervous system. The most recent research on ALL is focusing on new molecular therapies, like targeting specific biological structures in key points in the cell cycle, or using selective inhibitors for transmembranary proteins involved in cell signalling, and even aiming cell surface receptors with specifically designed antibodies for active targeting. Nanomedicine approaches, especially by the use of nanoparticle-based compounds for the delivery of drugs, cancer diagnosis or therapeutics may represent new and modern ways in the near future anti-cancer therapies. This review offers an overview on the recent role of nanomedicine in the detection and treatment of acute lymphoblastic leukemia as resulting from a thorough literature survey. A short introduction on the basics of ALL is presented followed by the description of the conventional methods used in the ALL detection and treatment. We follow our discussion by introducing some of the general nano-strategies used for cancer detection and treatment. The detailed role of organic and inorganic nanoparticles in ALL applications is further presented, with a special focus on gold nanoparticle-based nanocarriers of antileukemic drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)—Patient Version

    Science.gov (United States)

    Adult acute lymphoblastic leukemia (ALL; also called acute lymphocytic leukemia) is a blood cancer that often gets worse quickly if it is not treated. Treatments include chemotherapy, radiation therapy, stem cell transplant, and targeted therapy. Get detailed information about ALL in this expert-reviewed summary.

  7. Identification and cloning of a prethymic precursor T lymphocyte from a population of common acute lymphoblastic leukemia antigen (CALLA)-positive fetal bone marrow cells

    DEFF Research Database (Denmark)

    Hokland, P; Hokland, M; Daley, J

    1987-01-01

    We have cloned common acute lymphoblastic leukemia (CALLA)-positive cells from human fetal bone marrow containing less than 1 in 10,000 E-RFC in round-bottomed microtiter wells (one cell per well) using the autocloning unit of an EPICS-V cell sorter. Expansion of such cells (with IL-2 and heavily...... irradiated autologous thymocytes as feeder cells) resulted in growth in 6-14% of the wells (mean, 11%) with cells with mature T lymphocyte phenotype. Two-color fluorescence analysis of outgrowing cultures furthermore ascertained that these cells had differentiated through a phase of simultaneous expression...... of T4 and T8 antigens and at the same time expression of the thymocyte-associated T6 antigens. Thus, given the fact that 10-20% of T cell acute lymphoblastic leukemia (T-ALLs) are CALLA+, we have been able to identify a human prethymic T lymphocyte population that might be the normal counterpart...

  8. Core transcriptional regulatory circuit controlled by the TAL1 complex in human T cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Sanda, Takaomi; Lawton, Lee N; Barrasa, M Inmaculada; Fan, Zi Peng; Kohlhammer, Holger; Gutierrez, Alejandro; Ma, Wenxue; Tatarek, Jessica; Ahn, Yebin; Kelliher, Michelle A; Jamieson, Catriona H M; Staudt, Louis M; Young, Richard A; Look, A Thomas

    2012-08-14

    The oncogenic transcription factor TAL1/SCL is aberrantly expressed in over 40% of cases of human T cell acute lymphoblastic leukemia (T-ALL), emphasizing its importance in the molecular pathogenesis of T-ALL. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. We show that TAL1 forms a positive interconnected autoregulatory loop with GATA3 and RUNX1 and that the TAL1 complex directly activates the MYB oncogene, forming a positive feed-forward regulatory loop that reinforces and stabilizes the TAL1-regulated oncogenic program. One of the critical downstream targets in this circuitry is the TRIB2 gene, which is oppositely regulated by TAL1 and E2A/HEB and is essential for the survival of T-ALL cells. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia

    Science.gov (United States)

    Vicente, Carmen; Schwab, Claire; Broux, Michaël; Geerdens, Ellen; Degryse, Sandrine; Demeyer, Sofie; Lahortiga, Idoya; Elliott, Alannah; Chilton, Lucy; La Starza, Roberta; Mecucci, Cristina; Vandenberghe, Peter; Goulden, Nicholas; Vora, Ajay; Moorman, Anthony V.; Soulier, Jean; Harrison, Christine J.; Clappier, Emmanuelle; Cools, Jan

    2015-01-01

    T-cell acute lymphoblastic leukemia is caused by the accumulation of multiple oncogenic lesions, including chromosomal rearrangements and mutations. To determine the frequency and co-occurrence of mutations in T-cell acute lymphoblastic leukemia, we performed targeted re-sequencing of 115 genes across 155 diagnostic samples (44 adult and 111 childhood cases). NOTCH1 and CDKN2A/B were mutated/deleted in more than half of the cases, while an additional 37 genes were mutated/deleted in 4% to 20% of cases. We found that IL7R-JAK pathway genes were mutated in 27.7% of cases, with JAK3 mutations being the most frequent event in this group. Copy number variations were also detected, including deletions of CREBBP or CTCF and duplication of MYB. FLT3 mutations were rare, but a novel extracellular mutation in FLT3 was detected and confirmed to be transforming. Furthermore, we identified complex patterns of pairwise associations, including a significant association between mutations in IL7R-JAK genes and epigenetic regulators (WT1, PRC2, PHF6). Our analyses showed that IL7R-JAK genetic lesions did not confer adverse prognosis in T-cell acute lymphoblastic leukemia cases enrolled in the UK ALL2003 trial. Overall, these results identify interconnections between the T-cell acute lymphoblastic leukemia genome and disease biology, and suggest a potential clinical application for JAK inhibitors in a significant proportion of patients with T-cell acute lymphoblastic leukemia. PMID:26206799

  10. Preservation of high glycolytic phenotype by establishing new acute lymphoblastic leukemia cell lines at physiologic oxygen concentration

    Energy Technology Data Exchange (ETDEWEB)

    Sheard, Michael A., E-mail: msheard@chla.usc.edu [Developmental Therapeutics Program, USC-CHLA Institute for Pediatric Clinical Research, Division of Hematology-Oncology, Children' s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027 (United States); Ghent, Matthew V., E-mail: mattghent@gmail.com [Department of Pathology, Keck School of Medicine, University of Southern California, Health Sciences Campus, Los Angeles, CA 90089 (United States); Cabral, Daniel J., E-mail: dcabral14@gmail.com [Cancer Center and Departments of Cell Biology & Biochemistry, Pharmacology & Neuroscience, Internal Medicine and Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430 (United States); Lee, Joanne C., E-mail: joannebarnhart@gmail.com [Cancer Center and Departments of Cell Biology & Biochemistry, Pharmacology & Neuroscience, Internal Medicine and Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430 (United States); Khankaldyyan, Vazgen, E-mail: khangaldian@yahoo.com [Developmental Therapeutics Program, USC-CHLA Institute for Pediatric Clinical Research, Division of Hematology-Oncology, Children' s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027 (United States); Ji, Lingyun, E-mail: lingyun.ji@med.usc.edu [Developmental Therapeutics Program, USC-CHLA Institute for Pediatric Clinical Research, Division of Hematology-Oncology, Children' s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027 (United States); Wu, Samuel Q., E-mail: swu@chla.usc.edu [Medical Genetics, Children' s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027 (United States); Kang, Min H., E-mail: min.kang@ttuhsc.edu [Cancer Center and Departments of Cell Biology & Biochemistry, Pharmacology & Neuroscience, Internal Medicine and Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430 (United States); and others

    2015-05-15

    Cancer cells typically exhibit increased glycolysis and decreased mitochondrial oxidative phosphorylation, and they continue to exhibit some elevation in glycolysis even under aerobic conditions. However, it is unclear whether cancer cell lines employ a high level of glycolysis comparable to that of the original cancers from which they were derived, even if their culture conditions are changed to physiologically relevant oxygen concentrations. From three childhood acute lymphoblastic leukemia (ALL) patients we established three new pairs of cell lines in both atmospheric (20%) and physiologic (bone marrow level, 5%) oxygen concentrations. Cell lines established in 20% oxygen exhibited lower proliferation, survival, expression of glycolysis genes, glucose consumption, and lactate production. Interestingly, the effects of oxygen concentration used during cell line initiation were only partially reversible when established cell cultures were switched from one oxygen concentration to another for eight weeks. These observations indicate that ALL cell lines established at atmospheric oxygen concentration can exhibit relatively low levels of glycolysis and these levels are semi-permanent, suggesting that physiologic oxygen concentrations may be needed from the time of cell line initiation to preserve the high level of glycolysis commonly exhibited by leukemias in vivo. - Highlights: • Establishing new ALL cell lines in 5% oxygen resulted in higher glycolytic expression and function. • Establishing new ALL cell lines in 5% oxygen resulted in higher proliferation and lower cell death. • The divergent metabolic phenotypes selected in 5% and 20% oxygen are semi-permanent.

  11. Preservation of high glycolytic phenotype by establishing new acute lymphoblastic leukemia cell lines at physiologic oxygen concentration

    International Nuclear Information System (INIS)

    Sheard, Michael A.; Ghent, Matthew V.; Cabral, Daniel J.; Lee, Joanne C.; Khankaldyyan, Vazgen; Ji, Lingyun; Wu, Samuel Q.; Kang, Min H.

    2015-01-01

    Cancer cells typically exhibit increased glycolysis and decreased mitochondrial oxidative phosphorylation, and they continue to exhibit some elevation in glycolysis even under aerobic conditions. However, it is unclear whether cancer cell lines employ a high level of glycolysis comparable to that of the original cancers from which they were derived, even if their culture conditions are changed to physiologically relevant oxygen concentrations. From three childhood acute lymphoblastic leukemia (ALL) patients we established three new pairs of cell lines in both atmospheric (20%) and physiologic (bone marrow level, 5%) oxygen concentrations. Cell lines established in 20% oxygen exhibited lower proliferation, survival, expression of glycolysis genes, glucose consumption, and lactate production. Interestingly, the effects of oxygen concentration used during cell line initiation were only partially reversible when established cell cultures were switched from one oxygen concentration to another for eight weeks. These observations indicate that ALL cell lines established at atmospheric oxygen concentration can exhibit relatively low levels of glycolysis and these levels are semi-permanent, suggesting that physiologic oxygen concentrations may be needed from the time of cell line initiation to preserve the high level of glycolysis commonly exhibited by leukemias in vivo. - Highlights: • Establishing new ALL cell lines in 5% oxygen resulted in higher glycolytic expression and function. • Establishing new ALL cell lines in 5% oxygen resulted in higher proliferation and lower cell death. • The divergent metabolic phenotypes selected in 5% and 20% oxygen are semi-permanent

  12. In vivo and in vitro expression of myeloid antigens on B-lineage acute lymphoblastic leukemia cells.

    Science.gov (United States)

    Hara, J; Kawa-Ha, K; Yumura-Yagi, K; Kurahashi, H; Tawa, A; Ishihara, S; Inoue, M; Murayama, N; Okada, S

    1991-01-01

    The expression of myeloid antigens has been extensively examined using two-color analysis in 43 children with B-lineage acute lymphoblastic leukemia (ALL). On pre-culture cells, CD33 expression was frequently observed in CD19+, CD10- B-precursor ALL, and CD14 was expressed only on the cells from B-precursor ALL expressing CD19, CD10 and CD20, and B-ALL. After 2 or 3 days of culture without TPA, CD13 emerged on the cells from 21 of 29 patients irrespective of the presence or the absence of fetal calf serum in the culture. Of four patients with CD10+ B-precursor ALL, which showed no expression of CD13 after culture, two had T-cell associated antigens. Whereas the addition of TPA to the culture enhanced the expression of CD13 on the cells from acute non-lymphocytic leukemia (ANLL), TPA reduced the expression of this antigen on B-precursor cells. These findings suggest that the regulatory mechanism of CD13 expression may be different between B-precursor ALL and ANLL. Co-culture with cycloheximide mostly abrogated the induction of CD13, suggesting that CD13 expression was mainly dependent on de novo protein synthesis.

  13. Leukaemic infiltration and cytomegalovirus retinitis in a patient with acute T-cell lymphoblastic leukaemia in complete remission.

    Science.gov (United States)

    Saldaña Garrido, J D; Martínez Rubio, M; Carrión Campo, R; Moya Moya, M A; Rico Sergado, L

    2017-03-01

    A 43-year-old woman in remission from T- cell acute lymphoblastic leukaemia was referred to our hospital with suspected leukaemic retinitis. The funduscopic examination of her left eye revealed multifocal yellow-white peripheral retinitis and retinal haemorrhage. The patient was treated for cytomegalovirus retinitis after an extended haematological investigation showed no abnormalities. Initial improvement was followed by papillitis in the left eye and motility restriction in the right eye. Magnetic resonance and lumbar puncture confirmed leukaemia relapse. Specific treatment was initiated with complete resolution. Ocular involvement may precede haematological leukaemia relapse. Physicians should be alerted when ocular symptoms appear in these cases. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  14. Molecular Diagnostics, Targeted Therapy, and the Indication for Allogeneic Stem Cell Transplantation in Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Anthony Oyekunle

    2011-01-01

    Full Text Available In recent years, the panel of known molecular mutations in acute lymphoblastic leukemia (ALL has been continuously increased. In Philadelphia-positive ALL, deletions of the IKZF1 gene were identified as prognostically adverse factors. These improved insights in the molecular background and the clinical heterogeneity of distinct cytogenetic subgroups may allow most differentiated therapeutic decisions, for example, with respect to the indication to allogeneic HSCT within genetically defined ALL subtypes. Quantitative real-time PCR allows highly sensitive monitoring of the minimal residual disease (MRD load, either based on reciprocal gene fusions or immune gene rearrangements. Molecular diagnostics provided the basis for targeted therapy concepts, for example, combining the tyrosine kinase inhibitor imatinib with chemotherapy in patients with Philadelphia-positive ALL. Screening for BCR-ABL1 mutations in Philadelphia-positive ALL allows to identify patients who may benefit from second-generation tyrosine kinase inhibitors or from novel compounds targeting the T315I mutation. Considering the central role of the molecular techniques for the management of patients with ALL, efforts should be made to facilitate and harmonize immunophenotyping, cytogenetics, and molecular mutation screening. Furthermore, the potential of high-throughput sequencing should be evaluated for diagnosis and follow-up of patients with B-lineage ALL.

  15. Immunoglobulin genes and T-cell receptors as molecular markers in children with acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Lazić Jelena

    2009-01-01

    Full Text Available Introduction. Acute lymphoblastic leukaemia (ALL is a malignant clonal disease, one of the most common malignancies in childhood. Contemporary protocols ensure high remission rate and long term free survival. The ability of molecular genetic methods help to establish submicroscopic classification and minimal residual disease (MRD follow up, in major percent responsible for relapse. Objective. The aim of the study was to detect the frequency of IgH and TCR gene rearrangements and their correlation with clinical parameters. Methods. Forty-one children with ALL were enrolled in the study group, with initial diagnosis of IgH and TCR gene rearrangements by polimerase chain reaction ( PCR. MRD follow-up was performed in induction phase when morphological remission was expected, and after intensive chemiotherapy. Results. In the study group IgH rearrangement was detected in 82.9% of children at the diagnosis, while TCR rearrangement was seen in 56.1%. On induction day 33, clonal IgH rearrangements persisted in 39% and TCR rearrangements in 36.5% of children. Conclusion. Molecular analysis of genetic alterations and their correlation with standard prognostic parameters show the importance of risk stratification revision which leads to new therapy intensification approach. MRD stands out as a precise predictive factor for the relapse of disease.

  16. New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia

    Science.gov (United States)

    Moorman, Anthony V.

    2016-01-01

    Acute lymphoblastic leukemia (ALL) is a heterogeneous disease at the genetic level. Chromosomal abnormalities are used as diagnostic, prognostic and predictive biomarkers to provide subtype, outcome and drug response information. t(12;21)/ETV6-RUNX1 and high hyper-diploidy are good-risk prognostic biomarkers whereas KMT2A (MLL) translocations, t(17;19)/TCF3-HLF, haploidy or low hypodiploidy are high-risk biomarkers. t(9;22)/BCR-ABL1 patients require targeted treatment (imatinib/dasatinib), whereas iAMP21 patients achieve better outcomes when treated intensively. High-risk genetic biomarkers are four times more prevalent in adults compared to children. The application of genomic technologies to cases without an established abnormality (B-other) reveals copy number alterations which can be used either individually or in combination as prognostic biomarkers. Transcriptome sequencing studies have identified a network of fusion genes involving kinase genes - ABL1, ABL2, PDGFRB, CSF1R, CRLF2, JAK2 and EPOR. In vitro and in vivo studies along with emerging clinical observations indicate that patients with a kinase-activating aberration may respond to treatment with small molecular inhibitors like imatinib/dasatinib and ruxolitinib. Further work is required to determine the true frequency of these abnormalities across the age spectrum and the optimal way to incorporate such inhibitors into protocols. In conclusion, genetic biomarkers are playing an increasingly important role in the management of patients with ALL. PMID:27033238

  17. Piperlongumine inhibits the proliferation and survival of B-cell acute lymphoblastic leukemia cell lines irrespective of glucocorticoid resistance

    Energy Technology Data Exchange (ETDEWEB)

    Han, Seong-Su, E-mail: seong-su-han@uiowa.edu [Division of Pediatric Hematology-Oncology, University of Iowa Carver College of Medicine, Iowa City, IA (United States); Han, Sangwoo [Health and Human Physiology, University of Iowa Carver College of Medicine, Iowa City, IA (United States); Kamberos, Natalie L. [Division of Pediatric Hematology-Oncology, University of Iowa Carver College of Medicine, Iowa City, IA (United States)

    2014-09-26

    Highlights: • PL inhibits the proliferation of B-ALL cell lines irrespective of GC-resistance. • PL selectively kills B-ALL cells by increasing ROS, but not normal counterpart. • PL does not sensitize majority of B-ALL cells to DEX. • PL represses the network of constitutively activated TFs and modulates their target genes. • PL may serve as a new therapeutic molecule for GC-resistant B-ALL. - Abstract: Piperlongumine (PL), a pepper plant alkaloid from Piper longum, has anti-inflammatory and anti-cancer properties. PL selectively kills both solid and hematologic cancer cells, but not normal counterparts. Here we evaluated the effect of PL on the proliferation and survival of B-cell acute lymphoblastic leukemia (B-ALL), including glucocorticoid (GC)-resistant B-ALL. Regardless of GC-resistance, PL inhibited the proliferation of all B-ALL cell lines, but not normal B cells, in a dose- and time-dependent manner and induced apoptosis via elevation of ROS. Interestingly, PL did not sensitize most of B-ALL cell lines to dexamethasone (DEX). Only UoC-B1 exhibited a weak synergistic effect between PL and DEX. All B-ALL cell lines tested exhibited constitutive activation of multiple transcription factors (TFs), including AP-1, MYC, NF-κB, SP1, STAT1, STAT3, STAT6 and YY1. Treatment of the B-ALL cells with PL significantly downregulated these TFs and modulated their target genes. While activation of AURKB, BIRC5, E2F1, and MYB mRNA levels were significantly downregulated by PL, but SOX4 and XBP levels were increased by PL. Intriguingly, PL also increased the expression of p21 in B-ALL cells through a p53-independent mechanism. Given that these TFs and their target genes play critical roles in a variety of hematological malignancies, our findings provide a strong preclinical rationale for considering PL as a new therapeutic agent for the treatment of B-cell malignancies, including B-ALL and GC-resistant B-ALL.

  18. Piperlongumine inhibits the proliferation and survival of B-cell acute lymphoblastic leukemia cell lines irrespective of glucocorticoid resistance

    International Nuclear Information System (INIS)

    Han, Seong-Su; Han, Sangwoo; Kamberos, Natalie L.

    2014-01-01

    Highlights: • PL inhibits the proliferation of B-ALL cell lines irrespective of GC-resistance. • PL selectively kills B-ALL cells by increasing ROS, but not normal counterpart. • PL does not sensitize majority of B-ALL cells to DEX. • PL represses the network of constitutively activated TFs and modulates their target genes. • PL may serve as a new therapeutic molecule for GC-resistant B-ALL. - Abstract: Piperlongumine (PL), a pepper plant alkaloid from Piper longum, has anti-inflammatory and anti-cancer properties. PL selectively kills both solid and hematologic cancer cells, but not normal counterparts. Here we evaluated the effect of PL on the proliferation and survival of B-cell acute lymphoblastic leukemia (B-ALL), including glucocorticoid (GC)-resistant B-ALL. Regardless of GC-resistance, PL inhibited the proliferation of all B-ALL cell lines, but not normal B cells, in a dose- and time-dependent manner and induced apoptosis via elevation of ROS. Interestingly, PL did not sensitize most of B-ALL cell lines to dexamethasone (DEX). Only UoC-B1 exhibited a weak synergistic effect between PL and DEX. All B-ALL cell lines tested exhibited constitutive activation of multiple transcription factors (TFs), including AP-1, MYC, NF-κB, SP1, STAT1, STAT3, STAT6 and YY1. Treatment of the B-ALL cells with PL significantly downregulated these TFs and modulated their target genes. While activation of AURKB, BIRC5, E2F1, and MYB mRNA levels were significantly downregulated by PL, but SOX4 and XBP levels were increased by PL. Intriguingly, PL also increased the expression of p21 in B-ALL cells through a p53-independent mechanism. Given that these TFs and their target genes play critical roles in a variety of hematological malignancies, our findings provide a strong preclinical rationale for considering PL as a new therapeutic agent for the treatment of B-cell malignancies, including B-ALL and GC-resistant B-ALL

  19. Impact of cytogenetic abnormalities in adults with Ph-negative B-cell precursor acute lymphoblastic leukemia.

    Science.gov (United States)

    Lafage-Pochitaloff, Marina; Baranger, Laurence; Hunault, Mathilde; Cuccuini, Wendy; Lefebvre, Christine; Bidet, Audrey; Tigaud, Isabelle; Eclache, Virginie; Delabesse, Eric; Bilhou-Nabéra, Chrystèle; Terré, Christine; Chapiro, Elise; Gachard, Nathalie; Mozziconacci, Marie-Joelle; Ameye, Geneviève; Porter, Sarah; Grardel, Nathalie; Béné, Marie C; Chalandon, Yves; Graux, Carlos; Huguet, Françoise; Lhéritier, Véronique; Ifrah, Norbert; Dombret, Hervé

    2017-10-19

    Multiple cytogenetic subgroups have been described in adult Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), often comprising small numbers of patients. In this study, we aimed to reassess the prognostic value of cytogenetic abnormalities in a large series of 617 adult patients with Ph-negative BCP-ALL (median age, 38 years), treated in the intensified Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 trials. Combined data from karyotype, DNA index, fluorescence in situ hybridization, and polymerase chain reaction screening for relevant abnormalities were centrally reviewed and were informative in 542 cases (88%), allowing classification in 10 exclusive primary cytogenetic subgroups and in secondary subgroups, including complex and monosomal karyotypes. Prognostic analyses focused on cumulative incidence of failure (including primary refractoriness and relapse), event-free survival, and overall survival. Only 2 subgroups, namely t(4;11)/ KMT2A-AFF1 and 14q32/ IGH translocations, displayed a significantly worse outcome in this context, still observed after adjustment for age and after censoring patients who received allogeneic stem cell transplantation (SCT) in first remission at SCT time. A worse outcome was also observed in patients with low hypodiploidy/near triploidy, but this was likely related to their higher age and worse tolerance to therapy. The other cytogenetic abnormalities, including complex and monosomal karyotypes, had no prognostic value in these intensive protocols designed for adult patients up to the age of 60 years. © 2017 by The American Society of Hematology.

  20. Aberrant TAL1 activation is mediated by an interchromosomal interaction in human T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Patel, B; Kang, Y; Cui, K; Litt, M; Riberio, M S J; Deng, C; Salz, T; Casada, S; Fu, X; Qiu, Y; Zhao, K; Huang, S

    2014-02-01

    Long-range chromatin interactions control metazoan gene transcription. However, the involvement of intra- and interchromosomal interactions in development and oncogenesis remains unclear. TAL1/SCL is a critical transcription factor required for the development of all hematopoietic lineages; yet, aberrant TAL1 transcription often occurs in T-cell acute lymphoblastic leukemia (T-ALL). Here, we report that oncogenic TAL1 expression is regulated by different intra- and interchromosomal loops in normal hematopoietic and leukemic cells, respectively. These intra- and interchromosomal loops alter the cell-type-specific enhancers that interact with the TAL1 promoter. We show that human SET1 (hSET1)-mediated H3K4 methylations promote a long-range chromatin loop, which brings the +51 enhancer in close proximity to TAL1 promoter 1 in erythroid cells. The CCCTC-binding factor (CTCF) facilitates this long-range enhancer/promoter interaction of the TAL1 locus in erythroid cells while blocking the same enhancer/promoter interaction of the TAL1 locus in human T-cell leukemia. In human T-ALL, a T-cell-specific transcription factor c-Maf-mediated interchromosomal interaction brings the TAL1 promoter into close proximity with a T-cell-specific regulatory element located on chromosome 16, activating aberrant TAL1 oncogene expression. Thus, our study reveals a novel molecular mechanism involving changes in three-dimensional chromatin interactions that activate the TAL1 oncogene in human T-cell leukemia.

  1. The Role of Histone Protein Modifications and Mutations in Histone Modifiers in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Janczar, Szymon; Janczar, Karolina; Pastorczak, Agata; Harb, Hani; Paige, Adam J. W.; Zalewska-Szewczyk, Beata; Danilewicz, Marian; Mlynarski, Wojciech

    2017-01-01

    While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis. PMID:28054944

  2. Humanized CD7 nanobody-based immunotoxins exhibit promising anti-T-cell acute lymphoblastic leukemia potential.

    Science.gov (United States)

    Yu, Yuan; Li, Jialu; Zhu, Xuejun; Tang, Xiaowen; Bao, Yangyi; Sun, Xiang; Huang, Yuhui; Tian, Fang; Liu, Xiaomei; Yang, Lin

    2017-01-01

    Nanobodies, named as VHHs (variable domain of heavy chain of HCAb [heavy-chain antibodies]), are derived from heavy-chain-only antibodies that circulate in sera of camelids. Their exceptional physicochemical properties, possibility of humanization, and unique antigen recognition properties make them excellent candidates for targeted delivery of biologically active components, including immunotoxins. In our previous efforts, we have successfully generated the monovalent and bivalent CD7 nanobody-based immunotoxins, which can effectively trigger the apoptosis of CD7-positive malignant cells. To pursue the possibility of translating those immunotoxins into clinics, we humanized the nanobody sequences (designated as dhuVHH6) as well as further truncated the Pseudomonas exotoxin A (PE)-derived PE38 toxin to produce a more protease-resistant form, which is named as PE-LR, by deleting majority of PE domain II. Three new types of immunotoxins, dhuVHH6-PE38, dVHH6-PE-LR, and dhuVHH6-PE-LR, were successfully constructed. These recombinant immunotoxins were expressed in Escherichia coli and showed that nanobody immunotoxins have the benefits of easy soluble expression in a prokaryotic expression system. Flow cytometry results revealed that all immunotoxins still maintained the ability to bind specifically to CD7-positive T lymphocyte strains without binding to CD7-negative control cells. Laser scanning confocal microscopy revealed that these proteins can be endocytosed into the cytoplasm after binding with CD7-positive cells and that this phenomenon was not observed in CD7-negative cells. WST-8 experiments showed that all immunotoxins retained the highly effective and specific growth inhibition activity in CD7-positive cell lines and primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Further in vivo animal model experiments showed that humanized dhuVHH6-PE38 immunotoxin can tolerate higher doses and extend the survival of NOD-Prkdc em26 Il2rg em26 Nju (NCG) mice

  3. Preservation of high glycolytic phenotype by establishing new acute lymphoblastic leukemia cell lines at physiologic oxygen concentration.

    Science.gov (United States)

    Sheard, Michael A; Ghent, Matthew V; Cabral, Daniel J; Lee, Joanne C; Khankaldyyan, Vazgen; Ji, Lingyun; Wu, Samuel Q; Kang, Min H; Sposto, Richard; Asgharzadeh, Shahab; Reynolds, C Patrick

    2015-05-15

    Cancer cells typically exhibit increased glycolysis and decreased mitochondrial oxidative phosphorylation, and they continue to exhibit some elevation in glycolysis even under aerobic conditions. However, it is unclear whether cancer cell lines employ a high level of glycolysis comparable to that of the original cancers from which they were derived, even if their culture conditions are changed to physiologically relevant oxygen concentrations. From three childhood acute lymphoblastic leukemia (ALL) patients we established three new pairs of cell lines in both atmospheric (20%) and physiologic (bone marrow level, 5%) oxygen concentrations. Cell lines established in 20% oxygen exhibited lower proliferation, survival, expression of glycolysis genes, glucose consumption, and lactate production. Interestingly, the effects of oxygen concentration used during cell line initiation were only partially reversible when established cell cultures were switched from one oxygen concentration to another for eight weeks. These observations indicate that ALL cell lines established at atmospheric oxygen concentration can exhibit relatively low levels of glycolysis and these levels are semi-permanent, suggesting that physiologic oxygen concentrations may be needed from the time of cell line initiation to preserve the high level of glycolysis commonly exhibited by leukemias in vivo. Copyright © 2015. Published by Elsevier Inc.

  4. FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma.

    Science.gov (United States)

    Park, Myoung-Ja; Taki, Tomohiko; Oda, Megumi; Watanabe, Tomoyuki; Yumura-Yagi, Keiko; Kobayashi, Ryoji; Suzuki, Nobuhiro; Hara, Junichi; Horibe, Keizo; Hayashi, Yasuhide

    2009-04-01

    Mutation analysis of FBXW7 and NOTCH1 genes was performed in 55 T cell acute lymphoblastic leukaemia (T-ALL) and 14 T cell non-Hodgkin lymphoma (T-NHL) patients who were treated on the Japan Association of Childhood Leukaemia Study (JACLS) protocols ALL-97 and NHL-98. FBXW7 and/or NOTCH1 mutations were found in 22 (40.0%) of 55 T-ALL and 7 (50.0%) of 14 T-NHL patients. FBXW7 mutations were found in 8 (14.6%) of 55 T-ALL and 3 (21.4%) of 14 T-NHL patients, and NOTCH1 mutations in 17 (30.9%) of 55 T-ALL and 6 (42.9%) of 14 T-NHL patients. Three (5.4%) T-ALL and two (1.4%) T-NHL patients had mutations in both FBXW7 and NOTCH1. FBXW7 mutations included one insertion, one deletion, one deletion/insertion and nine missense mutations. NOTCH1 mutations were detected in the heterodimerization domain (HD) in 15 cases, in the PEST domain in seven cases, and in both the HD and PEST domains in one case. Five-year event-free survival and overall survival for patients with FBXW7 and/or NOTCH1 mutations were 95.5% (95% CI, 71.9-99.4%) and 100% respectively, suggesting that T-ALL patients with FBXW7 and/or NOTCH1 mutation represent a good prognosis compared to those without FBXW7 and/or NOTCH1 mutations (63.6%, P = 0.007 and 78.8%, P = 0.023, respectively).

  5. Humanized CD7 nanobody-based immunotoxins exhibit promising anti-T-cell acute lymphoblastic leukemia potential

    Directory of Open Access Journals (Sweden)

    Yu Y

    2017-03-01

    all immunotoxins still maintained the ability to bind specifically to CD7-positive T lymphocyte strains without binding to CD7-negative control cells. Laser scanning confocal microscopy revealed that these proteins can be endocytosed into the cytoplasm after binding with CD7-positive cells and that this phenomenon was not observed in CD7-negative cells. WST-8 experiments showed that all immunotoxins retained the highly effective and specific growth inhibition activity in CD7-positive cell lines and primary T-cell acute lymphoblastic leukemia (T-ALL cells. Further in vivo animal model experiments showed that humanized dhuVHH6-PE38 immunotoxin can tolerate higher doses and extend the survival of NOD-Prkdcem26Il2rgem26Nju (NCG mice transplanted with CEM cells without any obvious decrease in body weight. Further studies on NCG mice model with patient-derived T-ALL cells, dhuVHH6-PE38 treatment, significantly prolonged mice survival with ~40% survival improvement. However, it was also noticed that although dhuVHH6-PE-LR showed strong antitumor effect in vitro, its in vivo antitumor efficacy was disappointing. Conclusion: We have successfully constructed a targeted CD7 molecule-modified nanobody (CD7 molecule-improved nanobody immunotoxin dhuVHH6-PE38 and demonstrated its potential for treating CD7-positive malignant tumors, especially T-cell acute lymphoblastic leukemia. Keywords: CD7, humanized nanobody, T-cell acute lymphoblastic leukemia, patient-derived xenograft model, recombinant immunotoxins, Pseudomonas exotoxin A

  6. Identification of hepatic niche harboring human acute lymphoblastic leukemic cells via the SDF-1/CXCR4 axis.

    Directory of Open Access Journals (Sweden)

    Itaru Kato

    Full Text Available In acute lymphoblastic leukemia (ALL patients, the bone marrow niche is widely known to be an important element of treatment response and relapse. Furthermore, a characteristic liver pathology observed in ALL patients implies that the hepatic microenvironment provides an extramedullary niche for leukemic cells. However, it remains unclear whether the liver actually provides a specific niche. The mechanism underlying this pathology is also poorly understood. Here, to answer these questions, we reconstituted the histopathology of leukemic liver by using patients-derived primary ALL cells into NOD/SCID/Yc (null mice. The liver pathology in this model was similar to that observed in the patients. By using this model, we clearly demonstrated that bile duct epithelial cells form a hepatic niche that supports infiltration and proliferation of ALL cells in the liver. Furthermore, we showed that functions of the niche are maintained by the SDF-1/CXCR4 axis, proposing a novel therapeutic approach targeting the extramedullary niche by inhibition of the SDF-1/CXCR4 axis. In conclusion, we demonstrated that the liver dissemination of leukemia is not due to nonselective infiltration, but rather systematic invasion and proliferation of leukemic cells in hepatic niche. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells or leukemic niches such as bone marrow, we demonstrated that this axis works even in the extramedullary niche of leukemic cells. Our findings form the basis for therapeutic approaches that target the extramedullary niche by inhibiting the SDF-1/CXCR4 axis.

  7. Evidence for deterministic chaos in aperiodic oscillations of acute lymphoblastic leukemia cells in long-term culture

    Science.gov (United States)

    Lambrou, George I.; Chatziioannou, Aristotelis; Vlahopoulos, Spiros; Moschovi, Maria; Chrousos, George P.

    Biological systems are dynamic and possess properties that depend on two key elements: initial conditions and the response of the system over time. Conceptualizing this on tumor models will influence conclusions drawn with regard to disease initiation and progression. Alterations in initial conditions dynamically reshape the properties of proliferating tumor cells. The present work aims to test the hypothesis of Wolfrom et al., that proliferation shows evidence for deterministic chaos in a manner such that subtle differences in the initial conditions give rise to non-linear response behavior of the system. Their hypothesis, tested on adherent Fao rat hepatoma cells, provides evidence that these cells manifest aperiodic oscillations in their proliferation rate. We have tested this hypothesis with some modifications to the proposed experimental setup. We have used the acute lymphoblastic leukemia cell line CCRF-CEM, as it provides an excellent substrate for modeling proliferation dynamics. Measurements were taken at time points varying from 24h to 48h, extending the assayed populations beyond that of previous published reports that dealt with the complex dynamic behavior of animal cell populations. We conducted flow cytometry studies to examine the apoptotic and necrotic rate of the system, as well as DNA content changes of the cells over time. The cells exhibited a proliferation rate of nonlinear nature, as this rate presented oscillatory behavior. The obtained data have been fit in known models of growth, such as logistic and Gompertzian growth.

  8. PRAME overexpression predicted good outcome in pediatric B-cell acute lymphoblastic leukemia patients receiving chemotherapy.

    Science.gov (United States)

    Zhang, Yan-Huan; Lu, Ai-Dong; Yang, Lu; Li, Ling-Di; Chen, Wen-Min; Long, Ling-Yu; Zhang, Le-Ping; Qin, Ya-Zhen

    2017-01-01

    To investigate the prognostic value of PRAME expression in pediatric acute lymphoblastic leukemia(ALL), we measured PRAME transcript levels at diagnosis in 191 patients(146 B-ALL; 45T-ALL)receiving chemotherapy only. PRAME overexpression was defined as transcript levels higher than 0.30%, which is the upper limit of normal bone marrow and the optimal cutoff value derived from ROC curve analysis. PRAME overexpression was identified in 45.5% of patients. In B-ALL, PRAME overexpression was significantly associated with lower CIR(cumulative incidence of relapse), higher DFS (disease-freesurvival), and OS(overall survival) rates at 3 years, respectively (5.8% vs. 14.9%, P=0.014; 94.2% vs. 85.1%, P=0.014; 96.0% vs. 87.4%, P=0.039). PRAME overexpression had no impact on outcome in T-ALL patients. Among B-ALL patients with non-poor cytogenetic risk, those with PRAME overexpression showed significantly lower CIR, higher DFS and OS rates at 3 years, respectively (8.47% vs. 14.5%, P=0.009; 96.5% vs. 85.5%, P=0.009; 98.4% vs. 88.0%, P=0.023). Furthermore, PRAME overexpression was an independent good prognostic factor for relapse in all B-ALL patients and B-ALL patients with non-poor cytogenetic risk. Therefore, the prognostic significance of PRAME overexpression differed by ALL subtype; It predicted good outcome in pediatric B-ALL receiving chemotherapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Identification of CD34+ and CD34− leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia

    Science.gov (United States)

    Aoki, Yuki; Watanabe, Takashi; Saito, Yoriko; Kuroki, Yoko; Hijikata, Atsushi; Takagi, Masatoshi; Tomizawa, Daisuke; Eguchi, Mariko; Eguchi-Ishimae, Minenori; Kaneko, Akiko; Ono, Rintaro; Sato, Kaori; Suzuki, Nahoko; Fujiki, Saera; Koh, Katsuyoshi; Ishii, Eiichi; Shultz, Leonard D.; Ohara, Osamu; Mizutani, Shuki

    2015-01-01

    Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34+CD38+CD19+ and CD34−CD19+ cells initiated leukemia, and in MLL-AF9 patients, CD34−CD19+ cells were LICs. In MLL-ENL patients, either CD34+ or CD34− cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34+CD38−CD19−CD33− cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34+CD38−CD19−CD33− cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4+ single positive (SP), CD8+ SP, and CD4+CD8+ double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34+CD38+ and CD34− LICs but not in CD34+CD38−CD19−CD33− HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia. PMID:25538041

  10. The common oncogenomic program of NOTCH1 and NOTCH3 signaling in T-cell acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Sung Hee Choi

    Full Text Available Notch is a major oncogenic driver in T cell acute lymphoblastic leukemia (T-ALL, in part because it binds to an enhancer that increases expression of MYC. Here, we exploit the capacity of activated NOTCH1 and NOTCH3 to induce T-ALL, despite substantial divergence in their intracellular regions, as a means to elucidate a broad, common Notch-dependent oncogenomic program through systematic comparison of the transcriptomes and Notch-bound genomic regulatory elements of NOTCH1- and NOTCH3-dependent T-ALL cells. ChIP-seq studies show a high concordance of functional NOTCH1 and NOTCH3 genomic binding sites that are enriched in binding motifs for RBPJ, the transcription factor that recruits activated Notch to DNA. The interchangeability of NOTCH1 and NOTCH3 was confirmed by rescue of NOTCH1-dependent T-ALL cells with activated NOTCH3 and vice versa. Despite remarkable overall similarity, there are nuanced differences in chromatin landscapes near critical common Notch target genes, most notably at a Notch-dependent enhancer that regulates MYC, which correlates with responsiveness to Notch pathway inhibitors. Overall, a common oncogenomic program driven by binding of either Notch is sufficient to maintain T-ALL cell growth, whereas cell-context specific differences appear to influence the response of T-ALL cells to Notch inhibition.

  11. Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK.

    Science.gov (United States)

    Kim, Ekaterina; Hurtz, Christian; Koehrer, Stefan; Wang, Zhiqiang; Balasubramanian, Sriram; Chang, Betty Y; Müschen, Markus; Davis, R Eric; Burger, Jan A

    2017-03-02

    Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR + B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR + ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations. In pre-BCR + ALL, ibrutinib thwarted autonomous and induced pre-BCR signaling, resulting in deactivation of PI3K/Akt signaling. Ibrutinib modulated the expression of pre-BCR regulators (PTPN6, CD22, CD72, and PKCβ) and substantially reduced BCL6 levels. Ibrutinib inhibited ALL cell migration toward CXCL12 and beneath marrow stromal cells and reduced CD44 expression. CRISPR-Cas9 gene editing revealed that both BTK and B lymphocyte kinase (BLK) are relevant targets of ibrutinib in pre-BCR + ALL. Consequently, in mouse xenograft models of pre-BCR + ALL, ibrutinib treatment significantly prolonged survival. Combination treatment of ibrutinib with dexamethasone or vincristine demonstrated synergistic activity against pre-BCR + ALL. These data corroborate ibrutinib as a promising targeted agent for pre-BCR + ALL and highlight the importance of ibrutinib effects on alternative kinase targets. © 2017 by The American Society of Hematology.

  12. MicroRNA-125b-1 and BLID upregulation resulting from a novel IGH translocation in childhood B-Cell precursor acute lymphoblastic leukemia.

    Science.gov (United States)

    Tassano, Elisa; Acquila, Maura; Tavella, Elisa; Micalizzi, Concetta; Panarello, Claudio; Morerio, Cristina

    2010-08-01

    Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus are common abnormalities in mature B-cell neoplasms. Recent findings have also revealed their significant role in B-cell precursor acute lymphoblastic leukemia. As a rule, IGH translocations generate transcriptional activation of the oncogene localized in the proximity of the breakpoint. In this study, we describe a pediatric case of B-cell precursor acute lymphoblastic leukemia showing microRNA-125b-1 (MIR125B1) and BLID gene overexpression, resulting from a novel t(11;14)(q24.1;q32) translocation involving IGH. This is the first report describing the upregulation of a microRNA due to its juxtaposition to protein-coding gene regulatory elements and the overexpression of two neighboring genes as a consequence of transcriptional enhancers localized in the vicinity of the IGH gene.

  13. Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells

    Directory of Open Access Journals (Sweden)

    Zou Jie

    2013-01-01

    Full Text Available Abstract Background Notch1 is a potent regulator known to play an oncogenic role in many malignancies including T-cell acute lymphoblastic leukemia (T-ALL. Tumor hypoxia and increased hypoxia-inducible factor-1α (HIF-1α activity can act as major stimuli for tumor aggressiveness and progression. Although hypoxia-mediated activation of the Notch1 pathway plays an important role in tumor cell survival and invasiveness, the interaction between HIF-1α and Notch1 has not yet been identified in T-ALL. This study was designed to investigate whether hypoxia activates Notch1 signalling through HIF-1α stabilization and to determine the contribution of hypoxia and HIF-1α to proliferation, invasion and chemoresistance in T-ALL. Methods T-ALL cell lines (Jurkat, Sup-T1 transfected with HIF-1α or Notch1 small interference RNA (siRNA were incubated in normoxic or hypoxic conditions. Their potential for proliferation and invasion was measured by WST-8 and transwell assays. Flow cytometry was used to detect apoptosis and assess cell cycle regulation. Expression and regulation of components of the HIF-1α and Notch1 pathways and of genes related to proliferation, invasion and apoptosis were assessed by quantitative real-time PCR or Western blot. Results Hypoxia potentiated Notch1 signalling via stabilization and activation of the transcription factor HIF-1α. Hypoxia/HIF-1α-activated Notch1 signalling altered expression of cell cycle regulatory proteins and accelerated cell proliferation. Hypoxia-induced Notch1 activation increased the expression of matrix metalloproteinase-2 (MMP2 and MMP9, which increased invasiveness. Of greater clinical significance, knockdown of Notch1 prevented the protective effect of hypoxia/HIF-1α against dexamethasone-induced apoptosis. This sensitization correlated with losing the effect of hypoxia/HIF-1α on Bcl-2 and Bcl-xL expression. Conclusions Notch1 signalling is required for hypoxia/HIF-1α-induced proliferation

  14. Ezh2 Controls an Early Hematopoietic Program and Growth and Survival Signaling in Early T Cell Precursor Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Etienne Danis

    2016-03-01

    Full Text Available Early T cell precursor acute lymphoblastic leukemia (ETP-ALL is an aggressive subtype of ALL distinguished by stem-cell-associated and myeloid transcriptional programs. Inactivating alterations of Polycomb repressive complex 2 components are frequent in human ETP-ALL, but their functional role is largely undefined. We have studied the involvement of Ezh2 in a murine model of NRASQ61K-driven leukemia that recapitulates phenotypic and transcriptional features of ETP-ALL. Homozygous inactivation of Ezh2 cooperated with oncogenic NRASQ61K to accelerate leukemia onset. Inactivation of Ezh2 accentuated expression of genes highly expressed in human ETP-ALL and in normal murine early thymic progenitors. Moreover, we found that Ezh2 contributes to the silencing of stem-cell- and early-progenitor-cell-associated genes. Loss of Ezh2 also resulted in increased activation of STAT3 by tyrosine 705 phosphorylation. Our data mechanistically link Ezh2 inactivation to stem-cell-associated transcriptional programs and increased growth/survival signaling, features that convey an adverse prognosis in patients.

  15. Acute lymphoblastic leukemia in children with Down syndrome

    DEFF Research Database (Denmark)

    Buitenkamp, Trudy D; Izraeli, Shai; Zimmermann, Martin

    2014-01-01

    Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995...

  16. The evolving role of chemotherapy and hematopoietic cell transplants in Ph-positive acute lymphoblastic leukemia in adults.

    Science.gov (United States)

    Litzow, M R; Fielding, A K; Luger, S M; Paietta, E; Ofran, Y; Rowe, J M; Goldstone, A H; Tallman, M S; Lazarus, H M

    2017-12-01

    The introduction of the tyrosine kinase inhibitors (TKI) into the treatment of patients with Ph or BCR-ABL1-positive acute lymphoblastic leukemia has revolutionized the treatment of this poor prognosis acute leukemia. The combination of TKI with chemotherapy has improved response rates and allowed more patients to proceed to allogeneic hematopoietic cell transplant (alloHCT). Older patients have excellent responses to TKI and corticosteroids or in combination with minimal chemotherapy. This raises the question as to whether patients require full-intensity chemotherapy with TKI to achieve molecular remissions. The pediatricians have proposed that cure is achievable without alloHCT in children. These results have suggested that many patients may not require traditional chemotherapy in addition to TKI to achieve remission, and that patients who achieve a negative minimal residual disease state may not require alloHCT. The data in support of these questions is presented here and a suggested future clinical trial design based on these data is proposed.

  17. Is there a role for B lymphocyte chimerism in the monitoring of B-acute lymphoblastic leukemia patients receiving allogeneic stem cell transplantation?

    Directory of Open Access Journals (Sweden)

    Yi-Ning Yang

    2015-03-01

    Full Text Available Objective: To determine the sensitivity and significance of B-cell chimerism for the detection of early engraftment, transplant rejection, and disease relapse. Methods: The dynamic monitoring of lineage-specific cell subtypes (B, T, and NK cells was made in 20 B-cell acute lymphoblastic leukemia (B-ALL patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT. In the early period after allo-HSCT, the latest establishment of B-cell complete chimerism (CC was observed in a majority of patients. Results: The percentage of donor cells of B-cell lineage was lower than the percent of T-cell lineage in most of the mixed chimerism (MC patients. During graft rejection, the frequency of patients with decreasing MC of B-, T- and NK-cell lineage were 5/5, 2/5, and 2/5. When disease relapsed, five patients showed a faster decrease of the donor percent of B-cells than of T- or NK-cells. Only one patient displayed a more rapid decrease in NK-cells than in T- or B-cells. Conclusion: Monitoring of B-cell chimerism after HSCT seems to be valuable for insuring complete engraftment, anticipating graft rejection, and relapse in B-ALL patients. Keywords: B cell acute lymphoblastic leukemia (B-ALL, B-cell, T-cell, Chimerism, Allogeneic hematopoietic stem cell transplantation (allo-HSCT

  18. FBXW7 regulates glucocorticoid response in T-cell acute lymphoblastic leukaemia by targeting the glucocorticoid receptor for degradation.

    Science.gov (United States)

    Malyukova, A; Brown, S; Papa, R; O'Brien, R; Giles, J; Trahair, T N; Dalla Pozza, L; Sutton, R; Liu, T; Haber, M; Norris, M D; Lock, R B; Sangfelt, O; Marshall, G M

    2013-04-01

    Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor α (GRα) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 β-mediated phsophorylation. FBXW7 inactivation caused elevated GRα levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL samples, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GRα as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GRα levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies.

  19. Autophagy collaborates with ubiquitination to downregulate oncoprotein E2A/Pbx1 in B-cell acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Yuan, N; Song, L; Lin, W; Cao, Y; Xu, F; Liu, S; Zhang, A; Wang, Z; Li, X; Fang, Y; Zhang, H; Zhao, W; Hu, S; Wang, J; Zhang, S

    2015-01-01

    B-cell acute lymphoblastic leukemia (B-ALL) accounts for the most cancer incidences in children. We present here that autophagy is downregulated in pediatric B-ALL, suggesting a possible link between autophagy failure and pediatric B-ALL leukemogenesis. With a pediatric t(1;19) B-ALL xenograft mouse model, we show here that activation of autophagy by preventive administration of rapamycin improved the survival of leukemia animals by partial restoration of hematopoietic stem/progenitor cells, whereas treatment of the animals with rapamycin caused leukemia bone marrow cell-cycle arrest. Activation of autophagy in vitro or in vivo by rapamycin or starvation downregulated oncogenic fusion protein E2A/Pbx1. Furthermore, E2A/Pbx1 was found to be colocalized with autophagy marker LC3 in autolysosomes and with ubiquitin in response to autophagy stimuli, whereas autophagy or ubiquitination inhibitor blocked these colocalizations. Together, our data suggest a collaborative action between autophagy and ubiquitination in the degradation of E2A/Pbx1, thereby revealing a novel strategy for targeted preventive or treatment therapy on the pediatric ALL

  20. Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan

    International Nuclear Information System (INIS)

    Imamura, T; Kiyokawa, N; Kato, M; Imai, C; Okamoto, Y

    2016-01-01

    Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase–PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94 200/μl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined

  1. Chemotherapy alters the increased numbers of myeloid-derived suppressor and regulatory T cells in children with acute lymphoblastic leukemia.

    Science.gov (United States)

    Salem, Mohamed Labib; El-Shanshory, Mohamed R; Abdou, Said H; Attia, Mohamed S; Sobhy, Shymaa M; Zidan, Mona F; Zidan, Abdel-Aziz A

    2018-04-01

    Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children. The precise mechanism behind the relapse in this disease is not clearly known. One possible mechanism could be the accumulation of immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs) and T regulatory cells (T regs ) which we and others have reported to mediate suppression of anti-tumor immune responses. In this study, we aimed to analyze the numbers of these cells in a population of B-ALL pediatric patients. Peripheral blood samples withdrawn from B-ALL pediatric patients (n = 45 before, during and after the induction phase of chemotherapy. Using multi parametric flow cytometric analysis. MDSCs were identified as Lin - HLA-DR - CD33 + CD11b + ; and T reg cells were defined as CD4 + CD25 + CD127 -/low . Early diagnosed B-ALL patients showed significant increases in the numbers of MDSCs and T regs as compared to healthy volunteers. During induction of chemotherapy, however, the patients showed higher and lower numbers of MDSCs and T reg cells, respectively as compared to early diagnosed patients (i.e., before chemotherapy). After induction of chemotherapy, the numbers of MDSCs and T reg cells showed higher increases and decreases, respectively as compared to the numbers in patients during chemotherapy. Our results indicate that B-ALL patients harbor high numbers of both MDSCs and T regs cells. This pilot study opens a new avenue to investigate the mechanism mediating the emergence of these cells on larger number of B-ALL patients at different treatment stages.

  2. Acute Lymphoblastic Leukaemia presenting as Juvenile Idiopathic ...

    African Journals Online (AJOL)

    Background: Acute Lymphoblastic Leukaemia in children commonly presents with osteo articular manifestations that may mimic Juvenile Idiopathic Arthritis. This may create considerable diagnostic difficulty and lead to delay in commencing appropriate treatment. Case: An eight year old boy who presented with multiple ...

  3. Acute Lymphoblastic Leukemia Presented as Multiple Breast Masses

    International Nuclear Information System (INIS)

    Bayrak, Ilkay Koray; Yalin, Turkay; Ozmen, Zafer; Aksoz, Tolga; Doughanji, Roula

    2009-01-01

    Breast metastases in cases leukemia are very rare and occur primarily in patients with acute myeloid leukemia. We report the involvement of breast metastases in a 30-year-old woman with acute T cell lymphoblastic leukemia. The patient's mammograms revealed an extremely dense pattern with ill-defined, denser mass-like lesions in both breasts. A bilateral breast ultrasonographic evaluation revealed lobular-shaped and partly ill-defined hypoechoic masses with a multi-septated nodular (mottled) appearance

  4. RCSD1-ABL1 Translocation Associated with IKZF1 Gene Deletion in B-Cell Acute Lymphoblastic Leukemia

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    Shawana Kamran

    2015-01-01

    Full Text Available The RCSD1 gene has recently been identified as a novel gene fusion partner of the ABL1 gene in cases of B-cell Acute Lymphoblastic Leukemia (B-ALL. The RCSD1 gene is located at 1q23 and ABL1 is located at 9q34, so that the RCSD1-ABL1 fusion typically arises through a rare reciprocal translocation t(1;9(q23;q34. Only a small number of RCSD1-ABL1 positive cases of B-ALL have been described in the literature, and the full spectrum of clinical, morphological, immunophenotypic, and molecular features associated with this genetic abnormality has not been defined. We describe extensive genetic characterization of a case of B-ALL with RCSD1-ABL1 fusion, by using conventional cytogenetic analysis, Fluorescence In Situ Hybridization (FISH studies, and Chromosomal Microarray Analysis (CMA. The use of CMA resulted in detection of an approximately 70 kb deletion at 7p12.2, which caused a disruption of the IKZF1 gene. Deletions and mutations of IKZF1 are recurring abnormalities in B-ALL and are associated with a poor prognosis. Our findings highlight the association of the deletion of IKZF1 gene with the t(1;9(q24;q34 and illustrate the importance of comprehensive cytogenetic and molecular evaluation for accurate prediction of prognosis in patients with B-cell ALL.

  5. CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia.

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    Marco L Davila

    Full Text Available Although many adults with B cell acute lymphoblastic leukemia (B-ALL are induced into remission, most will relapse, underscoring the dire need for novel therapies for this disease. We developed murine CD19-specific chimeric antigen receptors (CARs and an immunocompetent mouse model of B-ALL that recapitulates the disease at genetic, cellular, and pathologic levels. Mouse T cells transduced with an all-murine CD3ζ/CD28-based CAR that is equivalent to the one being used in our clinical trials, eradicate B-ALL in mice and mediate long-term B cell aplasias. In this model, we find that increasing conditioning chemotherapy increases tumor eradication, B cell aplasia, and CAR-modified T cell persistence. Quantification of recipient B lineage cells allowed us to estimate an in vivo effector to endogenous target ratio for B cell aplasia maintenance. In mice exhibiting a dramatic B cell reduction we identified a small population of progenitor B cells in the bone marrow that may serve as a reservoir for long-term CAR-modified T cell stimulation. Lastly, we determine that infusion of CD8+ CAR-modified T cells alone is sufficient to maintain long-term B cell eradication. The mouse model we report here should prove valuable for investigating CAR-based and other therapies for adult B-ALL.

  6. on Lymphoblastic Leukemia Jurkat Cells

    African Journals Online (AJOL)

    human tumor cell line (Hela) by using MTT assay. [13]. In the present study, we have observed the cytotoxic effect of ethanolic extract of C. arvensis against Jurkat cells, a human lymphoblastic leukemia cell line, by using Trypan blue, MTS assay and FACS analysis. It was shown from the trypan blue exclusion assay that ...

  7. DIAGNOSIS AND SUBCLASSIFICATION OF ACUTE LYMPHOBLASTIC LEUKEMIA

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    Sabina Chiaretti

    2014-10-01

    Full Text Available Acute lymphoblastic leukemia (ALL is a disseminated malignancy of B- or T-lymphoblasts which imposes a rapid and accurate diagnostic process to support an optimal risk-oriented therapy and thus increase the curability rate. The need for a precise diagnostic algorithm is underlined by the awareness that both ALL therapy and related success rates may vary greatly in function of ALL subset, from standard chemotherapy in patients with standard-risk ALL, to allotransplantation (SCT and targeted therapy in high-risk patients and cases expressing suitable biological targets, respectively. This review offers a glimpse on how best identify ALL and the most relevant ALL subsets.

  8. Outcome of allogeneic hematopoietic stem cell transplantation for childhood acute lymphoblastic leukemia in second complete remission: a single institution study

    Directory of Open Access Journals (Sweden)

    Eun-Jung Lee

    2012-03-01

    Full Text Available Purpose : The survival rate for childhood acute lymphoblastic leukemia (ALL has improved significantly. However, overall prognosis for the 20 to 25% of patients who relapse is poor, and allogeneic hematopoietic stem cell transplantation (HSCT offers the best chance for cure. In this study, we identified significant prognostic variables by analyzing the outcomes of allogeneic HSCT in ALL patients in second complete remission (CR. Methods : Fifty-three ALL patients (42 men, 79% who received HSCT in second CR from August 1991 to February 2009 were included (26 sibling donor HSCTs, 49%; 42 bone marrow transplantations, 79%. Study endpoints included cumulative incidence of acute and chronic graft-versus-host disease (GVHD, relapse, 1-year transplant-related mortality (TRM, disease-free survival (DFS, and overall survival (OS. Results : Cumulative incidences of acute GVHD (grade 2 or above and chronic GVHD were 45.3% and 28.5%, respectively. The estimated 5-year DFS and OS for the cohort was 45.2¡?#?.8%; and 48.3¡?#?%,; respectively. Only donor type, i.e., sibling versus unrelated, showed significant correlation with DFS in multivariate analysis (P=0.010. The rates of relapse and 1 year TRM were 28.9¡?#?.4%; and 26.4¡?#?.1%;, respectively, and unrelated donor HSCT (P=0.002 and HLA mismatch (P =0.022 were significantly correlated with increased TRM in univariate analysis. Conclusion : In this single institution study spanning more than 17 years, sibling donor HSCT was the only factor predicting a favorable result in multivariate analysis, possibly due to increased TRM resulting from unrelated donor HSCT.

  9. Immunophenotypic investigation of infant acute lymphoblastic leukemia

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    A. M. Popov

    2012-01-01

    Full Text Available Aim of the study – immunophenotype description of infant acute lymphoblastic leukemia (ALL. 64 patients (29 boys and 35 girls with acute leukemia (AL aged from 0 to 11 months were included in the current study. ALL was found less frequently in infants than in older children (67.19 % and 87.69 %, respectively. BI-ALL was the most common immunological ALL type (60.46 % in infant ALL, while BII-ALL was notably less frequent compared with other age groups (30.23 %. Significant immunophenotypic differences were observed in patients with and without MLL gene rearrangements. Number of cases in those tumor cells expressed CD10, CD20, CD45, CD133, CD15, NG2 varied between MLL-positive and MLL-negative groups. CD10- and CD20-negativity, high CD45, CD15, CD65 and NG2 expression were immunophenotypic signatures of MLL-rearranged infant ALL, although NG2 had the highest diagnostic efficacy. High CD34 and CD65 expression was frequently associated with presence of MLL-AF4 fusion gene. Thus infants’ B-cell precursor ALL immunophenotype differs significantly due to the presence of MLL gene rearrangements. Diagnostic immunophenotyping of infants’ ALL allows predicting presence of MLL rearrangements and NG2 is the most applicable single marker.

  10. Immunophenotypic investigation of infant acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    A. M. Popov

    2014-07-01

    Full Text Available Aim of the study – immunophenotype description of infant acute lymphoblastic leukemia (ALL. 64 patients (29 boys and 35 girls with acute leukemia (AL aged from 0 to 11 months were included in the current study. ALL was found less frequently in infants than in older children (67.19 % and 87.69 %, respectively. BI-ALL was the most common immunological ALL type (60.46 % in infant ALL, while BII-ALL was notably less frequent compared with other age groups (30.23 %. Significant immunophenotypic differences were observed in patients with and without MLL gene rearrangements. Number of cases in those tumor cells expressed CD10, CD20, CD45, CD133, CD15, NG2 varied between MLL-positive and MLL-negative groups. CD10- and CD20-negativity, high CD45, CD15, CD65 and NG2 expression were immunophenotypic signatures of MLL-rearranged infant ALL, although NG2 had the highest diagnostic efficacy. High CD34 and CD65 expression was frequently associated with presence of MLL-AF4 fusion gene. Thus infants’ B-cell precursor ALL immunophenotype differs significantly due to the presence of MLL gene rearrangements. Diagnostic immunophenotyping of infants’ ALL allows predicting presence of MLL rearrangements and NG2 is the most applicable single marker.

  11. Immunophenotype and increased presence of CD4(+)CD25(+) regulatory T cells in patients with acute lymphoblastic leukemia.

    Science.gov (United States)

    Wu, Cui-Ping; Qing, Xi; Wu, Cui-Yun; Zhu, Hong; Zhou, Hai-Yan

    2012-02-01

    Acute lymphoblastic leukemia (ALL), cancer of the white blood cells, is a heterogeneous disease that mainly occurs due to the malignant cloning of original and naive lymphocytes. The aim of this study was to explore the immunophenotype, the percentage of CD4(+)CD25(+) regulatory T cells (Tregs) and the expression of cytokines interleukin (IL)-2, IL-10 and TGF-β in patients with ALL. The immunophenotype and levels of CD4(+)CD25(+) Tregs were detected using flow cytometry in the peripheral blood of 35 ALL patients, with 18 healthy individuals being selected as controls. The results suggested that 22 patients had B cell ALL (B-ALL) and 13 had T cell ALL (T-ALL) among the 35 ALL patients. In B-ALL patients, the surface antigen CD19 was most commonly expressed; in T-ALL patients, CD7 was most common. Furthermore, the percentage of CD4(+)CD25(+) Treg cells in the peripheral blood of B-ALL and T-ALL patients was higher compared to that of healthy individuals (Pcell culture supernatants from B-ALL and T-ALL patients were higher compared to those in the controls (Pcells, IL-2, IL-10 or TGF-β in B-ALL versus T-ALL patients. The authors concluded that CD19 and CD7 may serve as diagnostic markers of B-ALL and T-ALL, respectively. The increased presence of CD4(+)CD25(+) Treg cells and the altered levels of secreted cytokines are indicative of an immunosuppressive mechanism in the pathogenesis of ALL.

  12. Re-evaluation of DNA Index as a Prognostic Factor in Children with Precursor B Cell Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Noh, O Kyu; Park, Se Jin; Park, Hyeon Jin; Ju, HeeYoung; Han, Seung Hyon; Jung, Hyun Joo; Park, Jun Eun

    2017-09-01

    We aimed to investigate the prognostic value of DNA index (DI) in children with precursor B cell acute lymphoblastic lymphoma (pre-B ALL). From January 2003 to December 2014, 72 children diagnosed with pre-B ALL were analyzed. We analyzed the prognostic value of DI and its relations with other prognostic factors. The DI cut-point of 1.16 did not discriminate significantly the groups between high and low survivals (DI≥1.16 versus 1.90), and the survival of children with a DI between 1.00-1.90 were significantly higher than that of children with DI of 1.90 (5-year OS, 90.6% vs. 50.0%, p children with pre-B ALL. However, the DI divided by specific ranges of values remained an independent prognostic factor. Further studies are warranted to re-evaluate the prognostic value and cut-point of DI in children treated with recent treatment protocols. © 2017 by the Association of Clinical Scientists, Inc.

  13. Upregulation of microRNA-21 is a poor prognostic marker in patients with childhood B cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Labib, Hany Abedelmalik; Elantouny, Neveen G; Ibrahim, Nevin F; Alnagar, Ahmed A

    2017-08-01

    Many studies have demonstrated that microRNA-21 (miR-21) is an oncogene and is upregulated in tumor tissue. However, its association with B-cell acute lymphoblastic leukemia (B-ALL) remains poorly understood. The expression of miR-21 was detected by real-time quantitative PCR in 75 children with de novo B-ALL as well as in 50 healthy controls. This study was conducted to evaluate the miR-21 as a biomarker for risk assessment, diagnosis and prognosis. Compared with normal controls, miR-21 expression was significantly upregulated in childhood B-ALL patients. Using the receiver operating characteristic curve 3.23 was selected as the cut-off value of miR-21 expression in distinguishing patients from controls. Patients group with High miR-21 expression was significantly associated with those aged 10 years, lower platelets count, more incidence of CNS infiltration and poorer treatment outcome also, they showed a significantly poorer disease-free survival (DFS) and overall survival (OS) compared to those with low miR-21 expression group. Its expression was an independent prognostic marker according to multivariate analysis. This is the first report demonstrating the upregulation of miR-21 in childhood B-ALL, and its association with poor response to induction therapy, shorter DFS and OS. These results suggest that miR-21 upregulation represent an unfavorable prognostic marker in Childhood B-ALL.

  14. Epidemiology of acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Pendergrass, T.W.

    1985-01-01

    Although the etiology of acute leukemia is largely unknown, some facets of the puzzle are becoming clarified. Recognition of important patterns in age-specific mortality rates has suggested that events early in life, perhaps even prenatally, may have an influence on developing leukemia in childhood. The racial differences evident in mortality, incidence, and immunologic subtype of ALL suggest either differences in exposures to certain factors or differences in responses to those factors by white children. Hereditary factors appear to play a role. Familial and hereditary conditions exist that have high incidences of acute leukemia. Chromosomal anomalies are common in these conditions. Viral infections may play a role by contributing to alteration in genetic material through incorporation of the viral genome. How that virus is dealt with after primary infection seems important. The presence of immunodeficiency may allow wider dissemination or enhanced replication of such viruses, thereby increasing the likelihood of cellular transformation to an abnormal cell. Proliferation of that malignant cell to a clone may depend on other cofactors. Perhaps prolonged exposure to substances like benzene or alkylating agents may enhance these interactions between virus and genetic material. Does this change DNA repair mechanisms. Are viral infections handled differently. Is viral genomic information more easily integrated into host cells. Ionizing radiation has multiple effects. Alteration in genetic material occurs both at the molecular and chromosomal levels. DNA may be altered, lost, or added in the cell's attempt to recover from the injury

  15. New decision support tool for acute lymphoblastic leukemia classification

    Science.gov (United States)

    Madhukar, Monica; Agaian, Sos; Chronopoulos, Anthony T.

    2012-03-01

    In this paper, we build up a new decision support tool to improve treatment intensity choice in childhood ALL. The developed system includes different methods to accurately measure furthermore cell properties in microscope blood film images. The blood images are exposed to series of pre-processing steps which include color correlation, and contrast enhancement. By performing K-means clustering on the resultant images, the nuclei of the cells under consideration are obtained. Shape features and texture features are then extracted for classification. The system is further tested on the classification of spectra measured from the cell nuclei in blood samples in order to distinguish normal cells from those affected by Acute Lymphoblastic Leukemia. The results show that the proposed system robustly segments and classifies acute lymphoblastic leukemia based on complete microscopic blood images.

  16. How to train your T cell: genetically engineered chimeric antigen receptor T cells versus bispecific T-cell engagers to target CD19 in B acute lymphoblastic leukemia.

    Science.gov (United States)

    Ruella, Marco; Gill, Saar

    2015-06-01

    Antigen-specific T cell-based immunotherapy is getting its day in the sun. The contemporaneous development of two potent CD19-specific immunotherapeutic modalities for the treatment of B-cell malignancies provides exciting opportunities for patients, physicians and scientists alike. Patients with relapsed, refractory or poor-risk B-cell acute lymphoblastic leukemia (ALL) previously had few therapeutic options and now have two potential new lifelines. Physicians will have the choice between two powerful modalities and indeed could potentially enroll some patients on trials exploring both modalities if needed. For scientists interested in tumor immunology, the advent of chimeric antigen receptor T-cell therapy and of bispecific T-cell engagers (BiTEs) provides unprecedented opportunities to explore the promise and limitations of antigen-specific T-cell therapy in the context of human leukemia. In this article, we compare chimeric antigen receptor T cells and BiTEs targeting CD19 in B-cell ALL in the setting of the available clinical literature.

  17. Chemo-sensitivity in a panel of B-cell precursor acute lymphoblastic leukemia cell lines, YCUB series, derived from children.

    Science.gov (United States)

    Goto, Hiroaki; Naruto, Takuya; Tanoshima, Reo; Kato, Hiromi; Yokosuka, Tomoko; Yanagimachi, Masakatsu; Fujii, Hisaki; Yokota, Shumpei; Komine, Hiromi

    2009-10-01

    Sensitivity to 10 anticancer drugs was evaluated in 6 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cell lines. Authenticity of newly established cell lines was confirmed by genomic fingerprinting. The line YCUB-5R established at relapse was more resistant to 4-hydroperoxy-cyclophosphamide, cytarabine, L-asparaginase, topotecan, fludarabine, and etoposide than YCUB-5 from the same patient at diagnosis. Of the drugs tested, etoposide and SN-38 (irinotecan) showed highest efficacy in the panel, with 50% growth inhibition at 0.22-1.8 microg/ml and 0.57-3.6 ng/ml, respectively. This cell line panel offers an in vitro model for the development of new therapies for childhood BCP-ALL.

  18. Interleukin-7 receptor-α gene mutations are not detected in adult T-cell acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Rozovski, Uri; Li, Ping; Harris, David; Ohanian, Maro; Kantarjian, Hagop; Estrov, Zeev

    2014-01-01

    Somatic mutations in cancer cell genes are classified according to their functional significance. Those that provide the malignant cells with significant advantage are collectively referred to as driver mutations and those that do not, are the passenger mutations. Accordingly, analytical criteria to distinguish driver mutations from passenger mutations have been recently suggested. Recent studies revealed mutations in interleukin-7 receptor-α (IL7R) gene in 10% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients and in only a few cases of pediatric B-ALL. IL7R mutations are also frequently found in patients with lung cancer, but whereas in pediatric T-ALL IL7R mutations are “drivers” (consisting of gain-of-function mutations within a narrow 50-base pair interval at exon 6 that confer cytokine-independent cell growth and promote tumor transformation), in lung cancer, mutations are substitution mutations randomly distributed across the gene and are probably only “passenger” events. Because the treatment response of adult T-ALL is significantly poorer than that of childhood T-ALL and because exon 6 IL7R mutations play a role in the pathogenesis of childhood T-ALL, we sought to determine how the pattern of IL7R mutations varies between adult and childhood T-ALL. To that end, we sequenced the 50-base pair interval in exon 6 of the IL7R of DNA obtained from bone marrow samples of 35 randomly selected adult patients with T-ALL. Our analysis revealed that none of these 35 samples carried an IL7R mutation in exon 6. Whether differences in the genetic makeup of adult and childhood T-ALL explain the differential response to therapy remains to be determined

  19. The Role of Hematopoietic Stem-Cell Transplantation in First Remission in Pediatric Acute Lymphoblastic Leukemia: A Narrative Review

    Directory of Open Access Journals (Sweden)

    Neel S. Bhatt

    2017-05-01

    Full Text Available Context Survival after allogeneic hematopoietic stem-cell transplantation (HSCT for children with hematologic malignancies including acute lymphoblastic leukemia (ALL continues to improve in part due to advancement in HLA typing and enhanced supportive care. Despite improved outcomes with HSCT, the decision to offer it in first remission (CR1 in children with ALL remains a topic of debate and uncertainty. This review aims to discuss the role of HSCT in CR1 for children with high-risk subsets of ALL in the current era. Evidence Acquisition A thorough review of the literature was performed using electronic databases: PubMed, Google Scholar, and bibliographies. Studies focusing on high-risk subsets of ALL (Primary Induction Failure, Severe Hypodiploidy, Philadelphia-chromosome positive ALL, T-Cell ALL, Infant ALL, ALL with persistent minimal residual disease (MRD, and Philadelphia-like ALL were included. Publications in non- English language were excluded. Results Based on our review of the current literature, HSCT should be considered in first remission for patients with primary induction failure, severe hypodiploidy, T-cell ALL with poor response, high-risk infant ALL, and persistently positive MRD. In contrast, HSCT in CR1 may not be warranted for patients with early T-cell progenitor ALL or Philadelphia-chromosome positive ALL. Further data are needed to make specific recommendations regarding Philadelphia-like ALL. Conclusions As our understanding of high-risk leukemia biology continues to develop, the role of HSCT in ALL CR1 will need to be revisited.

  20. Brain Function in Young Patients Receiving Methotrexate for Acute Lymphoblastic Leukemia

    Science.gov (United States)

    2017-07-19

    Childhood B Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Cognitive Side Effects of Cancer Therapy; Long-Term Effects Secondary to Cancer Therapy in Children; Neurotoxicity Syndrome; Psychological Impact of Cancer; Untreated Childhood Acute Lymphoblastic Leukemia

  1. Establishment of a new human pre-B acute lymphoblastic leukemia cell line (KMO-90) with 1;19 translocation carrying p53 gene alterations.

    Science.gov (United States)

    Sotomatsu, M; Hayashi, Y; Kawamura, M; Yugami, S; Shitara, T

    1993-10-01

    A new human pre-B acute lymphoblastic leukemia cell line (KMO-90) was established from the bone marrow sample of a 12-year-old girl with acute lymphoblastic leukemia (ALL) carrying 1;19 chromosome translocation. KMO-90 cells expressed HLA-DR, CD10, CD19, and CD22 antigens. These cells had also cytoplasmic immunoglobulin lacking surface immunoglobulin, indicating that these had a pre-B phenotype. Chromosome analysis of this cell line showed 48, XX, +8, +19, t(1;19)(q23;p13). Southern blot analysis showed the same sized rearrangements of the E2A gene in KMO-90 cells as those in the original leukemic cells. By means of reverse transcriptase-polymerase chain reaction analysis, we detected E2A/PBX1 fusion transcripts in KMO-90 cells. KMO-90 is useful when studying the role of the 1;19 translocation in the etiology of pre-B ALL. Furthermore, we studied alterations of the p53 gene in this cell line by polymerase chain reaction, single-strand conformation polymorphism analysis. KMO-90 cells were identified to have a point mutation at codon 177 (CCC-->TCC) of the p53 gene, suggesting that alterations of the p53 gene may have an important role in the establishment of this cell line.

  2. DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Borssén, Magnus; Haider, Zahra; Landfors, Mattias; Norén-Nyström, Ulrika; Schmiegelow, Kjeld; Åsberg, Ann E; Kanerva, Jukka; Madsen, Hans O; Marquart, Hanne; Heyman, Mats; Hultdin, Magnus; Roos, Göran; Forestier, Erik; Degerman, Sofie

    2016-07-01

    Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y ) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD ≥0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making. © 2016 Wiley Periodicals, Inc.

  3. Effects of valproic acid and pioglitazone on cell cycle progression and proliferation of T-cell acute lymphoblastic leukemia Jurkat cells

    Directory of Open Access Journals (Sweden)

    Marie Saghaeian Jazi

    2016-07-01

    Full Text Available Objective(s: T-cell acute lymphoblastic leukemia (T-ALL is an aggressive hematologic malignant tumor. Administration of chemical compounds influencing apoptosis and T cell development has been discussed as promising novel therapeutic strategies. Valproic acid (VPA as a recently emerged anti-neoplastic histone deacetylase (HDAC inhibitor and pioglitazone (PGZ as a high-affinity peroxisome proliferator-activated receptor-gamma (PPARγ agonist have been shown to induce apoptosis and cell cycle arrest in different studies. Here, we aimed to investigate the underlying molecular mechanisms involved in anti-proliferative effects of these compounds on human Jurkat cells. Materials and Methods: Treated cells were evaluated for cell cycle progression and apoptosis using flowcytometry and MTT viability assay. Real-time RT-PCR was carried out to measure the alterations in key genes associated with cell death and cell cycle arrest. Results: Our findings illustrated that both VPA and PGZ can inhibit Jurkat E6.1 cells in vitro after   24 hr; however, PGZ 400 μM presents the most anti-proliferative effect. Interestingly, treated cells have been arrested in G2/M with deregulated cell division cycle 25A (Cdc25A phosphatase and cyclin-dependent kinase inhibitor 1B (CDKN1B or p27 expression. Expression of cyclin D1 gene was inhibited when DNA synthesis entry was declined. Cell cycle deregulation in PGZ and VPA-exposed cells generated an increase in the proportion of aneuploid cell population, which has not reported before. Conclusion: These findings define that anti-proliferative effects of PGZ and VPA on Jurkat cell line are mediated by cell cycle deregulation. Thus, we suggest PGZ and VPA may relieve potential therapeutic application against apoptosis-resistant malignancies.

  4. In Vitro Cytotoxic Effects of Cuscuta chinensis Whole Extract on Human Acute Lymphoblastic Leukemia Cell Line

    Directory of Open Access Journals (Sweden)

    Fatemeh Zeraati

    2010-12-01

    Full Text Available Background: One of the major paths for drug development isthe study of bioactivities of natural products. Therefore, theaim of this study was to compare the cytotoxic effects ofaqueous extract of whole Cuscuta chinensis Lam., which is atraditional medicinal herb commonly used in Iran and otheroriental countries, on the human caucasian acute lymphoblasticleukemia (CCRF-CEM and another human lymphocyte,Jurkat (JM cell lines.Methods: In vitro cytotoxic screening with various concentrations(0, 0.1, 1, 10, 25 and 50 μg/ml of the extract wasperformed using microscope and methyl tetrazolium bromidetest (MTT.Results: The minimum effective concentration of the plantextract was 1 μg/ml, and increasing the dose to 10 μg/mlinduced increasingly stronger effects. The inhibitory concentration50% (IC50 of the extract against CCRF wasabout 3 μg/ml in 24 hours and 2.5 μg/ml in 48 hrs. In contrast,the extract did not have cytotoxic effect for the JMcells at these doses.Conclusion: The findings of the present study suggest that C.chinensis is toxic against CCRF-CEM and JM tumor cells.Whether or not such effects can be employed for the treatmentof such tumors must await future studies.Iran J Med Sci 2010; 35(4: 310-314.

  5. MicroRNA-193b-3p acts as a tumor suppressor by targeting the MYB oncogene in T-cell acute lymphoblastic leukemia

    OpenAIRE

    Mets, E; Van der Meulen, J; Van Peer, G; Boice, M; Mestdagh, P; Van de Walle, I; Lammens, T; Goossens, S; De Moerloose, B; Benoit, Y; Van Roy, N; Clappier, E; Poppe, B; Vandesompele, J; Wendel, H-G

    2014-01-01

    The MYB oncogene is a leucine zipper transcription factor essential for normal and malignant hematopoiesis. In T-cell acute lymphoblastic leukemia (T-ALL), elevated MYB levels can arise directly through T-cell receptor-mediated MYB translocations, genomic MYB duplications or enhanced TAL1 complex binding at the MYB locus or indirectly through the TAL1/miR-223/FBXW7 regulatory axis. In this study, we used an unbiased MYB 3′untranslated region–microRNA (miRNA) library screen and identified 33 p...

  6. HA-1 T TCR T Cell Immunotherapy for the Treating of Patients With Relapsed or Refractory Acute Leukemia After Donor Stem Cell Transplant

    Science.gov (United States)

    2018-04-30

    HLA-A*0201 HA-1 Positive Cells Present; Minimal Residual Disease; Recurrent Acute Biphenotypic Leukemia; Recurrent Acute Undifferentiated Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

  7. Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia

    NARCIS (Netherlands)

    A. Holleman (Amy); M.L. den Boer (Monique); K.M. Kazemier (Karin); G.E. Janka-Schaub (Gritta); R. Pieters (Rob)

    2003-01-01

    textabstractResistance of leukemic cells to chemotherapeutic agents is associated with an unfavorable outcome in pediatric acute lymphoblastic leukemia (ALL). To investigate the underlying mechanisms of cellular drug resistance, the activation of various apoptotic parameters in

  8. Epigenetic analysis of childhood acute lymphoblastic leukemia.

    Science.gov (United States)

    Dunwell, Thomas L; Hesson, Luke B; Pavlova, Tatiana; Zabarovska, Veronika; Kashuba, Vladimir; Catchpoole, Daniel; Chiaramonte, Raffaella; Brini, Anna T; Griffiths, Mike; Maher, Eamonn R; Zabarovsky, Eugene; Latif, Farida

    2009-04-01

    We used a chromosome 3 wide NotI microarray for identification of epigenetically inactivated genes in childhood acute lymphoblastic leukemia (ALL). Three novel genes demonstrated frequent methylation in childhood ALL. PPP2R3A (protein phosphatase 2, regulatory subunit B", alpha) was frequently methylated in T (69%) and B (82%)-ALL. Whilst FBLN2 (fibulin 2) and THRB (thyroid hormone receptor, beta) showed frequent methylation in B-ALL (58%; 56% respectively), but were less frequently methylated in T-ALL (17% for both genes). Recently it was demonstrated that BNC1 (Basonuclin 1) and MSX1 (msh homeobox 1) were frequently methylated across common epithelial cancers. In our series of childhood ALL BNC1 was frequently methylated in both T (77%) and B-ALL (79%), whilst MSX1 showed T-ALL (25%) specific methylation. The methylation of the above five genes was cancer specific and expression of the genes could be restored in methylated leukemia cell lines treated with 5-aza-2'-deoxycytidine. This is the first report demonstrating frequent epigenetic inactivation of PPP2R3A, FBLN2, THRB, BNC1 and MSX1 in leukemia. The identification of frequently methylated genes showing cancer specific methylation will be useful in developing early cancer detection screens and for targeted epigenetic therapies.

  9. Allogeneic hematopoietic cell transplantation (allogeneic HCT) for treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

    Science.gov (United States)

    Burke, Michael J; Cao, Qing; Trotz, Barb; Weigel, Brenda; Kumar, Ashish; Smith, Angela; Verneris, Michael R

    2009-12-15

    Allogeneic hematopoietic cell transplant (HCT) with best available donor for children with Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) has previously been considered standard practice. Since the introduction of imatinib into the treatment of this disease, the role of allogeneic HCT is more uncertain. We investigated the impact of remission status, graft source, and imatinib use on transplant outcomes for 37 children with Ph+ ALL who received an allogeneic HCT at the University of Minnesota between 1990 and 2006. The median age at HCT was 7.47 (range; 1.4-16.4) years. Thirteen patients received imatinib therapy pre- and/or post-HCT (imatinib group) and 24 patients, received either no imatinib (n = 23) or only post-HCT relapse (n = 1) (non-imatinib group). There was no difference in disease-free survival (DFS) or relapse between the imatinib and non-imatinib groups at 3 years (62%/15% vs. 53%/26%; P = 0.99; 0.81, respectively). There was no significant difference in transplant outcomes between matched related donor or unrelated donor (umbilical cord blood or matched unrelated marrow) recipients whereas patients receiving allogeneic HCT in first remission (CR1) had superior DFS and less relapse compared to patients transplanted in >or=CR2 (71%/16% vs. 29%/36%; P = 0.01; P = 0.05). Based on this retrospective analysis at a single institution, the use of imatinib either pre- and/or post-transplant does not appear to significantly impact outcomes for children with Ph+ ALL and allogeneic HCT with the best available donor should be encouraged in CR1.

  10. Clonal origins of ETV6-RUNX1+ acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Alpar, D.; Wren, D.; Ermini, Luca

    2015-01-01

    Studies on twins with concordant acute lymphoblastic leukemia (ALL) have revealed that ETV6-RUNX1 gene fusion is a common, prenatal genetic event with other driver aberrations occurring subclonally and probably postnatally. The fetal cell type that is transformed by ETV6-RUNX1 is not identified...... by such studies or by the analysis of early B-cell lineage phenotype of derived progeny. Ongoing, clonal immunoglobulin (IG) and cross-lineage T-cell receptor (TCR) gene rearrangements are features of B-cell precursor leukemia and commence at the pro-B-cell stage of normal B-cell lineage development. We reasoned...

  11. Textural characteristics of bone marrow blast nucleus images with different variants of acute lymphoblastic leukemia

    Science.gov (United States)

    Nikitaev, V. G.; Pronichev, A. N.; Polyakov, E. V.; Mozhenkova, A. V.; Tupitsin, N. N.; Frenkel, M. A.

    2018-01-01

    The paper describes the method of recognition of T - and B - variants of acute lymphoblastic leukemia in microscopic images of blood cells. The method is based on the use of texture characteristics of images. Experimental recognition accuracy evaluation is obtained from the sample of 38 patients (17 with T-ALL and 21 with B-ALL variants of acute lymphoblastic leukemia). The obtained results show the possibility of applying of the proposed approach to the differential diagnosis of T- and B- variants of acute lymphoblastic leukemia.

  12. Acute Lymphoblastic Leukemia in a Man Treated With Fingolimod for Relapsing Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Stanley Cohan MD, PhD

    2015-03-01

    Full Text Available A man with relapsing multiple sclerosis, treated with fingolimod 0.5 mg/d for 15 months, developed acute lymphoblastic leukemia and died 4 months after immune ablation and bone marrow allograft, from graft versus host disease. To our knowledge, this is the first case of acute lymphoblastic leukemia reported in a patient treated with fingolimod. Although no causal relationship can be established between fingolimod use and acute lymphoblastic leukemia risk in this single case, future surveillance for lymphatic cell malignancies in patients treated with fingolimod appears justified.

  13. The role of ZAP70 kinase in acute lymphoblastic leukemia infiltration into the central nervous system.

    Science.gov (United States)

    Alsadeq, Ameera; Fedders, Henning; Vokuhl, Christian; Belau, Nele M; Zimmermann, Martin; Wirbelauer, Tim; Spielberg, Steffi; Vossen-Gajcy, Michaela; Cario, Gunnar; Schrappe, Martin; Schewe, Denis M

    2017-02-01

    Central nervous system infiltration and relapse are poorly understood in childhood acute lymphoblastic leukemia. We examined the role of zeta-chain-associated protein kinase 70 in preclinical models of central nervous system leukemia and performed correlative studies in patients. Zeta-chain-associated protein kinase 70 expression in acute lymphoblastic leukemia cells was modulated using short hairpin ribonucleic acid-mediated knockdown or ectopic expression. We show that zeta-chain-associated protein kinase 70 regulates CCR7/CXCR4 via activation of extracellular signal-regulated kinases. High expression of zeta-chain-associated protein kinase 70 in acute lymphoblastic leukemia cells resulted in a higher proportion of central nervous system leukemia in xenografts as compared to zeta-chain-associated protein kinase 70 low expressing counterparts. High zeta-chain-associated protein kinase 70 also enhanced the migration potential towards CCL19/CXCL12 gradients in vitro CCR7 blockade almost abrogated homing of acute lymphoblastic leukemia cells to the central nervous system in xenografts. In 130 B-cell precursor acute lymphoblastic leukemia and 117 T-cell acute lymphoblastic leukemia patients, zeta-chain-associated protein kinase 70 and CCR7/CXCR4 expression levels were significantly correlated. Zeta-chain-associated protein kinase 70 expression correlated with central nervous system disease in B-cell precursor acute lymphoblastic leukemia, and CCR7/CXCR4 correlated with central nervous system involvement in T-cell acute lymphoblastic leukemia patients. In multivariate analysis, zeta-chain-associated protein kinase 70 expression levels in the upper third and fourth quartiles were associated with central nervous system involvement in B-cell precursor acute lymphoblastic leukemia (odds ratio=7.48, 95% confidence interval, 2.06-27.17; odds ratio=6.86, 95% confidence interval, 1.86-25.26, respectively). CCR7 expression in the upper fourth quartile correlated with central

  14. High white blood cell count at diagnosis of childhood acute lymphoblastic leukaemia: biological background and prognostic impact. Results from the NOPHO ALL-92 and ALL-2000 studies

    DEFF Research Database (Denmark)

    Vaitkeviciene, G; Forestier, E; Hellebostad, M

    2011-01-01

    Prognostic impact of peripheral blood white blood cell count (WBC) at the diagnosis of childhood acute lymphoblastic leukaemia (ALL) was evaluated in a population-based consecutive series of 2666 children aged 1–15 treated for ALL between 1992 and 2008 in the five Nordic countries (Denmark, Finland.......58) and for T-ALL (pEFS5y 0.71 vs. 0.38). Whether the inferior EFS for the subset of patients with high WBC and slow initial response to treatment reflects rare or overlooked cytogenetic aberrations as well as the factors that determine WBC levels at diagnosis awaits exploration....

  15. The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia

    OpenAIRE

    Mansour, Marc R.; Sanda, Takaomi; Lawton, Lee N.; Li, Xiaoyu; Kreslavsky, Taras; Novina, Carl D.; Brand, Marjorie; Gutierrez, Alejandro; Kelliher, Michelle A.; Jamieson, Catriona H.M.; von Boehmer, Harald; Young, Richard A.; Look, A. Thomas

    2013-01-01

    The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1 occupancy by chromatin immunoprecipitation coupled to massively parallel DNA sequencing, we identified the miRNA genes directly controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GAT...

  16. A reliable Raman-spectroscopy-based approach for diagnosis, classification and follow-up of B-cell acute lymphoblastic leukemia

    Science.gov (United States)

    Managò, Stefano; Valente, Carmen; Mirabelli, Peppino; Circolo, Diego; Basile, Filomena; Corda, Daniela; de Luca, Anna Chiara

    2016-04-01

    Acute lymphoblastic leukemia type B (B-ALL) is a neoplastic disorder that shows high mortality rates due to immature lymphocyte B-cell proliferation. B-ALL diagnosis requires identification and classification of the leukemia cells. Here, we demonstrate the use of Raman spectroscopy to discriminate normal lymphocytic B-cells from three different B-leukemia transformed cell lines (i.e., RS4;11, REH, MN60 cells) based on their biochemical features. In combination with immunofluorescence and Western blotting, we show that these Raman markers reflect the relative changes in the potential biological markers from cell surface antigens, cytoplasmic proteins, and DNA content and correlate with the lymphoblastic B-cell maturation/differentiation stages. Our study demonstrates the potential of this technique for classification of B-leukemia cells into the different differentiation/maturation stages, as well as for the identification of key biochemical changes under chemotherapeutic treatments. Finally, preliminary results from clinical samples indicate high consistency of, and potential applications for, this Raman spectroscopy approach.

  17. T-cell acute lymphoblastic leukemia associated with complex karyotype and SET-NUP214 rearrangement: a case study and review of the literature.

    Science.gov (United States)

    Lee, Sang-Guk; Park, Tae Sung; Cho, Sun Young; Lim, Gayoung; Park, Gwang Jin; Oh, Seung Hwan; Cho, Eun Hae; Chong, So Young; Huh, Ji Young

    2011-01-01

    SET-NUP214 rearrangements have been rarely reported in T-cell acute lymphoblastic leukemia (T-ALL), acute undifferentiated leukemia, and acute myeloid leukemia, and most documented cases have been associated with normal karyotypes in conventional cytogenetic analyses. Here, we describe a novel case of T-ALL associated with a mediastinal mass and a SET-NUP214 rearrangement, which was masked by a complex karyotype at the time of initial diagnosis. Using multiplex reverse transcriptase-polymerase chain reaction analysis, we detected a cryptic SET-NUP214 rearrangement in our patient. As only 11 cases (including the present study) of T-ALL with SET-NUP214 rearrangement have been reported, the clinical features and treatment outcomes have not been fully determined. Further studies are necessary to evaluate the incidence of SET-NUP214 rearrangement in T-ALL patients and the treatment responses as well as prognosis of these patients.

  18. Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Bo Cai

    2016-11-01

    Full Text Available Abstract Background Elderly patients with relapsed and refractory acute lymphoblastic leukemia (ALL have poor prognosis. Autologous CD19 chimeric antigen receptor-modified T (CAR-T cells have potentials to cure patients with B cell ALL; however, safety and efficacy of allogeneic CD19 CAR-T cells are still undetermined. Case presentation We treated a 71-year-old female with relapsed and refractory ALL who received co-infusion of haplo-identical donor-derived CD19-directed CAR-T cells and mobilized peripheral blood stem cells (PBSC following induction chemotherapy. Undetectable minimal residual disease by flow cytometry was achieved, and full donor cell engraftment was established. The transient release of cytokines and mild fever were detected. Significantly elevated serum lactate dehydrogenase, alanine transaminase, bilirubin and glutamic-oxalacetic transaminase were observed from days 14 to 18, all of which were reversible after immunosuppressive therapy. Conclusions Our preliminary results suggest that co-infusion of haplo-identical donor-derived CAR-T cells and mobilized PBSCs may induce full donor engraftment in relapsed and refractory ALL including elderly patients, but complications related to donor cell infusions should still be cautioned. Trial registration Allogeneic CART-19 for Elderly Relapsed/Refractory CD19+ ALL. NCT02799550

  19. Effect of Taurine on Febrile Episodes in Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Mina Islambulchilar

    2015-03-01

    Full Text Available Purpose: The purpose of our study was to evaluate the effect of oral taurine on the incidence of febrile episodes during chemotherapy in young adults with acute lymphoblastic leukemia. Methods: Forty young adults with acute lymphoblastic leukemia, at the beginning of maintenance course of their chemotherapy, were eligible for this study. The study population was randomized in a double blind manner to receive either taurine or placebo (2 gram per day orally. Life quality and side effects including febrile episodes were assessed using questionnaire. Data were analyzed using Pearson’s Chi square test. Results: Of total forty participants, 43.8% were female and 56.3 % were male. The mean age was 19.16±1.95 years (ranges: 16-23 years. The results indicated that the levels of white blood cells are significantly (P<0.05 increased in taurine treated group. There was no elevation in blasts count. A total of 70 febrile episodes were observed during study, febrile episodes were significantly (P<0.05 lower in taurine patients in comparison to the control ones. Conclusion: The overall incidence of febrile episodes and infectious complications in acute lymphoblastic leukemia patients receiving taurine was lower than placebo group. Taurine’s ability to increase leukocyte count may result in lower febrile episodes.

  20. CD19/CD22 Chimeric Antigen Receptor T Cells and Chemotherapy in Treating Patients With Recurrent or Refractory CD19 Positive Diffuse Large B-Cell Lymphoma or B Acute Lymphoblastic Leukemia

    Science.gov (United States)

    2018-01-25

    B Acute Lymphoblastic Leukemia; CD19 Positive; Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Epstein-Barr Virus Positive Diffuse Large B-Cell Lymphoma of the Elderly; Minimal Residual Disease; Philadelphia Chromosome Positive; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

  1. Acute Lymphoblastic Leukemia Presented as Multiple Breast Masses

    Energy Technology Data Exchange (ETDEWEB)

    Bayrak, Ilkay Koray; Yalin, Turkay; Ozmen, Zafer; Aksoz, Tolga; Doughanji, Roula [Ondokuz Mayis University, Samsun (Turkmenistan)

    2009-10-15

    Breast metastases in cases leukemia are very rare and occur primarily in patients with acute myeloid leukemia. We report the involvement of breast metastases in a 30-year-old woman with acute T cell lymphoblastic leukemia. The patient's mammograms revealed an extremely dense pattern with ill-defined, denser mass-like lesions in both breasts. A bilateral breast ultrasonographic evaluation revealed lobular-shaped and partly ill-defined hypoechoic masses with a multi-septated nodular (mottled) appearance.

  2. Identification of residual leukemic cells by flow cytometry in childhood B-cell precursor acute lymphoblastic leukemia: verification of leukemic state by flow-sorting and molecular/cytogenetic methods

    DEFF Research Database (Denmark)

    Obro, Nina F; Ryder, Lars P; Madsen, Hans O

    2012-01-01

    Reduction in minimal residual disease, measured by real-time quantitative PCR or flow cytometry, predicts prognosis in childhood B-cell precursor acute lymphoblastic leukemia. We explored whether cells reported as minimal residual disease by flow cytometry represent the malignant clone harboring...... clone-specific genomic markers (53 follow-up bone marrow samples from 28 children with B-cell precursor acute lymphoblastic leukemia). Cell populations (presumed leukemic and non-leukemic) were flow-sorted during standard flow cytometry-based minimal residual disease monitoring and explored by PCR and....../or fluorescence in situ hybridization. We found good concordance between flow cytometry and genomic analyses in the individual flow-sorted leukemic (93% true positive) and normal (93% true negative) cell populations. Four cases with discrepant results had plausible explanations (e.g. partly informative...

  3. Discrimination and classification of acute lymphoblastic leukemia cells by Raman spectroscopy

    Science.gov (United States)

    Managò, Stefano; Valente, Carmen; Mirabelli, Peppino; De Luca, Anna Chiara

    2015-05-01

    Currently, a combination of technologies is typically required to identify and classify leukemia cells. These methods often lack the specificity and sensitivity necessary for early and accurate diagnosis. Here, we demonstrate the use of Raman spectroscopy to identify normal B cells, collected from healthy patients, and three ALL cell lines (RS4;11, REH and MN60 at different differentiation level, respectively). Raman markers associated with DNA and protein vibrational modes have been identified that exhibit excellent discriminating power for leukemia cell identification. Principal Component Analysis was finally used to confirm the significance of these markers for identify leukemia cells and classifying the data. The obtained results indicate a sorting accuracy of 96% between the three leukemia cell lines.

  4. Cell-targeted sup 114 In sup m and drug (BCNU) combination therapy in a rat acute lymphoblastic leukaemia. [Bischloroethylnitrosourea

    Energy Technology Data Exchange (ETDEWEB)

    Jackson, N.C.; Jackson, H.; Bock, M.; Sharma, H.L. (Manchester Univ. (United Kingdom). Dept. of Medical Biophysics); Ramsden, C. (Manchester Univ. (United Kingdom). Dept. of Immunology)

    1992-08-01

    A proportion of syngeneic female rats inoculated intramuscularly with a lethal T-cell lymphoblastic (Roser) leukaemia are cured by a single intraperitoneal injection of bischloroethylnitrosourea (BCNU) (Carmustine)(10 mg kg{sup -1}) given towards the end of the preleukaemic phase (day 7). Additional therapy on day 4, using intravenous leukaemia cells lethally labelled with the radionuclide {sup 114}In{sup m}, enhanced the overall cure rate by 30%. The spleen is a major site of indium concentration from the targeting cells so that the continuous local radiation field appears to result in a substantial reduction of the body load of leukaemia cells in the enlarged spleen particularly, thus enhancing the curative potential of the drug. The results demonstrate in principle that in patients in remission a single dose of targeted radiotherapy in the spleen combined sequentially with an appropriate drug might provide considerable aid in eliminating a residual population of leukaemia cells. (author).

  5. Acute Central Nervous System Complications in Pediatric Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Baytan, Birol; Evim, Melike Sezgin; Güler, Salih; Güneş, Adalet Meral; Okan, Mehmet

    2015-10-01

    The outcome of childhood acute lymphoblastic leukemia has improved because of intensive chemotherapy and supportive care. The frequency of adverse events has also increased, but the data related to acute central nervous system complications during acute lymphoblastic leukemia treatment are sparse. The purpose of this study is to evaluate these complications and to determine their long term outcome. We retrospectively analyzed the hospital reports of 323 children with de novo acute lymphoblastic leukemia from a 13-year period for acute neurological complications. The central nervous system complications of leukemic involvement, peripheral neuropathy, and post-treatment late-onset encephalopathy, and neurocognitive defects were excluded. Twenty-three of 323 children (7.1%) suffered from central nervous system complications during acute lymphoblastic leukemia treatment. The majority of these complications (n = 13/23; 56.5%) developed during the induction period. The complications included posterior reversible encephalopathy (n = 6), fungal abscess (n = 5), cerebrovascular lesions (n = 5), syndrome of inappropriate secretion of antidiuretic hormone (n = 4), and methotrexate encephalopathy (n = 3). Three of these 23 children (13%) died of central nervous system complications, one from an intracranial fungal abscess and the others from intracranial thrombosis. Seven of the survivors (n = 7/20; 35%) became epileptic and three of them had also developed mental and motor retardation. Acute central neurological complications are varied and require an urgent approach for proper diagnosis and treatment. Collaboration among the hematologist, radiologist, neurologist, microbiologist, and neurosurgeon is essential to prevent fatal outcome and serious morbidity. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Clinical Significance of Immuno phenotypic Markers in Pediatric T-cell Acute Lymphoblastic Leukemia

    International Nuclear Information System (INIS)

    SIDHOM, I.; SHAABAN, Kh.; SOLIMAN, S.; HAMDY, N.; YASSIN, D.; SALEM, Sh.; HASSANEIN, H.; MANSOUR, M.T.; EZZAT, S.; EL-ANWAR, W.

    2008-01-01

    Background: Cell-marker profiling has led to conflicting conclusions about its prognostic significance in T-ALL. Aim: To investigate the prevalence of the expression of CD34, CD10 and myeloid associated antigens (CD13/ CD33) in childhood T-ALL and to relate their presence to initial clinical and biologic features and early response to therapy. Patients and Methods: This study included 67 consecutive patients with newly diagnosed T-ALL recruited from the Children's Cancer Hospital in Egypt during the time period from July 2007 to June 2008. Immuno phenotypic markers and minimal residual disease (MRD) were studied by five-color flow cytometry. Results: The frequency of CD34 was 34.9%, CD10 33.3%, while CD13/CD33 was 18.8%. No significant association was encountered between CD34, CD10 or myeloid antigen positivity and the presenting clinical features as age, sex, TLC and CNS leukemia. Only CD10+ expression had significant association with initial CNS involvement (p=0.039). CD34 and CD13/CD33 expression was significantly associated with T-cell maturation stages (p<0.05). No relationship was observed for age, TLC, gender, NCI risk or CNS involvement with early response to therapy illustrated by BM as well as MRD day 15 and day 42. CD34+, CD13/CD33+ and early T-cell stage had high MRD levels on day 15 that was statistically highly significant (p<0.01), but CD10+ had statistically significant lower MRD level on day 15 (p=0.049). However, only CD34 retained its significance at an MRD cut-off level of 0.01%. Conclusion: CD34, CD10, CD13/CD33 expression, as well as T-cell maturation stages, may have prognostic significance in pediatric T-ALL as they have a significant impact on early clearance of leukemic cells detected by MRD day 15.

  7. The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia.

    Science.gov (United States)

    Furness, Caroline L; Mansur, Marcela B; Weston, Victoria J; Ermini, Luca; van Delft, Frederik W; Jenkinson, Sarah; Gale, Rosemary; Harrison, Christine J; Pombo-de-Oliveira, Maria S; Sanchez-Martin, Marta; Ferrando, Adolfo A; Kearns, Pamela; Titley, Ian; Ford, Anthony M; Potter, Nicola E; Greaves, Mel

    2018-03-20

    Single-cell genetics were used to interrogate clonal complexity and the sequence of mutational events in STIL-TAL1+ T-ALL. Single-cell multicolour FISH was used to demonstrate that the earliest detectable leukaemia subclone contained the STIL-TAL1 fusion and copy number loss of 9p21.3 (CDKN2A/CDKN2B locus), with other copy number alterations including loss of PTEN occurring as secondary subclonal events. In three cases, multiplex qPCR and phylogenetic analysis were used to produce branching evolutionary trees recapitulating the snapshot history of T-ALL evolution in this leukaemia subtype, which confirmed that mutations in key T-ALL drivers, including NOTCH1 and PTEN, were subclonal and reiterative in distinct subclones. Xenografting confirmed that self-renewing or propagating cells were genetically diverse. These data suggest that the STIL-TAL1 fusion is a likely founder or truncal event. Therapies targeting the TAL1 auto-regulatory complex are worthy of further investigation in T-ALL.

  8. Identification of residual leukemic cells by flow cytometry in childhood B-cell precursor acute lymphoblastic leukemia: verification of leukemic state by flow-sorting and molecular/cytogenetic methods.

    Science.gov (United States)

    Øbro, Nina F; Ryder, Lars P; Madsen, Hans O; Andersen, Mette K; Lausen, Birgitte; Hasle, Henrik; Schmiegelow, Kjeld; Marquart, Hanne V

    2012-01-01

    Reduction in minimal residual disease, measured by real-time quantitative PCR or flow cytometry, predicts prognosis in childhood B-cell precursor acute lymphoblastic leukemia. We explored whether cells reported as minimal residual disease by flow cytometry represent the malignant clone harboring clone-specific genomic markers (53 follow-up bone marrow samples from 28 children with B-cell precursor acute lymphoblastic leukemia). Cell populations (presumed leukemic and non-leukemic) were flow-sorted during standard flow cytometry-based minimal residual disease monitoring and explored by PCR and/or fluorescence in situ hybridization. We found good concordance between flow cytometry and genomic analyses in the individual flow-sorted leukemic (93% true positive) and normal (93% true negative) cell populations. Four cases with discrepant results had plausible explanations (e.g. partly informative immunophenotype and antigen modulation) that highlight important methodological pitfalls. These findings demonstrate that with sufficient experience, flow cytometry is reliable for minimal residual disease monitoring in B-cell precursor acute lymphoblastic leukemia, although rare cases require supplementary PCR-based monitoring.

  9. Matrine induced G0/G1 arrest and apoptosis in human acute T-cell lymphoblastic leukemia (T-ALL cells

    Directory of Open Access Journals (Sweden)

    Aslı Tetik Vardarlı

    2018-05-01

    Full Text Available Matrine, a natural product extracted from the root of Sophora flavescens, is a promising alternative drug in different types of cancer. Here, we aimed to investigate the therapeutic effects and underlying molecular mechanisms of matrine on human acute lymphoblastic leukemia (ALL cell line, CCRF-CEM. Cell viability and IC50 values were determined by WST-1 cell cytotoxicity assay. Cell cycle distribution and apoptosis rates were analyzed by flow cytometry. Expression patterns of 44 selected miRNAs and 44 RNAs were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR using the Applied Biosystems 7500 Fast Real-Time PCR System. Matrine inhibited cell viability and induced apoptosis of CCRF-CEM cells in a dose-dependent manner. Cell cycle analysis demonstrated that matrine-treated CCRF-CEM cells significantly accumulated in the G0/G1 phase compared with the untreated control cells. hsa-miR-376b-3p (-37.09 fold, p = 0.008 and hsa-miR-106b-3p (-16.67 fold, p = 0.028 expressions were decreased, whereas IL6 (95.47 fold, p = 0.000011 and CDKN1A (140.03 fold, p = 0.000159 expressions were increased after matrine treatment. Our results suggest that the downregulation of hsa-miR-106b-3p leads to the upregulation of target p21 gene, CDKN1A, and plays a critical role in the cell cycle progression by arresting matrine-treated cells in the G0/G1 phase.

  10. Acute lymphoblastic leukemia: a comprehensive review and 2017 update

    Science.gov (United States)

    Terwilliger, T; Abdul-Hay, M

    2017-01-01

    Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults, with an incidence of over 6500 cases per year in the United States alone. The hallmark of ALL is chromosomal abnormalities and genetic alterations involved in differentiation and proliferation of lymphoid precursor cells. In adults, 75% of cases develop from precursors of the B-cell lineage, with the remainder of cases consisting of malignant T-cell precursors. Traditionally, risk stratification has been based on clinical factors such age, white blood cell count and response to chemotherapy; however, the identification of recurrent genetic alterations has helped refine individual prognosis and guide management. Despite advances in management, the backbone of therapy remains multi-agent chemotherapy with vincristine, corticosteroids and an anthracycline with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of ALL. PMID:28665419

  11. miR-664 negatively regulates PLP2 and promotes cell proliferation and invasion in T-cell acute lymphoblastic leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Hong; Miao, Mei-hua; Ji, Xue-qiang; Xue, Jun; Shao, Xue-jun, E-mail: xuejunshao@hotmail.com

    2015-04-03

    MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in leukaemia, particularly T-cell acute lymphoblastic leukaemia (T-ALL), has remained elusive. Here, we identified miR-664 and its predicted target gene PLP2 were differentially expressed in T-ALL using bioinformatics methods. In T-ALL cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-664, while miR-664 inhibitor could significantly inhibited the proliferation. Moreover, migration and invasion assay showed that overexpression of miR-664 could significantly promoted the migration and invasion of T-ALL cells, whereas miR-664 inhibitor could reduce cell migration and invasion. luciferase assays confirmed that miR-664 directly bound to the 3'untranslated region of PLP2, and western blotting showed that miR-664 suppressed the expression of PLP2 at the protein levels. This study indicated that miR-664 negatively regulates PLP2 and promotes proliferation and invasion of T-ALL cell lines. Thus, miR-664 may represent a potential therapeutic target for T-ALL intervention. - Highlights: • miR-664 mimics promote the proliferation and invasion of T-ALL cells. • miR-664 inhibitors inhibit the proliferation and invasion of T-ALL cells. • miR-664 targets 3′ UTR of PLP2 in T-ALL cells. • miR-664 negatively regulates PLP2 in T-ALL cells.

  12. C22:0- and C24:0-dihydroceramides confer mixed cytotoxicity in T-cell acute lymphoblastic leukemia cell lines.

    Directory of Open Access Journals (Sweden)

    Michael W Holliday

    Full Text Available We previously reported that fenretinide (4-HPR was cytotoxic to acute lymphoblastic leukemia (ALL cell lines in vitro in association with increased levels of de novo synthesized dihydroceramides, the immediate precursors of ceramides. However, the cytotoxic potentials of native dihydroceramides have not been defined. Therefore, we determined the cytotoxic effects of increasing dihydroceramide levels via de novo synthesis in T-cell ALL cell lines and whether such cytotoxicity was dependent on an absolute increase in total dihydroceramide mass versus an increase of certain specific dihydroceramides. A novel method employing supplementation of individual fatty acids, sphinganine, and the dihydroceramide desaturase-1 (DES inhibitor, GT-11, was used to increase de novo dihydroceramide synthesis and absolute levels of specific dihydroceramides and ceramides. Sphingolipidomic analyses of four T-cell ALL cell lines revealed strong positive correlations between cytotoxicity and levels of C22:0-dihydroceramide (ρ = 0.74-0.81, P ≤ 0.04 and C24:0-dihydroceramide (ρ = 0.84-0.90, P ≤ 0.004, but not between total or other individual dihydroceramides, ceramides, or sphingoid bases or phosphorylated derivatives. Selective increase of C22:0- and C24:0-dihydroceramide increased level and flux of autophagy marker, LC3B-II, and increased DNA fragmentation (TUNEL assay in the absence of an increase of reactive oxygen species; pan-caspase inhibition blocked DNA fragmentation but not cell death. C22:0-fatty acid supplemented to 4-HPR treated cells further increased C22:0-dihydroceramide levels (P ≤ 0.001 and cytotoxicity (P ≤ 0.001. These data demonstrate that increases of specific dihydroceramides are cytotoxic to T-cell ALL cells by a caspase-independent, mixed cell death mechanism associated with increased autophagy and suggest that dihydroceramides may contribute to 4-HPR-induced cytotoxicity. The targeted increase of specific acyl chain dihydroceramides

  13. Myeloblastic and lymphoblastic markers in acute undifferentiated leukemia and chronic myelogenous leukemia in blast crisis.

    Science.gov (United States)

    Shumak, K H; Baker, M A; Taub, R N; Coleman, M S

    1980-11-01

    Blast cells were obtained from 17 patients with acute undifferentiated leukemia and 13 patients with chronic myelogenous leukemia in blast crisis. The blasts were tested with anti-i serum in cytotoxicity tests and with antisera to myeloblastic leukemia-associated antigens in immunofluorescence tests. The terminal deoxynucleotidyl transferase (TDT) content of the blasts was also measured. Lymphoblasts react strongly with anti-i, do not react with anti-myeloblast serum, and have high levels of TDT; myeloblasts react weakly with anti-i, do not react with anti-myeloblast serum, and have very low levels of TDT. Of the 17 patients with acute undifferentiated leukemia, there were six with blasts which reacted like lymphoblasts, six with blasts which reacted like myeloblasts, and five with blasts bearing different combinations of these lymphoblastic and myeloblastic markers. Eight of the 11 patients with lymphoblastic or mixed lymphoblastic-myeloblastic markers, but only one of the six with myeloblastic markers, achieved complete or partial remission in response to therapy. Thus, in acute undifferentiated leukemia, classification of blasts with these markers may be of prognostic value. Of the 13 patients with chronic myelogenous leukemia in blast crises, the markers were concordant (for myeloblasts) in only two cases. Three of the 13 patients had TDT-positive blasts, but the reactions of these cells with anti-i and with anti-myeloblast serum differed from those seen with lymphoblasts from patients with acute lymphoblastic leukemia. Although the cell involved in "lymphoid" blast crisis of chronic myelogenous leukemia is similar in many respects to that involved in acute lymphoblastic leukemia, these cells are not identical.

  14. Andrographolide inhibits growth of human T-cell acute lymphoblastic leukemia Jurkat cells by downregulation of PI3K/AKT and upregulation of p38 MAPK pathways

    Directory of Open Access Journals (Sweden)

    Yang T

    2016-04-01

    Full Text Available Tingfang Yang,1 Shuluan Yao,2 Xianfeng Zhang,3 Yan Guo2 1Department of Pediatrics, Jining No 1 People’s Hospital, Shandong Province, People’s Republic of China; 2Department of Respiratory Medicine, Jining Medical University Affiliated Hospital, Shandong Province, People’s Republic of China; 3Department of Psychiatry, Jining Psychiatric Hospital, Shandong Province, People’s Republic of China Abstract: T-cell acute lymphoblastic leukemia (T-ALL as a prevalent hematologic malignancy is one of the most common malignant tumors worldwide in children. Andrographolide (Andro, the major active component from Andrographis paniculata, has been shown to possess antitumor activities in several types of cancer cells. However, whether Andro would inhibit T-ALL cell growth remains unclear. In this study, we investigated the cytotoxic effect of Andro on human T-ALL Jurkat cells and explored the mechanisms of cell death. Cell apoptosis was assayed by flow cytometry, and the signaling transduction for Andro was analyzed by Western blotting. The results indicated 10 µg/mL Andro could significantly induce Jurkat cells’ apoptosis, depending on the inhibition of PI3K/AKT pathway. Moreover, Andro-induced apoptosis is enhanced by AKT-selective inhibitor LY294002. ERK- or JNK-selective inhibitors PD98059 and SP600125 had no effect on Andro-induced apoptosis. In addition, p38 inhibitor SB203580 could reverse Andro-induced apoptosis in Jurkat cells. We also found that the protein expression of p-p53 and p-p38 were increased after Andro treatments. The result of an in vivo study also demonstrated Andro’s dose-dependent inhibition in subcutaneous Jurkat xenografts. In conclusion, our findings explained a novel mechanism of drug action by Andro in Jurkat cells and suggested that Andro might be developed into a new candidate therapy for T-ALL patients in the coming days. Keywords: andrographolide, PI3K, AKT, Burkitt lymphoma, Jurkat cell

  15. Pathogenetic, Clinical, and Prognostic Features of Adult t(4;11(q21;q23/MLL-AF4 Positive B-Cell Acute Lymphoblastic Leukemia

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    F. Marchesi

    2011-01-01

    Full Text Available Translocation t(4;11(q21;q23 leading to formation of MLL-AF4 fusion gene is found in about 10% of newly diagnosed B-cell acute lymphoblastic leukemia (ALL in adult patients. Patients expressing this chromosomal aberration present typical biological, immunophenotypic, and clinical features. This form of leukemia is universally recognized as high-risk leukemia and treatment intensification with allogeneic hematopoietic stem cell transplantation (HSCT in first complete remission (CR could be a valid option to improve prognosis, but data obtained from the literature are controversial. In this review, we briefly describe pathogenetic, clinical, and prognostic characteristics of adult t(4;11(q21;q23/MLL-AF4 positive ALL and provide a review of the clinical outcome reported by the most important cooperative groups worldwide.

  16. Andrographolide inhibits growth of human T-cell acute lymphoblastic leukemia Jurkat cells by downregulation of PI3K/AKT and upregulation of p38 MAPK pathways

    Science.gov (United States)

    Yang, Tingfang; Yao, Shuluan; Zhang, Xianfeng; Guo, Yan

    2016-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) as a prevalent hematologic malignancy is one of the most common malignant tumors worldwide in children. Andrographolide (Andro), the major active component from Andrographis paniculata, has been shown to possess antitumor activities in several types of cancer cells. However, whether Andro would inhibit T-ALL cell growth remains unclear. In this study, we investigated the cytotoxic effect of Andro on human T-ALL Jurkat cells and explored the mechanisms of cell death. Cell apoptosis was assayed by flow cytometry, and the signaling transduction for Andro was analyzed by Western blotting. The results indicated 10 μg/mL Andro could significantly induce Jurkat cells’ apoptosis, depending on the inhibition of PI3K/AKT pathway. Moreover, Andro-induced apoptosis is enhanced by AKT-selective inhibitor LY294002. ERK- or JNK-selective inhibitors PD98059 and SP600125 had no effect on Andro-induced apoptosis. In addition, p38 inhibitor SB203580 could reverse Andro-induced apoptosis in Jurkat cells. We also found that the protein expression of p-p53 and p-p38 were increased after Andro treatments. The result of an in vivo study also demonstrated Andro’s dose-dependent inhibition in subcutaneous Jurkat xenografts. In conclusion, our findings explained a novel mechanism of drug action by Andro in Jurkat cells and suggested that Andro might be developed into a new candidate therapy for T-ALL patients in the coming days. PMID:27114702

  17. Regulatory network of GATA3 in pediatric acute lymphoblastic leukemia

    OpenAIRE

    Hou, Qianqian; Liao, Fei; Zhang, Shouyue; Zhang, Duyu; Zhang, Yan; Zhou, Xueyan; Xia, Xuyang; Ye, Yuanxin; Yang, Hanshuo; Li, Zhaozhi; Wang, Leiming; Wang, Xi; Ma, Zhigui; Zhu, Yiping; Ouyang, Liang

    2017-01-01

    GATA3 polymorphisms were reported to be significantly associated with susceptibility of pediatric B-lineage acute lymphoblastic leukemia (ALL), by impacting on GATA3 expression. We noticed that ALL-related GATA3 polymorphism located around in the tissue-specific enhancer, and significantly associated with GATA3 expression. Although the regulatory network of GATA3 has been well reported in T cells, the functional status of GATA3 is poorly understood in B-ALL. We thus conducted genome-wide gene...

  18. Lymphoid Progenitor Cells from Childhood Acute Lymphoblastic Leukemia Are Functionally Deficient and Express High Levels of the Transcriptional Repressor Gfi-1

    Directory of Open Access Journals (Sweden)

    Jessica Purizaca

    2013-01-01

    Full Text Available Acute lymphoblastic leukemia (ALL is the most frequent malignancy of childhood. Substantial progress on understanding the cell hierarchy within ALL bone marrow (BM has been recorded in the last few years, suggesting that both primitive cell fractions and committed lymphoid blasts with immature stem cell-like properties contain leukemia-initiating cells. Nevertheless, the biology of the early progenitors that initiate the lymphoid program remains elusive. The aim of the present study was to investigate the ability of lymphoid progenitors from B-cell precursor ALL BM to proliferate and undergo multilineage differentiation. By phenotype analyses, in vitro proliferation assays, and controlled culture systems, the lymphoid differentiation potentials were evaluated in BM primitive populations from B-cell precursor ALL pediatric patients. When compared to their normal counterparts, functional stem and progenitor cell contents were substantially reduced in ALL BM. Moreover, neither B nor NK or dendritic lymphoid-cell populations developed recurrently from highly purified ALL-lymphoid progenitors, and their proliferation and cell cycle status revealed limited proliferative capacity. Interestingly, a number of quiescence-associated transcription factors were elevated, including the transcriptional repressor Gfi-1, which was highly expressed in primitive CD34+ cells. Together, our findings reveal major functional defects in the primitive hematopoietic component of ALL BM. A possible contribution of high levels of Gfi-1 expression in the regulation of the stem/progenitor cell biology is suggested.

  19. Posterior reversible encephalopathy syndrome in a B-cell acute lymphoblastic leukemia young adult patient treated with a pediatric-like chemotherapeutic schedule

    Directory of Open Access Journals (Sweden)

    Cristina Papayannidis

    2014-09-01

    Full Text Available We report here the case of a young adult affected by pre B-cell acute lymphoblastic leukemia (ALL, who developed, during a pediatric-like chemotherapy consolidation schedule with high dosage of Methotrexate, a severe neurological toxicity. Clinical presentation and neuroimaging data were diagnostic for posterior reversible encephalopathy syndrome (PRES. A complete resolution was quickly obtained with medical blood pressure control and anticonvulsants administration. To the best of our knowledge, this is the first case of PRES described in the adult ALL setting. Currently, the clinical management of this aggressive disease is moving towards a pediatric-like approach also in adult patients, due to the better outcome reached with intensive chemotherapeutic regimens in children population. However, therapy-related toxicities have to be taken into account, since their onset may adversely affect patients’ clinical outcome.

  20. IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study.

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    Yunlei Li

    2016-12-01

    Full Text Available Pediatric acute lymphoblastic leukemia (ALL is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with resistance to treatment, including steroids, which are currently the cornerstone for treating ALL; moreover, initial steroid response strongly predicts survival and cure. However, the cellular mechanisms underlying steroid resistance in T-ALL patients are poorly understood. In this study, we combined various genomic datasets in order to identify candidate genetic mechanisms underlying steroid resistance in children undergoing T-ALL treatment.We performed whole genome sequencing on paired pre-treatment (diagnostic and post-treatment (remission samples from 13 patients, and targeted exome sequencing of pre-treatment samples from 69 additional T-ALL patients. We then integrated mutation data with copy number data for 151 mutated genes, and this integrated dataset was tested for associations of mutations with clinical outcomes and in vitro drug response. Our analysis revealed that mutations in JAK1 and KRAS, two genes encoding components of the interleukin 7 receptor (IL7R signaling pathway, were associated with steroid resistance and poor outcome. We then sequenced JAK1, KRAS, and other genes in this pathway, including IL7R, JAK3, NF1, NRAS, and AKT, in these 69 T-ALL patients and a further 77 T-ALL patients. We identified mutations in 32% (47/146 of patients, the majority of whom had a specific T-ALL subtype (early thymic progenitor ALL or TLX. Based on the outcomes of these patients and their prednisolone responsiveness measured in vitro, we then confirmed that these mutations were associated with both steroid resistance and poor outcome. To explore how these mutations in IL7R signaling pathway genes cause steroid resistance and subsequent poor outcome, we expressed wild

  1. IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study

    Science.gov (United States)

    Stubbs, Andrew P.; Vroegindeweij, Eric M.; Smits, Willem K.; van Marion, Ronald; Dinjens, Winand N. M.; Horstmann, Martin; Kuiper, Roland P.; Zaman, Guido J. R.; van der Spek, Peter J.; Pieters, Rob; Meijerink, Jules P. P.

    2016-01-01

    Background Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with resistance to treatment, including steroids, which are currently the cornerstone for treating ALL; moreover, initial steroid response strongly predicts survival and cure. However, the cellular mechanisms underlying steroid resistance in T-ALL patients are poorly understood. In this study, we combined various genomic datasets in order to identify candidate genetic mechanisms underlying steroid resistance in children undergoing T-ALL treatment. Methods and Findings We performed whole genome sequencing on paired pre-treatment (diagnostic) and post-treatment (remission) samples from 13 patients, and targeted exome sequencing of pre-treatment samples from 69 additional T-ALL patients. We then integrated mutation data with copy number data for 151 mutated genes, and this integrated dataset was tested for associations of mutations with clinical outcomes and in vitro drug response. Our analysis revealed that mutations in JAK1 and KRAS, two genes encoding components of the interleukin 7 receptor (IL7R) signaling pathway, were associated with steroid resistance and poor outcome. We then sequenced JAK1, KRAS, and other genes in this pathway, including IL7R, JAK3, NF1, NRAS, and AKT, in these 69 T-ALL patients and a further 77 T-ALL patients. We identified mutations in 32% (47/146) of patients, the majority of whom had a specific T-ALL subtype (early thymic progenitor ALL or TLX). Based on the outcomes of these patients and their prednisolone responsiveness measured in vitro, we then confirmed that these mutations were associated with both steroid resistance and poor outcome. To explore how these mutations in IL7R signaling pathway genes cause steroid resistance and subsequent poor outcome, we

  2. CD20 positivity and white blood cell count predict treatment outcomes in Philadelphia chromosome-negative acute lymphoblastic leukemia patients ineligible for pediatric-inspired chemotherapy.

    Science.gov (United States)

    Isshiki, Yusuke; Ohwada, Chikako; Sakaida, Emiko; Onoda, Masahiro; Aotsuka, Nobuyuki; Tanaka, Hiroaki; Fukazawa, Motoharu; Cho, Ryuko; Sugawara, Takeaki; Kawaguchi, Takeharu; Hara, Satoru; Yokota, Akira

    2017-11-01

    The efficacy of conventional chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been controversial as post-remission therapies for adult Philadelphia chromosome-negative acute lymphoblastic leukemia patients. We retrospectively analyzed 96 adolescent and adult cases of Philadelphia chromosome-negative acute lymphoblastic leukemia to evaluate whether allo-HSCT should be performed after first complete remission (1CR). In total, 34 patients received chemotherapy followed by allo-HSCT (HSCT group) and 62 received chemotherapy alone (chemotherapy group). No significant differences in the event-free survival (EFS) or overall survival were observed between the two groups. In the chemotherapy group, use of pediatric regimens was significantly associated with favorable EFS, while high white blood cell (WBC) count and CD20 positivity were associated with poor outcome. In patients who received pediatric regimens, subsequent allo-HSCT did not influence EFS. In patients who received conventional chemotherapy (adult regimen), subsequent allo-HSCT did not improve EFS. High WBC count and CD20 positivity were also significantly associated with poor EFS in patients who received adult regimens. Patients with low WBC count and absence of CD20 who received adult regimens did not benefit from allo-HSCT. Allo-HSCT may not be required in the pediatric regimen-eligible patients; however, pediatric regimen-ineligible patients with either CD20 positivity or high WBC count should receive allo-HSCT after achieving 1CR. This study was registered at http://www.umin.ac.jp/ctr/ as #C000016287. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  3. Biological, functional and genetic characterization of bone marrow-derived mesenchymal stromal cells from pediatric patients affected by acute lymphoblastic leukemia.

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    Antonella Conforti

    Full Text Available Alterations in hematopoietic microenvironment of acute lymphoblastic leukemia patients have been claimed to occur, but little is known about the components of marrow stroma in these patients. In this study, we characterized mesenchymal stromal cells (MSCs isolated from bone marrow (BM of 45 pediatric patients with acute lymphoblastic leukemia (ALL-MSCs at diagnosis (day+0 and during chemotherapy treatment (days: +15; +33; +78, the time points being chosen according to the schedule of BM aspirates required by the AIEOP-BFM ALL 2009 treatment protocol. Morphology, proliferative capacity, immunophenotype, differentiation potential, immunomodulatory properties and ability to support long-term hematopoiesis of ALL-MSCs were analysed and compared with those from 41 healthy donors (HD-MSCs. ALL-MSCs were also genetically characterized through array-CGH, conventional karyotyping and FISH analysis. Moreover, we compared ALL-MSCs generated at day+0 with those isolated during chemotherapy. Morphology, immunophenotype, differentiation potential and in vitro life-span did not differ between ALL-MSCs and HD-MSCs. ALL-MSCs showed significantly lower proliferative capacity (p<0.001 and ability to support in vitro hematopoiesis (p = 0.04 as compared with HD-MSCs, while they had similar capacity to inhibit in vitro mitogen-induced T-cell proliferation (p = N.S.. ALL-MSCs showed neither the typical translocations carried by the leukemic clone (when present, nor other genetic abnormalities acquired during ex vivo culture. Our findings indicate that ALL-MSCs display reduced ability to proliferate and to support long-term hematopoiesis in vitro. ALL-MSCs isolated at diagnosis do not differ from those obtained during treatment.

  4. Expression, regulation and function of phosphofructo-kinase/fructose-biphosphatases (PFKFBs) in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia cells

    International Nuclear Information System (INIS)

    Carlet, Michela; Kofler, Reinhard; Janjetovic, Kristina; Rainer, Johannes; Schmidt, Stefan; Panzer-Grümayer, Renate; Mann, Georg; Prelog, Martina; Meister, Bernhard; Ploner, Christian

    2010-01-01

    Glucocorticoids (GCs) cause apoptosis and cell cycle arrest in lymphoid cells and constitute a central component in the therapy of lymphoid malignancies, most notably childhood acute lymphoblastic leukemia (ALL). PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-2), a kinase controlling glucose metabolism, was identified by us previously as a GC response gene in expression profiling analyses performed in children with ALL during initial systemic GC mono-therapy. Since deregulation of glucose metabolism has been implicated in apoptosis induction, this gene and its relatives, PFKFB1, 3, and 4, were further analyzed. Gene expression analyses of isolated lymphoblasts were performed on Affymetrix HGU133 Plus 2.0 microarrays. GCRMA normalized microarray data were analyzed using R-Bioconductor packages version 2.5. Functional gene analyses of PFKFB2-15A and -15B isoforms were performed by conditional gene over-expression experiments in the GC-sensitive T-ALL model CCRF-CEM. Expression analyses in additional ALL children, non-leukemic individuals and leukemic cell lines confirmed frequent PFKFB2 induction by GC in most systems sensitive to GC-induced apoptosis, particularly T-ALL cells. The 3 other family members, in contrast, were either absent or only weakly expressed (PFKFB1 and 4) or not induced by GC (PFKFB3). Conditional PFKFB2 over-expression in the CCRF-CEM T-ALL in vitro model revealed that its 2 splice variants (PFKFB2-15A and PFKFB2-15B) had no detectable effect on cell survival. Moreover, neither PFKFB2 splice variant significantly affected sensitivity to, or kinetics of, GC-induced apoptosis. Our data suggest that, at least in the model system investigated, PFKFB2 is not an essential upstream regulator of the anti-leukemic effects of GC

  5. Radiobiological heterogeneity of leukemic lymphocyte precursors from acute lymphoblastic leukemia patients

    International Nuclear Information System (INIS)

    Uckun, F.M.; Kim, T.H.; Ramsay, N.C.; Min, W.S.; Song, C.W.

    1989-01-01

    The report outlines the authors' findings on the radiobiological features of leukemic lymphocyte precursors from acute lymphoblastic leukemia (ALL) patients. A marked heterogeneity existed between different cell lines, with a remarkable radioresistance and repair capacity in some ALL patients and an acute radiosensitivity in the absence of a detectable repair capacity in others. (U.K.)

  6. Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)—Health Professional Version

    Science.gov (United States)

    Adult Acute Lymphoblastic Leukemia (ALL; also called acute lymphocytic leukemia) is an aggressive cancer that can progress quickly without treatment. Treatments include chemotherapy, radiation therapy, stem cell transplant, and targeted therapy. Get detailed information about the molecular genetics, prognosis, and treatment of ALL in this clinician summary.

  7. Macrophage and NK-mediated killing of precursor-B acute lymphoblastic leukemia cells targeted with a-fucosylated anti-CD19 humanized antibodies.

    Science.gov (United States)

    Matlawska-Wasowska, K; Ward, E; Stevens, S; Wang, Y; Herbst, R; Winter, S S; Wilson, B S

    2013-06-01

    This work reports the tumoricidal effects of a novel investigational humanized anti-CD19 monoclonal antibody (Medi-551). An a-fucosylated antibody with increased affinity for human FcγRIIIA, Medi-551 is shown to mediate both antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Medi-551/CD19 complexes internalize slowly (>5 h) and thus remain accessible to effector cells for prolonged periods. We evaluated in vitro ADCC and ADCP activities of primary human natural killer (NK) cells and macrophages against precursor-B (pre-B) acute lymphoblastic leukemia (ALL) cell lines and pediatric patient blasts. Fluorescent imaging studies document immunological synapses formed between anti-CD19-bound target leukemia cells and effector cells and capture the kinetics of both NK-mediated killing and macrophage phagocytosis. Genetic polymorphisms in FcγRIIIA-158F/V modulate in vitro activities of effector cells, with FcγRIIIA-158V homozygotes or heterozygotes showing the strongest activity. Medi-551 treatment of severe combined immunodeficiency (SCID) mice engrafted with human pre-B cells led to prolonged animal survival and markedly reduced disease burden in blood, liver and bone marrow. These data show that anti-CD19 antibodies effectively recruit immune cells to pre-B ALL cells and support a move forward to early phase trials in this disease.

  8. Acute lymphoblastic leukemia in a child with fanconi's anaemia

    International Nuclear Information System (INIS)

    Mushtaq, N.; Fadoo, Z.; Saleem, A.F.

    2012-01-01

    Fanconi anaemia (FA) is an autosomal recessive inherited disorder with progressive bone marrow failure, associated congenital malformation and solid and haematological malignancies. Acute myeloid leukemia is the commonest haematological malignancy followed by myelodysplastic syndrome in children with FA. FA transformed into acute lymphoblastic leukemia (ALL) is a rare phenomenon and one of the rarest haematological malignancies associated with this disorder. We are reporting a 13 years old girl with FA and positive chromosomal breakage. She required regular blood product transfusion. She was planned for haematopoietic stem cell transplantation (HSCT) but the sibling-matched donor was found to have chromosomal breaks as well. Later on, her peripheral smear showed blast cell. Bone marrow showed pre-B ALL. She was started on chemotherapy but died shortly due to complications of the treatment. For this rare condition conservative management is indeed essential, however, safe and appropriate chemotherapy regimen is needed. (author)

  9. Fusion of NUP98 and the SET binding protein 1 (SETBP1) gene in a paediatric acute T cell lymphoblastic leukaemia with t(11;18)(p15;q12)

    DEFF Research Database (Denmark)

    Panagopoulos, Ioannis; Kerndrup, Gitte; Carlsen, Niels

    2007-01-01

    Three NUP98 chimaeras have previously been reported in T cell acute lymphoblastic leukaemia (T-ALL): NUP98/ADD3, NUP98/CCDC28A, and NUP98/RAP1GDS1. We report a T-ALL with t(11;18)(p15;q12) resulting in a novel NUP98 fusion. Fluorescent in situ hybridisation showed NUP98 and SET binding protein 1(...... in leukaemias; however, it encodes a protein that specifically interacts with SET, fused to NUP214 in a case of acute undifferentiated leukaemia.......Three NUP98 chimaeras have previously been reported in T cell acute lymphoblastic leukaemia (T-ALL): NUP98/ADD3, NUP98/CCDC28A, and NUP98/RAP1GDS1. We report a T-ALL with t(11;18)(p15;q12) resulting in a novel NUP98 fusion. Fluorescent in situ hybridisation showed NUP98 and SET binding protein 1...

  10. The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells

    International Nuclear Information System (INIS)

    Kuwatsuka, Y; Minami, M; Minami, Y; Sugimoto, K; Hayakawa, F; Miyata, Y; Abe, A; Goff, D J; Kiyoi, H; Naoe, T

    2011-01-01

    In Ph-positive (Ph + ) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph + acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγ null (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G 0 cells in the CD34 + CD38 − population compared with the CD34 + CD38 + and CD34 − populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34 + CD38 − population than in the other populations. Although slow-cycling G 0 cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34 + CD38 − population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34 + cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph + leukemia due to quiescence

  11. Dietary resveratrol does not delay engraftment, sensitize to vincristine, or inhibit growth of high-risk acute lymphoblastic leukemia cells in NOD/SCID mice

    Science.gov (United States)

    Acute lymphoblastic leukemia (ALL) with translocation t(4;11) is a high-risk leukemia found in 60-85% of infants with ALL and is often refractory to conventional chemotherapeutics after relapse. Although resveratrol is able to kill high-risk leukemia in vitro, this agent has not been evaluated agai...

  12. Childhood pre-B cell acute lymphoblastic leukemia with translocation t(1;19)(q21.1;p13.3) and two additional chromosomal aberrations involving chromosomes 1, 6, and 13: a case report.

    Science.gov (United States)

    Wafa, Abdulsamad; As'sad, Manar; Liehr, Thomas; Aljapawe, Abdulmunim; Al Achkar, Walid

    2017-04-07

    The translocation t(1;19)(q23;p13), which results in the TCF3-PBX1 chimeric gene, is one of the most frequent rearrangements observed in B cell acute lymphoblastic leukemia. It appears in both adult and pediatric patients with B cell acute lymphoblastic leukemia at an overall frequency of 3 to 5%. Most cases of pre-B cell acute lymphoblastic leukemia carrying the translocation t(1;19) have a typical immunophenotype with homogeneous expression of CD19, CD10, CD9, complete absence of CD34, and at least diminished CD20. Moreover, the translocation t(1;19) correlates with known clinical high risk factors, such as elevated white blood cell count, high serum lactate dehydrogenase levels, and central nervous system involvement; early reports indicated that patients with translocation t(1;19) had a poor outcome under standard treatment. We report the case of a 15-year-old Syrian boy with pre-B cell acute lymphoblastic leukemia with abnormal karyotype with a der(19)t(1;19)(q21.1;p13.3) and two yet unreported chromosomal aberrations: an interstitial deletion 6q12 to 6q26 and a der(13)t(1;13)(q21.1;p13). According to the literature, cases who are translocation t(1;19)-positive have a significantly higher incidence of central nervous system relapse than patients with acute lymphoblastic leukemia without the translocation. Of interest, central nervous system involvement was also seen in our patient. To the best of our knowledge, this is the first case of childhood pre-B cell acute lymphoblastic leukemia with an unbalanced translocation t(1;19) with two additional chromosomal aberrations, del(6)(q12q26) and t(1;13)(q21.3;p13), which seem to be recurrent and could influence clinical outcome. Also the present case confirms the impact of the translocation t(1;19) on central nervous system relapse, which should be studied for underlying mechanisms in future.

  13. Defective quorum sensing of acute lymphoblastic leukemic cells: evidence of collective behavior of leukemic populations as semi-autonomous aberrant ecosystems

    Science.gov (United States)

    Patel, Sapan J; Dao, Su; Darie, Costel C; Clarkson, Bayard D

    2016-01-01

    Quorum sensing (QS) is a generic term used to describe cell-cell communication and collective decision making by bacterial and social insects to regulate the expression of specific genes in controlling cell density and other properties of the populations in response to nutrient supply or changes in the environment. QS mechanisms also have a role in higher organisms in maintaining homeostasis, regulation of the immune system and collective behavior of cancer cell populations. In the present study, we used a p190BCR-ABL driven pre-B acute lymphoblastic leukemia (ALL3) cell line derived from the pleural fluid of a terminally ill patient with ALL to test the QS hypothesis in leukemia. ALL3 cells don’t grow at low density (LD) in liquid media but grow progressively faster at increasingly high cell densities (HD) in contrast to other established leukemic cell lines that grow well at very low starting cell densities. The ALL3 cells at LD are poised to grow but shortly die without additional stimulation. Supernates of ALL3 cells (HDSN) and some other primary cells grown at HD stimulate the growth of the LD ALL3 cells without which they won’t survive. To get further insight into the activation processes we performed microarray analysis of the LD ALL3 cells after stimulation with ALL3 HDSN at days 1, 3, and 6. This screen identified several candidate genes, and we linked them to signaling networks and their functions. We observed that genes involved in lipid, cholesterol, fatty acid metabolism, and B cell activation are most up- or down-regulated upon stimulation of the LD ALL3 cells using HDSN. We also discuss other pathways that are differentially expressed upon stimulation of the LD ALL3 cells. Our findings suggest that the Ph+ ALL population achieves dominance by functioning as a collective aberrant ecosystem subject to defective quorum-sensing regulatory mechanisms. PMID:27429840

  14. [Childhood acute lymphoblastic leukemia in Norway 1992-2000].

    Science.gov (United States)

    Kolmannskog, Svein; Flaegstad, Trond; Helgestad, Jon; Hellebostad, Marit; Zeller, Bernward; Glomstein, Anders

    2007-05-31

    Acute lymphoblastic leukemia is the most common malignancy in childhood. The survival rate has increased steadily over the last 40 years. All children aged 0-15 years and diagnosed in Norway in the period 1992-2000, were included in the study (n = 301). The patients were followed up until 1.1. 2005. The diagnosis was made in 301 children, 33 new cases per year (range 24 to 40) on average. The peak incidence was between 2 and 5 years. Four of 6 infants with acute lymphoblastic leukemia and all 4 with mature B-cell leukemia are alive. Two of the remaining 291 children died before treatment was started. 289 were all treated according to the common Nordic NOPHO-ALL 1992 protocol. All children achieved remission (99.7%), except for one who died before remission was achieved. 55 children (19%) relapsed. Radiation to the brain as part of central nervous system prophylaxis was given to just 10% of the children. The 10-year event-free survival (p-EFS) was 76%, and 244 of 289 (84%) were alive 4-13 years after the diagnosis was made. The data are comparable with the best international results.

  15. Cooperation of IRAK1/4 inhibitor and ABT-737 in nanoparticles for synergistic therapy of T cell acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Wu X

    2017-10-01

    Full Text Available Xiaoyan Wu,1 Lin Wang,1 Yining Qiu,1 Bingyu Zhang,1 Zhenhua Hu,2 Runming Jin1 1Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 2Department of Pharmacy, Shanghai Jiao Tong University, Shanghai, China Abstract: T cell acute lymphoblastic leukemia (T-ALL is caused by clonal expansion of variant T cell progenitors and is considered as a high risk leukemia. Contemporary single chemotherapy has a limited effect due to dynamic and versatile properties of T-ALL. Here IRAK1/4 inhibitor and ABT-737 were co-encapsulated into polyethylene glycol modified poly (lactic-co-glycolic acid nanoparticles (IRAK/ABT-NP to enhance synergistic therapy of T-ALL. The formulation was optimized to achieve high drug loading using Box-Behnken design and response surface methodology. The optimal parameter comprised 2.98% polymer in acetonitrile, a ratio of oil phase to water phase of 1:8.33, and 2.12% emulsifier concentration. High drug loading and uniform spherical shape was achieved. In vitro release study showed sustained release of IRAK1/4 inhibitor for 72 hours as well as sustained release of ABT-737 for more than 120 hours. Uptake efficiency of IRAK/ABT-NP and induced apoptotic T-ALL fraction by IRAK/ABT-NP were much higher than the IRAK1/4 and ABT-737 combined solution. IC50 of IRAK/ABT-NP was two-fold lower than free drug combination in Jurkat cells. Additionally, we conducted in vivo experiments in which IRAK/ABT-NP exhibited greater cytotoxicity toward T-ALL cells, the capacity to significantly restore white blood cell number in peripheral blood, and improved survival time of T-ALL mouse model compared to the IRAK1/4 and ABT-737 combined solution. Keywords: T cell acute lymphoblastic leukemia, IRAK1/4 inhibitor, ABT-737, Box-Behnken design and response surface methodology, PEG-PLGA

  16. The TEL-AML1 fusion protein of acute lymphoblastic leukemia modulates IRF3 activity during early B-cell differentiation.

    Science.gov (United States)

    de Laurentiis, A; Hiscott, J; Alcalay, M

    2015-12-03

    The t(12;21) translocation is the most common genetic rearrangement in childhood acute lymphoblastic leukemia (ALL) and gives rise to the TEL-AML1 fusion gene. Many studies on TEL-AML1 describe specific properties of the fusion protein, but a thorough understanding of its function is lacking. We exploited a pluripotent hematopoietic stem/progenitor cell line, EML1, and generated a cell line (EML-TA) stably expressing the TEL-AML1 fusion protein. EML1 cells differentiate to mature B-cells following treatment with IL7; whereas EML-TA display an impaired differentiation capacity and remain blocked at an early stage of maturation. Global gene expression profiling of EML1 cells at different stages of B-lymphoid differentiation, compared with EML-TA, identified the interferon (IFN)α/β pathway as a primary target of repression by TEL-AML1. In particular, expression and phosphorylation of interferon-regulatory factor 3 (IRF3) was decreased in EML-TA cells; strikingly, stable expression of IRF3 restored the capacity of EML-TA cells to differentiate into mature B-cells. Similarly, IRF3 silencing in EML1 cells by siRNA was sufficient to block B-lymphoid differentiation. The ability of TEL-AML1 to block B-cell differentiation and downregulate the IRF3-IFNα/β pathway was confirmed in mouse and human primary hematopoietic precursor cells (Lin- and CD34+ cells, respectively), and in a patient-derived cell line expressing TEL-AML1 (REH). Furthermore, treatment of TEL-AML1 expressing cells with IFNα/β was sufficient to overcome the maturation block. Our data provide new insight on TEL-AML1 function and may offer a new therapeutic opportunity for B-ALL.

  17. MicroRNA-193b-3p acts as a tumor suppressor by targeting the MYB oncogene in T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Mets, E; Van der Meulen, J; Van Peer, G; Boice, M; Mestdagh, P; Van de Walle, I; Lammens, T; Goossens, S; De Moerloose, B; Benoit, Y; Van Roy, N; Clappier, E; Poppe, B; Vandesompele, J; Wendel, H-G; Taghon, T; Rondou, P; Soulier, J; Van Vlierberghe, P; Speleman, F

    2015-04-01

    The MYB oncogene is a leucine zipper transcription factor essential for normal and malignant hematopoiesis. In T-cell acute lymphoblastic leukemia (T-ALL), elevated MYB levels can arise directly through T-cell receptor-mediated MYB translocations, genomic MYB duplications or enhanced TAL1 complex binding at the MYB locus or indirectly through the TAL1/miR-223/FBXW7 regulatory axis. In this study, we used an unbiased MYB 3'untranslated region-microRNA (miRNA) library screen and identified 33 putative MYB-targeting miRNAs. Subsequently, transcriptome data from two independent T-ALL cohorts and different subsets of normal T-cells were used to select miRNAs with relevance in the context of normal and malignant T-cell transformation. Hereby, miR-193b-3p was identified as a novel bona fide tumor-suppressor miRNA that targets MYB during malignant T-cell transformation thereby offering an entry point for efficient MYB targeting-oriented therapies for human T-ALL.

  18. CD19 CAR-T cell therapy for relapsed/refractory acute lymphoblastic leukemia: factors affecting toxicities and long-term efficacies.

    Science.gov (United States)

    Zhang, Li-Na; Song, Yongping; Liu, Delong

    2018-03-15

    The prognosis of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) remains dismal even at this day and age. With salvage chemotherapy, only 29% (range 18 to 44%) of the patients with R/R ALL can be induced into complete remission (CR), with a median overall survival (OS) of 4 months (range 2-6 months). Blinatumomab and inotuzumab ozogamycin (IO) are immunotherapeutic agents that increased CR to 80% and extended survival to 7.7 months in this high-risk population of patients. In the last few years, chimeric antigen receptor (CAR)--engineered T cells have led to major progress in cancer immunotherapy. CD-19 CAR-T cells have been recently approved for high-risk R/R ALL and lymphoma. The data from long-term follow-up of a single-center phase I study of 19-28z CAR-T cell therapy for adult R/R ALL were just published. At the same time, a multicenter phase II study of 19-41BB CAR-T cell therapy for children and young adults with R/R B cell ALL was also published. The two studies provided fresh information with long-term follow-up. This research highlight analyzed the data and proposed future perspectives for further investigation in this rapidly evolving field.

  19. The role of ABC-transporters in childhood and adult acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Plasschaert, Sabine Louise Anne

    2005-01-01

    Acute lymphoblastic leukemia is a disease characterized by an uncontrolled proliferation and maturation arest of lymphoid progenitor cells in the bone marrow, resulting in an excesso f malignant cells. The disease has a peak incidence between the age of 2-5 years, and a low and steady rise from the

  20. [Epigenetic alterations in acute lymphoblastic leukemia].

    Science.gov (United States)

    Navarrete-Meneses, María Del Pilar; Pérez-Vera, Patricia

    Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. It is well-known that genetic alterations constitute the basis for the etiology of ALL. However, genetic abnormalities are not enough for the complete development of the disease, and additional alterations such as epigenetic modifications are required. Such alterations, like DNA methylation, histone modifications, and noncoding RNA regulation have been identified in ALL. DNA hypermethylation in promoter regions is one of the most frequent epigenetic modifications observed in ALL. This modification frequently leads to gene silencing in tumor suppressor genes, and in consequence, contributes to leukemogenesis. Alterations in histone remodeling proteins have also been detected in ALL, such as the overexpression of histone deacetylases enzymes, and alteration of acetyltransferases and methyltransferases. ALL also shows alteration in the expression of miRNAs, and in consequence, the modification in the expression of their target genes. All of these epigenetic modifications are key events in the malignant transformation since they lead to the deregulation of oncogenes as BLK, WNT5B and WISP1, and tumor suppressors such as FHIT, CDKN2A, CDKN2B, and TP53, which alter fundamental cellular processes and potentially lead to the development of ALL. Both genetic and epigenetic alterations contribute to the development and evolution of ALL. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

  1. [Acute lymphoblastic leukemia: a genomic perspective].

    Science.gov (United States)

    Jiménez-Morales, Silvia; Hidalgo-Miranda, Alfredo; Ramírez-Bello, Julián

    In parallel to the human genome sequencing project, several technological platforms have been developed that let us gain insight into the genome structure of human entities, as well as evaluate their usefulness in the clinical approach of the patient. Thus, in acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, genomic tools promise to be useful to detect patients at high risk of relapse, either at diagnosis or during treatment (minimal residual disease), and they also increase the possibility to identify cases at risk of adverse reactions to chemotherapy. Therefore, the physician could offer patient-tailored therapeutic schemes. A clear example of the useful genomic tools is the identification of single nucleotide polymorphisms (SNPs) in the thiopurine methyl transferase (TPMT) gene, where the presence of two null alleles (homozygous or compound heterozygous) indicates the need to reduce the dose of mercaptopurine by up to 90% to avoid toxic effects which could lead to the death of the patient. In this review, we provide an overview of the genomic perspective of ALL, describing some strategies that contribute to the identification of biomarkers with potential clinical application. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

  2. Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration

    Science.gov (United States)

    Yang, Jun J.; Hunger, Stephen P.; Pieters, Rob; Schrappe, Martin; Biondi, Andrea; Vora, Ajay; Baruchel, André; Silverman, Lewis B.; Schmiegelow, Kjeld; Escherich, Gabriele; Horibe, Keizo; Benoit, Yves C.M.; Izraeli, Shai; Yeoh, Allen Eng Juh; Liang, Der-Cherng; Downing, James R.; Evans, William E.; Relling, Mary V.; Mullighan, Charles G.

    2015-01-01

    Purpose To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. Methods A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups. Results With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome–positive, and Philadelphia chromosome–like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL. Conclusion The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL. PMID:26304874

  3. Comparing outcomes of matched related donor and matched unrelated donor hematopoietic cell transplants in adults with B-Cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Segal, Eric; Martens, Michael; Wang, Hai-Lin; Brazauskas, Ruta; Weisdorf, Daniel; Sandmaier, Brenda M; Khoury, H Jean; de Lima, Marcos; Saber, Wael

    2017-09-01

    Allogeneic hematopoietic cell transplantation (HCT) using human leukocyte antigen (HLA)-matched related donors (RDs) and allogeneic HCT using HLA-matched unrelated donors (URDs) produce similar outcomes for patients with acute myelogenous leukemia, whereas the donor source has been reported to be a predictor of outcomes in myelodysplastic syndrome. Post-HCT outcomes for 1458 acute lymphoblastic leukemia patients from 2000 to 2011 were analyzed, and RD and URD transplants were compared. The median age was 37 years (range, 18-69 years). In the multivariate analysis, HLA 8/8 allele-matched URD recipients had similar transplant-related mortality (TRM) and all-cause mortality in comparison with RD recipients (hazard ratios [HRs], 1.16 [95% confidence interval (CI), 0.91-1.48] and 1.01 [95% CI, 0.85-1.19], respectively); 7/8 URD recipients had a greater risk of TRM and all-cause mortality in comparison with RD recipients (HRs, 1.92 [95% CI, 1.47-2.52] and 1.29 [95% CI, 1.05-1.58], respectively). The risk of TRM and all-cause mortality was also greater for 7/8 URD recipients versus 8/8 URD recipients. Compared with RD recipients, both 8/8 and 7/8 URD recipients had a lower risk of relapse (HRs, 0.77 [95% CI, 0.62-0.97] and 0.75 [95% CI, 0.56-1.00], respectively). Both 8/8 and 7/8 URD recipients had a greater risk of acute graft-versus-host disease (GVHD; HRs, 2.18 [95% CI, 1.76-2.70] and 2.65 [95% CI, 2.06-3.42], respectively) and chronic GVHD (HRs, 1.28 [95% CI, 1.06-1.55] and 1.46 [95% CI, 1.14-1.88], respectively) in comparison with RD recipients. In the absence of RD transplantation, 8/8 URD transplantation is a viable alternative with similar survival outcomes, whereas 7/8 URD transplantation is associated with poorer overall survival. Cancer 2017;123:3346-55. © 2017 American Cancer Society. © 2017 American Cancer Society.

  4. Regulation of CD95 expression and CD95-mediated cell death by interferon-gamma in acute lymphoblastic leukemia with chromosomal translocation t(4;11).

    Science.gov (United States)

    Dörrie, J; Schuh, W; Keil, A; Bongards, E; Greil, J; Fey, G H; Zunino, S J

    1999-10-01

    The regulatory effects of IFNgamma on CD95 expression and CD95-mediated cell death were investigated in three high-risk pro-B acute lymphoblastic leukemia (ALL) lines that carry the chromosomal translocation t(4;11)(q21;q23). These leukemias are characteristically refractory to conventional chemotherapeutic treatments operating through the induction of apoptosis. However, the mechanisms leading to increased cell survival and resistance to cell death in these leukemias are largely unknown. Interferon-gamma (IFNgamma), a potent inhibitor of hematopoiesis, acts in part by upregulating CD95 and sensitizing cells to CD95-induced apoptosis. The t(4;11) lines SEM, RS4;11, and MV4;11 expressed low levels of CD95, but were completely resistant to CD95-mediated death. Addition of IFNgamma markedly upregulated CD95 expression in SEM (8-9-fold), RS4;11 (2-3-fold), and MV4;11 (2-3-fold) lines. However, after treatment with IFNgamma, only an 11% increase in sensitivity to CD95-mediated cell death was observed in SEM cells, whereas RS4;11 and MV4;11 cells remained resistant. Cycloheximide, but not actinomycin D or brefeldin A, increased CD95-specific cell death only in IFNgamma-treated RS4;11 cells by approximately 12%. Abundant levels of Bcl-2 and Bcl-XL, known to inhibit CD95-signaling in some cells, were present suggesting a possible role for both molecules in the resistance to CD95-mediated cell death. Resistance of the leukemic blasts to CD95-mediated cell death and the failure of IFNgamma to substantially sensitize the CD95-signaling pathway may contribute to the highly malignant phenotype of pro-B ALL with translocation t(4;11).

  5. Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Ooko, Edna [Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz (Germany); Alsalim, Tahseen; Saeed, Bahjat [Department of Chemistry, College of Education for Pure Sciences, University of Basrah, P.O. Box 49 Basrah, Al Basrah (Iraq); Saeed, Mohamed E.M.; Kadioglu, Onat [Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz (Germany); Abbo, Hanna S. [Department of Chemistry, University of the Western Cape, P/B X17, Bellville, 7535 Cape Town (South Africa); Titinchi, Salam J.J., E-mail: stitinchi@uwc.ac.za [Department of Chemistry, University of the Western Cape, P/B X17, Bellville, 7535 Cape Town (South Africa); Efferth, Thomas, E-mail: efferth@uni-mainz.de [Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz (Germany)

    2016-08-15

    Background: Multidrug resistance (MDR) and drug transporter P-glycoprotein (P-gp) represent major obstacles in cancer chemotherapy. We investigated 19 synthetic curcumin derivatives in drug-sensitive acute lymphoblastic CCRF–CEM leukemia cells and their multidrug-resistant P-gp-overexpressing subline, CEM/ADR5000. Material and methods: Cytotoxicity was tested by resazurin assays. Doxorubicin uptake was assessed by flow cytometry. Binding modes of compounds to P-gp were analyzed by molecular docking. Chemical features responsible for bioactivity were studied by quantitative structure activity relationship (QSAR) analyses. A 7-descriptor QSAR model was correlated with doxorubicin uptake values, IC{sub 50} values and binding energies. Results: The compounds displayed IC{sub 50} values between 0.7 ± 0.03 and 20.2 ± 0.25 μM. CEM/ADR5000 cells exhibited cross-resistance to 10 compounds, collateral sensitivity to three compounds and regular sensitivity to the remaining six curcumins. Molecular docking studies at the intra-channel transmembrane domain of human P-gp resulted in lowest binding energies ranging from − 9.00 ± 0.10 to − 6.20 ± 0.02 kcal/mol and pKi values from 0.24 ± 0.04 to 29.17 ± 0.88 μM. At the ATP-binding site of P-gp, lowest binding energies ranged from − 9.78 ± 0.17 to − 6.79 ± 0.01 kcal/mol and pKi values from 0.07 ± 0.02 to 0.03 ± 0.03 μM. CEM/ADR5000 cells accumulated approximately 4-fold less doxorubicin than CCRF–CEM cells. The control P-gp inhibitor, verapamil, partially increased doxorubicin uptake in CEM/ADR5000 cells. Six curcumins increased doxorubicin uptake in resistant cells or even exceeded uptake levels compared to sensitive one. QSAR yielded good activity prediction (R = 0.797 and R = 0.794 for training and test sets). Conclusion: Selected derivatives may serve to guide future design of novel P-gp inhibitors and collateral sensitive drugs to combat MDR. - Highlights: • Novel derivatives of curcumin in reversing

  6. Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines

    International Nuclear Information System (INIS)

    Ooko, Edna; Alsalim, Tahseen; Saeed, Bahjat; Saeed, Mohamed E.M.; Kadioglu, Onat; Abbo, Hanna S.; Titinchi, Salam J.J.; Efferth, Thomas

    2016-01-01

    Background: Multidrug resistance (MDR) and drug transporter P-glycoprotein (P-gp) represent major obstacles in cancer chemotherapy. We investigated 19 synthetic curcumin derivatives in drug-sensitive acute lymphoblastic CCRF–CEM leukemia cells and their multidrug-resistant P-gp-overexpressing subline, CEM/ADR5000. Material and methods: Cytotoxicity was tested by resazurin assays. Doxorubicin uptake was assessed by flow cytometry. Binding modes of compounds to P-gp were analyzed by molecular docking. Chemical features responsible for bioactivity were studied by quantitative structure activity relationship (QSAR) analyses. A 7-descriptor QSAR model was correlated with doxorubicin uptake values, IC 50 values and binding energies. Results: The compounds displayed IC 50 values between 0.7 ± 0.03 and 20.2 ± 0.25 μM. CEM/ADR5000 cells exhibited cross-resistance to 10 compounds, collateral sensitivity to three compounds and regular sensitivity to the remaining six curcumins. Molecular docking studies at the intra-channel transmembrane domain of human P-gp resulted in lowest binding energies ranging from − 9.00 ± 0.10 to − 6.20 ± 0.02 kcal/mol and pKi values from 0.24 ± 0.04 to 29.17 ± 0.88 μM. At the ATP-binding site of P-gp, lowest binding energies ranged from − 9.78 ± 0.17 to − 6.79 ± 0.01 kcal/mol and pKi values from 0.07 ± 0.02 to 0.03 ± 0.03 μM. CEM/ADR5000 cells accumulated approximately 4-fold less doxorubicin than CCRF–CEM cells. The control P-gp inhibitor, verapamil, partially increased doxorubicin uptake in CEM/ADR5000 cells. Six curcumins increased doxorubicin uptake in resistant cells or even exceeded uptake levels compared to sensitive one. QSAR yielded good activity prediction (R = 0.797 and R = 0.794 for training and test sets). Conclusion: Selected derivatives may serve to guide future design of novel P-gp inhibitors and collateral sensitive drugs to combat MDR. - Highlights: • Novel derivatives of curcumin in reversing multidrug

  7. Clinical and cytogenetic features of pediatric dic(9;20)(p13.2;q11.2)-positive B-cell precursor acute lymphoblastic leukemias: a Nordic series of 24 cases and review of the literature

    DEFF Research Database (Denmark)

    Forestier, Erik; Gauffin, Fredrika; Andersen, Mette K

    2008-01-01

    Although dic(9;20)(p13.2;q11.2) is a characteristic abnormality in childhood B-cell precursor acute lymphoblastic leukemias (BCP ALL), little is known about its clinical impact or the type and frequency of additional aberrations it may occur together with. We here review the clinical and cytogene......Although dic(9;20)(p13.2;q11.2) is a characteristic abnormality in childhood B-cell precursor acute lymphoblastic leukemias (BCP ALL), little is known about its clinical impact or the type and frequency of additional aberrations it may occur together with. We here review the clinical...... a mediastinal mass at diagnosis. Risk group stratification was nonstandard risk in 79%. The event-free survival and overall survival at 5 years for the 24 Nordic cases was 0.62 and 0.82, respectively. Thus, although relapses are quite common, postrelapse treatment of many patients is successful....

  8. Total body irradiation in a patient with fragile X syndrome for acute lymphoblastic leukemia in preparation for stem cell transplantation: A case report and literature review.

    Science.gov (United States)

    Collins, D T; Mannina, E M; Mendonca, M

    2015-10-01

    Fragile X syndrome (FXS) is a congenital disorder caused by expansion of CGG trinucleotide repeat at the 5' end of the fragile X mental retardation gene 1 (FMR1) on the X chromosome that leads to chromosomal instability and diminished serum levels of fragile X mental retardation protein (FMRP). Afflicted individuals often have elongated features, marfanoid habitus, macroorchidism and intellectual impairment. Evolving literature suggests the condition may actually protect from malignancy while chromosomal instability would presumably elevate the risk. Increased sensitivity to ionizing radiation should also be predicted by unstable sites within the DNA. Interestingly, in this report, we detail a patient with FXS diagnosed with acute lymphoblastic leukemia treated with induction followed by subsequent cycles of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) with a complete response who then was recommended to undergo peripheral stem cell transplantation. The patient underwent total body irradiation (TBI) as a component of his conditioning regimen and despite the concern of his clinicians, developed minimal acute toxicity and successful engraftment. The pertinent literature regarding irradiation of patients with FXS is also reviewed. © 2015 Wiley Periodicals, Inc.

  9. Management of acute lymphoblastic leukemia in young adults.

    Science.gov (United States)

    Muffly, Lori S; Reizine, Natalie; Stock, Wendy

    2018-02-01

    Substantial interest in acute lymphoblastic leukemia (ALL) in young adults (YAs) and investigations focused on this patient population have resulted in therapeutic advancements that are changing the management paradigm and improving outcomes. The pediatric ALL approach is feasible and effective when administered by medical oncologists. Advanced diagnostics and minimal residual disease measurements aid in prognostication and have resulted in shifting recommendations regarding allogeneic hematopoietic cell transplant in first remission. Blinatumomab, inotuzumab, and chimeric antigen receptor T-cell therapies are transforming the treatment of relapsed/refractory ALL. This comprehensive review of the current management of ALL in YAs summarizes recent scientific developments and clinical trial findings related to ALL biology, frontline management approaches, novel therapies, and supportive care specific to this patient population. Finally, a practical guide to modern YA management for practicing clinicians is provided.

  10. The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL).

    Science.gov (United States)

    Gazi, Mohiuddin; Moharram, Sausan A; Marhäll, Alissa; Kazi, Julhash U

    2017-04-28

    Although significant improvements have been made in the treatment of acute lymphoblastic leukemia (ALL), there is a substantial subset of high-risk T-cell ALL (T-ALL) patients with relatively poor prognosis. Like in other leukemia types, alterations of the PI3K/mTOR pathway are predominant in ALL which is also responsible for treatment failure and relapse. In this study, we show that relapsed T-ALL patients display an enrichment of the PI3K/mTOR pathway. Using a panel of inhibitors targeting multiple components of the PI3K/mTOR pathway, we observed that the dual-specific PI3K/mTOR inhibitor PKI-587 was the most selective inhibitor for T-ALL cells dependent on the PI3K/mTOR pathway. Furthermore, we observed that PKI-587 blocked proliferation and colony formation of T-ALL cell lines. Additionally, PKI-587 selectively abrogated PI3K/mTOR signaling without affecting MAPK signaling both in in vitro and in vivo. Inhibition of the PI3K/mTOR pathway using PKI-587 delayed tumor progression, reduced tumor load and enhanced the survival rate in immune-deficient mouse xenograft models without inducing weight loss in the inhibitor treated mice. This preclinical study shows beneficial effects of PKI-587 on T-ALL that warrants further investigation in the clinical setting. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies.

    Science.gov (United States)

    Bernasconi-Elias, P; Hu, T; Jenkins, D; Firestone, B; Gans, S; Kurth, E; Capodieci, P; Deplazes-Lauber, J; Petropoulos, K; Thiel, P; Ponsel, D; Hee Choi, S; LeMotte, P; London, A; Goetcshkes, M; Nolin, E; Jones, M D; Slocum, K; Kluk, M J; Weinstock, D M; Christodoulou, A; Weinberg, O; Jaehrling, J; Ettenberg, S A; Buckler, A; Blacklow, S C; Aster, J C; Fryer, C J

    2016-11-24

    Notch receptors have been implicated as oncogenic drivers in several cancers, the most notable example being NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). To characterize the role of activated NOTCH3 in cancer, we generated an antibody that detects the neo-epitope created upon gamma-secretase cleavage of NOTCH3 to release its intracellular domain (ICD3), and sequenced the negative regulatory region (NRR) and PEST (proline, glutamate, serine, threonine) domain coding regions of NOTCH3 in a panel of cell lines. We also characterize NOTCH3 tumor-associated mutations that result in activation of signaling and report new inhibitory antibodies. We determined the structural basis for receptor inhibition by obtaining the first co-crystal structure of a NOTCH3 antibody with the NRR protein and defined two distinct epitopes for NRR antibodies. The antibodies exhibit potent anti-leukemic activity in cell lines and tumor xenografts harboring NOTCH3 activating mutations. Screening of primary T-ALL samples reveals that 2 of 40 tumors examined show active NOTCH3 signaling. We also identified evidence of NOTCH3 activation in 12 of 24 patient-derived orthotopic xenograft models, 2 of which exhibit activation of NOTCH3 without activation of NOTCH1. Our studies provide additional insights into NOTCH3 activation and offer a path forward for identification of cancers that are likely to respond to therapy with NOTCH3 selective inhibitory antibodies.

  12. Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Wolthers, Benjamin O.; Frandsen, Thomas L.; Baruchel, André

    2017-01-01

    BACKGROUND: Survival for childhood acute lymphoblastic leukaemia surpasses 90% with contemporary therapy; however, patients remain burdened by the severe toxic effects of treatment, including asparaginase-associated pancreatitis. To investigate the risk of complications and risk of re......-exposing patients with asparaginase-associated pancreatitis to asparaginase, 18 acute lymphoblastic leukaemia trial groups merged data for this observational study. METHODS: Patient files from 26 trials run by 18 trial groups were reviewed on children (aged 1·0-17·9 years) diagnosed with t(9;22)-negative acute...... lymphoblastic leukaemia between June 1, 1996, and Jan 1, 2016, who within 50 days of asparaginase exposure developed asparaginase-associated pancreatitis. Asparaginase-associated pancreatitis was defined by at least two criteria: abdominal pain, pancreatic enzymes at least three times the upper limit of normal...

  13. The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Kuwatsuka, Y; Minami, M; Minami, Y; Sugimoto, K; Hayakawa, F; Miyata, Y; Abe, A [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan); Goff, D J [Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA (United States); Kiyoi, H [Department of Infectious Diseases, Nagoya University Hospital, Nagoya (Japan); Naoe, T [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan)

    2011-05-01

    In Ph-positive (Ph{sup +}) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph{sup +} acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγ{sup null} (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G{sub 0} cells in the CD34{sup +}CD38{sup −} population compared with the CD34{sup +}CD38{sup +} and CD34{sup −} populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34{sup +}CD38{sup −} population than in the other populations. Although slow-cycling G{sub 0} cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34{sup +}CD38{sup −} population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34{sup +} cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph{sup +} leukemia due to quiescence.

  14. CD19-Targeted CAR T Cells as Novel Cancer Immunotherapy for Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

    OpenAIRE

    Davila, Marco L.; Brentjens, Renier J.

    2016-01-01

    Immunotherapy has demonstrated significant potential for the treatment of patients with chemotherapy-resistant hematologic malignancies and solid tumors. One type of immunotherapy involves the adoptive transfer of T cells that have been genetically modified with a chimeric antigen receptor (CAR) to target a tumor. These hybrid proteins are composed of the antigen-binding domains of an antibody fused to T-cell receptor signaling machinery. CAR T cells that target CD19 recently have made the ju...

  15. Feasibility of the fluorometric microculture cytotoxicity assay (FMCA) for cytotoxic drug sensitivity testing of tumor cells from patients with acute lymphoblastic leukemia.

    Science.gov (United States)

    Nygren, P; Kristensen, J; Jonsson, B; Sundström, C; Lönnerholm, G; Kreuger, A; Larsson, R

    1992-11-01

    The automated fluorometric microculture cytotoxicity assay (FMCA) was used for chemotherapeutic drug sensitivity testing of fresh and cryopreserved tumor cells from patients with acute lymphoblastic leukemia (ALL) at diagnosis and relapse. The technique success rate was 87% for fresh and 81% for cryopreserved samples. Up to 16 different cytotoxic drugs were routinely tested, but neither asparaginase nor methotrexate produced dose-response related cell kill. FMCA data showed good correlation to the well established Disc assay and the drug sensitivity reported by the FMCA was in good agreement with known clinical activity. Samples from children and initial ALL tended to be more drug sensitive than those from adults and ALL at relapse, respectively. For 36 samples clinical outcome was correlated to the quartile position in comparison to all other samples for the most in vitro active drug actually given to the patient. For patients with samples in the first, second, third, and fourth quartiles, the probabilities of complete remission were 89, 57, 38, and 0%, respectively. Using the median value as cut-off line, the sensitivity and specificity of the assay were 87 and 62%, respectively. It is concluded that the FMCA with a minimum of effort and with high success rate report clinically relevant drug sensitivity profiles for ALL.

  16. Allogeneic stem cell transplantation in children with acute lymphoblastic leukemia after isolated central nervous system relapse: our experiences and review of the literature.

    Science.gov (United States)

    Yoshihara, T; Morimoto, A; Kuroda, H; Imamura, T; Ishida, H; Tsunamoto, K; Naya, M; Hibi, S; Todo, S; Imashuku, S

    2006-01-01

    The prognosis of patients with acute lymphoblastic leukemia (ALL) and central nervous system (CNS) relapse has historically been very poor. Although chemo-radiotherapy has improved outcomes, some patients still have a poor prognosis after CNS relapse. Therefore, allogeneic hematopoietic stem cell transplantation (allo-SCT) has recently become an option for treatment of CNS leukemia; however, information, particularly on the long-term outcome of transplant recipients, is limited. We performed allo-SCT in eight pediatric patients with ALL (n=7) or T-cell type non-Hodgkin's lymphoma (n=1), who had isolated CNS relapse. All patients survived for a median of 70.5 (range, 13-153) months after SCT. Sequelae developed late in some patients: mental retardation (IQ=47) in one patient, severe alopecia in two patients, limited chronic graft-versus-host-disease in three patients, and amenorrhea and/or hypothyroidism in three patients. Except for a pre-school child with post transplant CNS relapse, six out of seven patients show normal school/social performance. Our results clearly indicate a high cure rate of isolated CNS relapse by allo-SCT in pediatric lymphoid malignancies; however, there needs to be further studies to determine which are the appropriate candidates for transplantation and what is the best transplant regimen to achieve high cure rate and maintain good quality of life.

  17. Early presentation of osteonecrosis in acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Mogensen, Signe Sloth; Harila-Saari, Arja; Frandsen, Thomas Leth

    2017-01-01

    Osteonecrosis (ON) is usually considered treatment related in patients with acute lymphoblastic leukemia (ALL). We report two patients with presentation of ON at the time of ALL diagnosis. Both were females and diagnosed with ALL at age 8 and 14 years. In the latter, some symptoms and radiologica......Osteonecrosis (ON) is usually considered treatment related in patients with acute lymphoblastic leukemia (ALL). We report two patients with presentation of ON at the time of ALL diagnosis. Both were females and diagnosed with ALL at age 8 and 14 years. In the latter, some symptoms...

  18. Relapsed childhood acute lymphoblastic leukemia in the Nordic countries

    DEFF Research Database (Denmark)

    Oskarsson, Trausti; Söderhäll, Stefan; Arvidson, Johan

    2016-01-01

    Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the up-front therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following acute lymphoblastic...... leukemia relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications, and identify additional prognostic factors for overall survival. Altogether, 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were...

  19. Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Nielsen, Stine Nygaard; Grell, Kathrine; Nersting, Jacob

    2016-01-01

    PURPOSE: Normal white blood cell counts (WBC) are unknown in children with acute lymphoblastic leukemia (ALL). Accordingly, 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy is adjusted by a common WBC target of 1.5-3.0 × 10(9)/L. Consequently, the absolute degree...

  20. CD22: A Promising Target for Acute Lymphoblastic Leukemia Treatment | Center for Cancer Research

    Science.gov (United States)

    There are about 4,000 new cases of acute lymphoblastic leukemia (ALL) in the United States each year. Great improvements have been made in the treatment of ALL, but many patients suffer from side effects of standard therapy and continue to die of this disease. One of the most promising therapeutic strategies includes engineering T cells with a chimeric antigen receptor (CAR)

  1. Mutational analysis of Bax and Bcl-2 in childhood acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Salomons, G. S.; Buitenhuis, C. K.; Martínez Muñoz, C.; Verwijs-Jassen, M.; Behrendt, H.; Zsiros, J.; Smets, L. A.

    1998-01-01

    In childhood acute lymphoblastic leukaemia there are large interpatient variations in levels of the apoptosis-regulating proteins Bax and Bcl-2, but the molecular basis for this variation is unknown. Point-mutations in bax have been reported in cell lines derived from haematological malignancies.

  2. Treatment of Young Adults with Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Kansagra, Ankit; Litzow, Mark

    2017-06-01

    Young adults with acute lymphoblastic leukemia are a distinctive category of patients, with substantial difference in disease biology and response to therapy; hence, they pose unique challenges and issues beyond those faced by children and older adults. Despite inferior survival compared to children, there is growing evidence to suggest that young adults have improved outcomes when treated with pediatric-based approaches. With better supportive care and toxicity management and multidisciplinary team and approach, we have made great improvement in outcomes of young adults with ALL. However, despite significant progress, patients with persistence of minimal residual disease have a poor prognosis. This review discusses current controversies in the management of young adults with ALL, outcomes following pediatric and adult protocols, and the role of allogeneic stem cell transplantation. We also explore recent advances in disease monitoring and highlight our approach to incorporation of novel therapies in the management of young adults with ALL.

  3. CREBBP knockdown enhances RAS/RAF/MEK/ERK signaling in Ras pathway mutated acute lymphoblastic leukemia but does not modulate chemotherapeutic response.

    Science.gov (United States)

    Dixon, Zach A; Nicholson, Lindsay; Zeppetzauer, Martin; Matheson, Elizabeth; Sinclair, Paul; Harrison, Christine J; Irving, Julie A E

    2017-04-01

    Relapsed acute lymphoblastic leukemia is the most common cause of cancer-related mortality in young people and new therapeutic strategies are needed to improve outcome. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP , are particularly frequent in relapsed childhood acute lymphoblastic leukemia and associated with a hyperdiploid karyotype and KRAS mutations. To study the functional impact of CREBBP haploinsufficiency in acute lymphoblastic leukemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukemia cell lines and various primagraft acute lymphoblastic leukemia cells. We demonstrate that attenuation of CREBBP results in reduced acetylation of histone 3 lysine 18, but has no significant impact on cAMP-dependent target gene expression. Impaired induction of glucocorticoid receptor targets was only seen in 1 of 4 CREBBP knockdown models, and there was no significant difference in glucocorticoid-induced apoptosis, sensitivity to other acute lymphoblastic leukemia chemotherapeutics or histone deacetylase inhibitors. Importantly, we show that CREBBP directly acetylates KRAS and that CREBBP knockdown enhances signaling of the RAS/RAF/MEK/ERK pathway in Ras pathway mutated acute lymphoblastic leukemia cells, which are still sensitive to MEK inhibitors. Thus, CREBBP mutations might assist in enhancing oncogenic RAS signaling in acute lymphoblastic leukemia but do not alter response to MEK inhibitors. Copyright© Ferrata Storti Foundation.

  4. Country-Level Macroeconomic Indicators Predict Early Post-Allogeneic Hematopoietic Cell Transplantation Survival in Acute Lymphoblastic Leukemia: A CIBMTR Analysis.

    Science.gov (United States)

    Wood, William A; Brazauskas, Ruta; Hu, Zhen-Huan; Abdel-Azim, Hisham; Ahmed, Ibrahim A; Aljurf, Mahmoud; Badawy, Sherif; Beitinjaneh, Amer; George, Biju; Buchbinder, David; Cerny, Jan; Dedeken, Laurence; Diaz, Miguel Angel; Freytes, Cesar O; Ganguly, Siddhartha; Gergis, Usama; Almaguer, David Gomez; Gupta, Ashish; Hale, Gregory; Hashmi, Shahrukh K; Inamoto, Yoshihiro; Kamble, Rammurti T; Adekola, Kehinde; Kindwall-Keller, Tamila; Knight, Jennifer; Kumar, Lalit; Kuwatsuka, Yachiyo; Law, Jason; Lazarus, Hillard M; LeMaistre, Charles; Olsson, Richard F; Pulsipher, Michael A; Savani, Bipin N; Schultz, Kirk R; Saad, Ayman A; Seftel, Matthew; Seo, Sachiko; Shea, Thomas C; Steinberg, Amir; Sullivan, Keith; Szwajcer, David; Wirk, Baldeep; Yared, Jean; Yong, Agnes; Dalal, Jignesh; Hahn, Theresa; Khera, Nandita; Bonfim, Carmem; Atsuta, Yoshiko; Saber, Wael

    2018-03-19

    For patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic cell transplantation (alloHCT) offers a potential cure. Life-threatening complications can arise from alloHCT that require the application of sophisticated health care delivery. The impact of country-level economic conditions on post-transplantation outcomes is not known. Our objective was to assess whether these variables were associated with outcomes for patients transplanted for ALL. Using data from the Center for Blood and Marrow Transplant Research, we included 11,261 patients who received a first alloHCT for ALL from 303 centers across 38 countries between the years of 2005 and 2013. Cox regression models were constructed using the following macroeconomic indicators as main effects: Gross national income per capita, health expenditure per capita, and Human Development Index (HDI). The outcome was overall survival at 100 days following transplantation. In each model, transplants performed within lower resourced environments were associated with inferior overall survival. In the model with the HDI as the main effect, transplants performed in the lowest HDI quartile (n = 697) were associated with increased hazard for mortality (hazard ratio, 2.42; 95% confidence interval, 1.64 to 3.57; P macroeconomic indices were associated with lower survival at 100 days after alloHCT for ALL. The reasons for this disparity require further investigation. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  5. SNP association mapping across the extended major histocompatibility complex and risk of B-cell precursor acute lymphoblastic leukemia in children.

    Directory of Open Access Journals (Sweden)

    Kevin Y Urayama

    Full Text Available The extended major histocompatibility complex (xMHC is the most gene-dense region of the genome and harbors a disproportionately large number of genes involved in immune function. The postulated role of infection in the causation of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL suggests that the xMHC may make an important contribution to the risk of this disease. We conducted association mapping across an approximately 4 megabase region of the xMHC using a validated panel of single nucleotide polymorphisms (SNPs in childhood BCP-ALL cases (n=567 enrolled in the Northern California Childhood Leukemia Study (NCCLS compared with population controls (n=892. Logistic regression analyses of 1,145 SNPs, adjusted for age, sex, and Hispanic ethnicity indicated potential associations between several SNPs and childhood BCP-ALL. After accounting for multiple comparisons, one of these included a statistically significant increased risk associated with rs9296068 (OR=1.40, 95% CI=1.19-1.66, corrected p=0.036, located in proximity to HLA-DOA. Sliding window haplotype analysis identified an additional locus located in the extended class I region in proximity to TRIM27 tagged by a haplotype comprising rs1237485, rs3118361, and rs2032502 (corrected global p=0.046. Our findings suggest that susceptibility to childhood BCP-ALL is influenced by genetic variation within the xMHC and indicate at least two important regions for future evaluation.

  6. Acute Lymphoblastic Leukemia in Infants: 20 years of Experience

    Directory of Open Access Journals (Sweden)

    Amanda Ibagy

    2013-01-01

    Full Text Available Objective: To analyze patients younger than 2 years with acute lymphoblastic leukemia, treated in the period between 1990 and 2010 in a state reference center. Methods: This was a clinical-epidemiological, cross-sectional, observational, and descriptive study. It included patients younger than 2 years with acute lymphoblastic leukemia, treated in the period of 1990 to 2010 in a pediatric oncology unit of a state reference center, totaling 41 cases. Results: All patients were white ethnicity, and 60.9% were females. Regarding age, 24.38% were younger than 6 months, 17.07% were between 6 months and 1 year, and 58.53% were older than 1 year. The age of 6 months was statistically significant for the outcome of death. Predominant signs and symptoms were fever, bruising, and petechiae. A leukocyte count > 100,000 was found in 34.14% of cases, hemoglobin count < 11 in 95.13%, and platelet count < 100,000 in 75.61. Infiltration of central nervous system was present in 12.91% of patients. According to the lineage, B-cell lineage predominated (73%, but the T-cell line was statistically significant for death. 39% of patients had disease recurrence. In relation to vital status, 70.73% of the patients died; septic shock was the main cause. Conclusions: Acute lymphoblastic leukemia in infants has a high mortality rate, especially in children under 1 year and those with T-cell derived lineage. Resumo: Objetivo: Analisar pacientes com menos de dois anos de idade com leucemia linfoblásti- ca aguda atendidos no período de 1990 a 2010, em um centro de referência estadual. Métodos: Estudo clínico, epidemiológico, transversal, descritivo e observacional. Pacientes incluídos tinham menos de dois anos de idade, com leucemia linfoblástica aguda, tratados no período de 1990 a 2010 na unidade de oncologia pediátrica de um centro de referência estadual, totalizando 41 casos. Resultados: Todos os pacientes eram Caucasianos e 60,9% eram do sexo feminino. Com rela

  7. Comparison of Cyclophosphamide Combined with Total Body Irradiation, Oral Busulfan, or Intravenous Busulfan for Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Mitsuhashi, Kenjiro; Kako, Shinichi; Shigematsu, Akio; Atsuta, Yoshiko; Doki, Noriko; Fukuda, Takahiro; Kanamori, Heiwa; Onizuka, Makoto; Takahashi, Satoshi; Ozawa, Yukiyasu; Kurokawa, Mineo; Inoue, Yoshiko; Nagamura-Inoue, Tokiko; Morishima, Yasuo; Mizuta, Shuichi; Tanaka, Junji

    2016-12-01

    We conducted a retrospective analysis to compare outcomes in adult patients with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic cell transplantation (allo-HCT) with conditioning regimens containing cyclophosphamide (CY) in combination with total body irradiation (TBI), oral busulfan (p.o. BU), or intravenous busulfan (i.v. BU). We used data for January 2000 to December 2012 from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation. We identified 2130 patients treated with TBI/CY (n = 2028), p.o. BU/CY (n = 60), or i.v. BU/CY (n = 42). Two-year overall survival (OS) and 2-year relapse-free survival rates were 69.0% and 62.1%, respectively, in the TBI/CY group, 55.9% and 54.2% in the p.o. BU/CY group, and 71.0% and 46.8% in the i.v. BU/CY group. In multivariate analysis, compared with TBI/CY, p.o. BU/CY, but not i.v. BU/CY, was associated with lower OS (hazard ratio [HR], 1.46; P = .047) and a higher incidence of sinusoidal obstruction syndrome (HR, 3.36; P = .030). No between-group differences were seen in the incidence of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), or chronic GVHD. We suggest that i.v. BU/CY might be a possible alternative allo-HCT conditioning regimen for adults with ALL who are not suitable for TBI. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  8. ACUTE LYMPHOBLASTIC LEUKEMIA WITHOUT CIRCULATING BLASTS PRESENTING AS SEVERE HYPERCALCEMIA

    Directory of Open Access Journals (Sweden)

    Z. Oloomi

    2007-05-01

    Full Text Available Hypercalcemia complicating malignancy is a rare complication in pediatric age group. In this article, we present a case with acute lymphoblastic leukemia presenting as severe hypercalcemia. A 10 years old girl presented with an acute onset of fever, nausea, vomiting, loss of weight, costovertebral pain and frequency. She was admitted with a presumptive diagnosis of acute pyelonephritis. Her examination showed mild hepatosplenomegaly. In laboratory studies she had sever hypercalcemia. Despite the absence of circulating blast, bone marrow aspiration was diagnostic of acute lymphoblastic leukemia. The hypercalcemia was initially treated with intravenous hydration and furosemide but the serum calcium levels normalized only after the beginning of specific chemotherapy. Hypercalcemia represents an emergency in children, and acute leukemia must be considered in differential diagnosis even when there are no circulating blasts.

  9. Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Oskarsson, Trausti; Söderhäll, Stefan; Arvidson, Johan

    2018-01-01

    BACKGROUND: Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment-related toxicity impacts survival...

  10. Pharmacogenetics Influence Treatment Efficacy in Childhood Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Devidsen, M.L.; Dalhoff, K.; Schmiegelow, K.

    2008-01-01

    in treatment resistance and toxic side effects. As most childhood acute lymphoblastic leukemia treatment protocols include up to 13 different chemotherapeutic agents, the impact of individual SNPs has been difficult to evaluate. So far Focus has mainly been on the widely used glucocorticosteroids, methotrexate...

  11. Etiology of common childhood acute lymphoblastic leukemia: the adrenal hypothesis

    DEFF Research Database (Denmark)

    Schmiegelow, K.; Vestergaard, T.; Nielsen, S.M.

    2008-01-01

    The pattern of infections in the first years of life modulates our immune system, and a low incidence of infections has been linked to an increased risk of common childhood acute lymphoblastic leukemia (ALL). We here present a new interpretation of these observations--the adrenal hypothesis...

  12. Neurodevelopmental Sequelae of Pediatric Acute Lymphoblastic Leukemia and Its Treatment

    Science.gov (United States)

    Janzen, Laura A.; Spiegler, Brenda J.

    2008-01-01

    This review will describe the neurocognitive outcomes associated with pediatric acute lymphoblastic leukemia (ALL) and its treatment. The literature is reviewed with the aim of addressing methodological issues, treatment factors, risks and moderators, special populations, relationship to neuroimaging findings, and directions for future research.…

  13. L-asparaginase treatment in acute lymphoblastic leukemia

    NARCIS (Netherlands)

    R. Pieters (Rob); S.P. Hunger (Stephen); J. Boos (Joachim); C. Rizzari (Carmelo); L.B. Silverman (Lewis); A. Baruchel (André); N. Goekbuget (Nicola); M. Schrappe (Martin); C.H. Pui (Ching-Hon)

    2011-01-01

    textabstractAsparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive

  14. Asparaginase-Associated toxicity in children with acute lymphoblastic leukemia

    NARCIS (Netherlands)

    N. Hijiya (Nobuko); I.M. van der Sluis (Inge)

    2016-01-01

    textabstractAsparaginase is an integral component of multiagent chemotherapy regimens for the treatment of children with acute lymphoblastic leukemia. Positive outcomes are seen in patients who are able to complete their entire prescribed course of asparaginase therapy. Toxicities associated with

  15. Bone histomorphometry in children with newly diagnosed acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Leeuw, JA; Koudstaal, J; Wiersema-Buist, J; Kamps, WA; Timens, W

    2003-01-01

    The objective of this study was to obtain insight into bone formation and resorption in children with newly diagnosed untreated acute lymphoblastic leukemia (ALL). In 23 consecutive children with ALL, a bone biopsy was taken from the crista iliaca posterior under ketamine anesthesia, together with

  16. Second Malignant Neoplasms After Treatment of Childhood Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Schmiegelow, K.; Levinsen, Mette Frandsen; Attarbaschi, Andishe

    2013-01-01

    PURPOSE: Second malignant neoplasms (SMNs) after diagnosis of childhood acute lymphoblastic leukemia (ALL) are rare events. PATIENTS AND METHODS: We analyzed data on risk factors and outcomes of 642 children with SMNs occurring after treatment for ALL from 18 collaborative study groups between 19...

  17. Potent anti-leukemia activities of humanized CD19-targeted CAR-T cells in patients with relapsed/refractory acute lymphoblastic leukemia.

    Science.gov (United States)

    Cao, Jiang; Wang, Gang; Cheng, Hai; Wei, Chen; Qi, Kunming; Sang, Wei; Zhenyu, Li; Shi, Ming; Li, Huizhong; Qiao, Jianlin; Pan, Bin; Zhao, Jing; Wu, Qingyun; Zeng, Lingyu; Niu, Mingshan; Jing, Guangjun; Zheng, Junnian; Xu, Kailin

    2018-04-10

    Chimeric antigen receptor T (CAR-T) cell therapy has shown promising results for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). The immune response induced by murine single-chain variable fragment (scFv) of the CAR may limit CAR-T cell persistence and thus increases the risk of leukemia relapse. In this study, we developed a novel humanized scFv from the murine FMC63 antibody. A total of 18 R/R ALL patients with or without prior murine CD19 CAR-T therapy were treated with humanized CD19-targeted CAR-T cells (hCART19s). After lymphodepletion chemotherapy with cyclophosphamide and fludarabine, the patients received a single dose (1 × 10 6 /kg) of autologous hCART19s infusion. Among the 14 patients without previous CAR-T therapy, 13 (92.9%) achieved complete remission (CR) or CR with incomplete count recovery (CRi) on day 30, whereas 1 of the 3 patients who failed a second murine CAR-T infusion achieved CR after hCART19s infusion. At day 180, the overall and leukemia-free survival rates were 65.8% and 71.4%, respectively. The cumulative incidence of relapse was 22.6%, and the non-relapse mortality rate was 7.1%. During treatment, 13 patients developed grade 1-2 cytokine release syndrome (CRS), 4 patients developed grade 3-5 CRS, and 1 patient experienced reversible neurotoxicity. These results indicated that hCART19s could induce remission in patients with R/R B-ALL, especially in patients who received a reinfusion of murine CAR-T. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

  18. L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Rosilio, C.; Nebout, M.; Imbert, V.; Griessinger, E.; Neffati, Z.; Benadiba, J.; Hagenbeek, T.; Spits, H.; Reverso, J.; Ambrosetti, D.; Michiels, J.-F.; Bailly-Maitre, B.; Endou, H.; Wempe, M. F.; Peyron, J.-F.

    2015-01-01

    The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute

  19. Maintenance therapy of childhood acute lymphoblastic leukemia revisited—Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

    DEFF Research Database (Denmark)

    Schmiegelow, Kjeld; Nersting, Jacob; Nielsen, Stine Nygaard

    2016-01-01

    BACKGROUND: 6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose...... levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 10(9) /l rise [1...

  20. Effect of purified fractions from cell culture supernate of high-density pre-B acute lymphoblastic leukemia cells (ALL3) on the growth of ALL3 cells at low density.

    Science.gov (United States)

    Patel, Sapan J; Darie, Costel C; Clarkson, Bayard D

    2017-02-01

    The mechanisms underlying the aberrant growth and interactions between cells are not understood very well. The pre-B acute lymphoblastic leukemia cells directly obtained from an adult patient grow very poorly or do not grow at all at low density (LD), but grow better at high starting cell density (HD). We found that the LD ALL3 cells can be stimulated to grow in the presence of diffusible, soluble factors secreted by ALL3 cells themselves growing at high starting cell density. We then developed a biochemical purification procedure that allowed us to purify the factor(s) with stimulatory activity and analyzed them by nanoliquid chromatography-tandem mass spectrometry (nanoLC-MS/MS). Using nanoLC-MS/MS we have identified several proteins which were further processed using various bioinformatics tools. This resulted in eight protein candidates which might be responsible for the growth activity on non-growing LD ALL3 cells and their involvement in the stimulatory activity are discussed. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. MLL duplication in a pediatric patient with B-cell lymphoblastic lymphoma.

    Science.gov (United States)

    Mater, David Van; Goodman, Barbara K; Wang, Endi; Gaca, Ana M; Wechsler, Daniel S

    2012-04-01

    Lymphoblastic lymphoma is the second most common type of non-Hodgkin lymphoma seen in children. Approximately, 90% of lymphoblastic lymphomas arise from T cells, with the remaining 10% being B-cell-lineage derived. Although T-cell lymphoblastic lymphoma most frequently occurs in the anterior mediastinum (thymus), B-cell lymphoblastic lymphoma (B-LBL) predominates in extranodal sites such as skin and bone. Here, we describe a pediatric B-LBL patient who presented with extensive abdominal involvement and whose lymphoma cells displayed segmental duplication of the mixed lineage leukemia (MLL) gene. MLL duplication/amplification has been described primarily in acute myeloid leukemia and myelodysplastic syndrome with no published reports of discrete MLL duplication/amplification events in B-LBL. The MLL gene duplication noted in this case may represent a novel mechanism for tumorigenesis in B-LBL.

  2. Maintenance therapy of childhood acute lymphoblastic leukemia revisited-Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

    Science.gov (United States)

    Schmiegelow, Kjeld; Nersting, Jacob; Nielsen, Stine Nygaard; Heyman, Mats; Wesenberg, Finn; Kristinsson, Jon; Vettenranta, Kim; Schrøeder, Henrik; Weinshilboum, Richard; Jensen, Katrine Lykke; Grell, Kathrine; Rosthoej, Susanne

    2016-12-01

    6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines. To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 10 9 /l. After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 10 9 /l rise [1.00-1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 10 9 /l rise [1.3-2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1-6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, r s  = 0.77; P best hematological target for dose adjustments of maintenance therapy. © 2016 Wiley Periodicals, Inc.

  3. A case of hypotriploid chromosome in a patient with acute lymphoblastic leukaemia.

    Science.gov (United States)

    Khan, Bilal Ahmed; Ali Baig, Mirza Faris; Siddiqui, Nadir

    2017-11-01

    TA 58-61, XXXX, hypotriploid chromosome was detected in the cytogenetics report of a 28 years old female patient, known case of B-cell Acute Lymphoblastic Leukaemia. On admission, the patient had normal physical examination findings and mental status, except history of fever spikes and generalized bone pains. The patient was admitted for induction of chemotherapy. Bone Marrow/Trephine biopsy report showed diffuse infiltration with blast cells with overall cellularity around 80-85% and suppressed normal haematopoiesis. Hypotriploid chromosome number in patients with B-cell Acute Lymphoblastic Leukaemia is a unique finding which, according to WHO classification of ALL, is an important prognostic factor itself and these cases have a favourable prognosis. There are only a few medical reports published about cases with similar presentations in Pakistan. Therefore, this case is very unique and further work should be done for better understanding of similar presentations and to find out more about its epidemiology.

  4. Acute lymphoblastic leukemia presenting with bilateral serous macular detachment

    Directory of Open Access Journals (Sweden)

    Luisa Vieira

    2015-12-01

    Full Text Available ABSTRACT Acute lymphoblastic leukemia is a malignant hematopoietic neoplasia, which is rare in adults. Although ocular fundus alterations may be commonly observed in the course of the disease, such alterations are rarely the presenting signs of the disease. Here we describe the case of a patient with painless and progressive loss of visual acuity (right eye, 2/10; left eye, 3/10 developing over two weeks, accompanied by fever and cervical lymphadenopathy. Fundus examination showed bilateral macular serous detachment, which was confirmed by optical coherence tomography. Fluorescein angiography revealed hyperfluorescent pinpoints in the posterior poles. The limits of the macular detachment were revealed in the late phase of the angiogram. The results of blood count analysis triggered a thorough, systematic patient examination. The diagnosis of acute lymphoblastic leukemia B (CD10+ was established, and intensive systemic chemotherapy was immediately initiated. One year after the diagnosis, the patient remains in complete remission without any ophthalmologic alterations.

  5. Regulatory network of GATA3 in pediatric acute lymphoblastic leukemia.

    Science.gov (United States)

    Hou, Qianqian; Liao, Fei; Zhang, Shouyue; Zhang, Duyu; Zhang, Yan; Zhou, Xueyan; Xia, Xuyang; Ye, Yuanxin; Yang, Hanshuo; Li, Zhaozhi; Wang, Leiming; Wang, Xi; Ma, Zhigui; Zhu, Yiping; Ouyang, Liang; Wang, Yuelan; Zhang, Hui; Yang, Li; Xu, Heng; Shu, Yang

    2017-05-30

    GATA3 polymorphisms were reported to be significantly associated with susceptibility of pediatric B-lineage acute lymphoblastic leukemia (ALL), by impacting on GATA3 expression. We noticed that ALL-related GATA3 polymorphism located around in the tissue-specific enhancer, and significantly associated with GATA3 expression. Although the regulatory network of GATA3 has been well reported in T cells, the functional status of GATA3 is poorly understood in B-ALL. We thus conducted genome-wide gene expression association analyses to reveal expression associated genes and pathways in nine independent B-ALL patient cohorts. In B-ALL patients, 173 candidates were identified to be significantly associated with GATA3 expression, including some reported GATA3-related genes (e.g., ITM2A) and well-known tumor-related genes (e.g., STAT4). Some of the candidates exhibit tissue-specific and subtype-specific association with GATA3. Through overexpression and down-regulation of GATA3 in leukemia cell lines, several reported and novel GATA3 regulated genes were validated. Moreover, association of GATA3 expression and its targets can be impacted by SNPs (e.g., rs4894953), which locate in the potential GATA3 binding motif. Our findings suggest that GATA3 may be involved in multiple tumor-related pathways (e.g., STAT/JAK pathway) in B-ALL to impact leukemogenesis through epigenetic regulation.

  6. Philadelphia chromosome-positive acute lymphoblastic leukemia in childhood

    Directory of Open Access Journals (Sweden)

    Hong Hoe Koo

    2011-03-01

    Full Text Available In pediatric patients with acute lymphoblastic leukemia (ALL, the Philadelphia chromosome translocation is uncommon, with a frequency of less than 5%. However, it is classified as a high or very high risk, and only 20&#8210;30% of Philadelphia chromosome-positive (Ph+ children with ALL are cured with chemotherapy alone. Allogeneic hematopoietic stem cell transplantation from a closely matched donor cures 60% of patients in first complete remission. Recent data suggest that chemotherapy plus tyrosine kinase inhibitors (TKIs may be the initial treatment of choice for Ph+ ALL in children. However, longer observation is required to determine whether long-term outcome with intensive imatinib and chemotherapy is indeed equivalent to that with allogeneic related or alternative donor hematopoietic stem cell transplantation (HSCT. Reports on the use of second-generation TKIs in children with Ph+ ALL are limited. A few case reports have indicated the feasibility and clinical benefit of using dasatinib as salvage therapy enabling HSCT. However, more extensive data from clinical trials are needed to determine whether the administration of secondgeneration TKIs in children is comparable to that in adults. Because Ph+ ALL is rare in children, the question of whether HSCT could be a dispensable part of their therapy may not be answered for some time. An international multicenter study is needed to answer the question of whether imatinib plus chemotherapy could replace sibling allogeneic HSCT in children with Ph+ ALL.

  7. Optic nerve infiltration by acute lymphoblastic leukemia: MRI contribution

    Energy Technology Data Exchange (ETDEWEB)

    Soares, Maria de Fatima; Braga, Flavio Tulio [Federal University of Sao Paulo, Department of Diagnostic Imaging, Paulista School of Medicine, Sao Paulo (Brazil); Rocha, Antonio Jose da [Santa Casa de Misericordia de Sao Paulo, Servico de Diagnostico por Imagem, Sao Paulo (Brazil); Lederman, Henrique Manoel [Federal University of Sao Paulo, Division of Diagnostic Imaging in Pediatrics, Department of Diagnostic Imaging, Sao Paulo (Brazil)

    2005-08-01

    We describe the clinical presentation and imaging features of a patient with acute lymphoblastic leukemia (ALL) that was complicated by optic nerve infiltration. The clinical and diagnostic characteristics of this complication must be recognized so that optimal therapy can be started to prevent blindness. MR imaging is useful in early detection and should be performed in any leukemic patient with ocular complaints, even during remission. (orig.)

  8. Optic nerve infiltration by acute lymphoblastic leukemia: MRI contribution

    International Nuclear Information System (INIS)

    Soares, Maria de Fatima; Braga, Flavio Tulio; Rocha, Antonio Jose da; Lederman, Henrique Manoel

    2005-01-01

    We describe the clinical presentation and imaging features of a patient with acute lymphoblastic leukemia (ALL) that was complicated by optic nerve infiltration. The clinical and diagnostic characteristics of this complication must be recognized so that optimal therapy can be started to prevent blindness. MR imaging is useful in early detection and should be performed in any leukemic patient with ocular complaints, even during remission. (orig.)

  9. Blinatumomab for the treatment of acute lymphoblastic leukemia.

    Science.gov (United States)

    Kaplan, Jason B; Grischenko, Marina; Giles, Francis J

    2015-12-01

    Acute lymphoblastic leukemia (ALL) is a potentially fatal disease that involves clonal expansion of early lymphoid progenitor cells. Much of drug development for ALL treatment involves targeting antigens of the clonal cell surface. Blinatumomab belongs to an emerging class of anti-cancer therapeutics referred to as bispecific T-cell engaging antibodies. The Food and Drug Administration approved its use in relapsed or refractory adult Philadelphia chromosome-negative B-cell precursor ALL in December of 2014. Blinatumomab contains both an anti-CD3 and anti-CD19 arm, allowing for the juxtaposition of CD3+ T-cells to malignant CD19+ B-cells, thereby resulting in granzyme- and perforin-mediated B-cell apoptosis. Preclinical studies suggest that blinatumomab's efficacy is related to the effector-to-target ratio and to the difference between its affinity for CD19 and CD3. Preclinical and early phase clinical studies have allowed for the characterization of the pharmacokinetics of blinatumomab, including the determination of its short half-life. The metabolic pathway has not been fully characterized but is thought to be similar to that of other antibodies. Phase I and II studies led to the identification of an ideal stepwise dose, involving long-term continuous intravenous infusion (CIVI), to optimize its efficacy and reduce the risk of certain toxicities. A high remission rate and duration were noted among a relapsed/refractory population of patients. The results of clinical trials have identified cytokine release syndrome and neurotoxicity, among others, as serious drug-related toxicities, leading to the institution of a Risk Evaluation and Mitigation Strategy. Blinatumomab represents a significant addition to the treatment options for ALL, but it is not without its limitations, of which are its short-half life, necessitating long-term CIVI, and the eventual emergence of CD19-negative clones. Continual development of the agent involves assessing its role in the frontline

  10. Phenotyping and Target Expression Profiling of CD34+/CD38− and CD34+/CD38+ Stem- and Progenitor cells in Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Katharina Blatt

    2018-06-01

    Full Text Available Leukemic stem cells (LSCs are an emerging target of curative anti-leukemia therapy. In acute lymphoblastic leukemia (ALL, LSCs frequently express CD34 and often lack CD38. However, little is known about markers and targets expressed in ALL LSCs. We have examined marker- and target expression profiles in CD34+/CD38− LSCs in patients with Ph+ ALL (n = 22 and Ph− ALL (n = 27 by multi-color flow cytometry and qPCR. ALL LSCs expressed CD19 (B4, CD44 (Pgp-1, CD123 (IL-3RA, and CD184 (CXCR4 in all patients tested. Moreover, in various subgroups of patients, LSCs also displayed CD20 (MS4A1 (10/41 = 24%, CD22 (12/20 = 60%, CD33 (Siglec-3 (20/48 = 42%, CD52 (CAMPATH-1 (17/40 = 43%, IL-1RAP (13/29 = 45%, and/or CD135 (FLT3 (4/20 = 20%. CD25 (IL-2RA and CD26 (DPPIV were expressed on LSCs in Ph+ ALL exhibiting BCR/ABL1p210, whereas in Ph+ ALL with BCR/ABL1p190, LSCs variably expressed CD25 but did not express CD26. In Ph− ALL, CD34+/CD38− LSCs expressed IL-1RAP in 6/18 patients (33%, but did not express CD25 or CD26. Normal stem cells stained negative for CD25, CD26 and IL-1RAP, and expressed only low amounts of CD52. In xenotransplantation experiments, CD34+/CD38− and CD34+/CD38+ cells engrafted NSG mice after 12–20 weeks, and targeting with antibodies against CD33 and CD52 resulted in reduced engraftment. Together, LSCs in Ph+ and Ph− ALL display unique marker- and target expression profiles. In Ph+ ALL with BCR/ABL1p210, the LSC-phenotype closely resembles the marker-profile of CD34+/CD38− LSCs in chronic myeloid leukemia, confirming the close biologic relationship of these neoplasms. Targeting of LSCs with specific antibodies or related immunotherapies may facilitate LSC eradication in ALL.

  11. Nanoparticle targeted therapy against childhood acute lymphoblastic leukemia

    Science.gov (United States)

    Satake, Noriko; Lee, Joyce; Xiao, Kai; Luo, Juntao; Sarangi, Susmita; Chang, Astra; McLaughlin, Bridget; Zhou, Ping; Kenney, Elaina; Kraynov, Liliya; Arnott, Sarah; McGee, Jeannine; Nolta, Jan; Lam, Kit

    2011-06-01

    The goal of our project is to develop a unique ligand-conjugated nanoparticle (NP) therapy against childhood acute lymphoblastic leukemia (ALL). LLP2A, discovered by Dr. Kit Lam, is a high-affinity and high-specificity peptidomimetic ligand against an activated α4β1 integrin. Our study using 11 fresh primary ALL samples (10 precursor B ALL and 1 T ALL) showed that childhood ALL cells expressed activated α4β1 integrin and bound to LLP2A. Normal hematopoietic cells such as activated lymphocytes and monocytes expressed activated α4β1 integrin; however, normal hematopoietic stem cells showed low expression of α4β1 integrin. Therefore, we believe that LLP2A can be used as a targeted therapy for childhood ALL. The Lam lab has developed novel telodendrimer-based nanoparticles (NPs) which can carry drugs efficiently. We have also developed a human leukemia mouse model using immunodeficient NOD/SCID/IL2Rγ null mice engrafted with primary childhood ALL cells from our patients. LLP2A-conjugated NPs will be evaluated both in vitro and in vivo using primary leukemia cells and this mouse model. NPs will be loaded first with DiD near infra-red dye, and then with the chemotherapeutic agents daunorubicin or vincristine. Both drugs are mainstays of current chemotherapy for childhood ALL. Targeting properties of LLP2A-conjugated NPs will be evaluated by fluorescent microscopy, flow cytometry, MTS assay, and mouse survival after treatment. We expect that LLP2A-conjugated NPs will be preferentially delivered and endocytosed to leukemia cells as an effective targeted therapy.

  12. Cholinergic Machinery as Relevant Target in Acute Lymphoblastic T Leukemia

    Directory of Open Access Journals (Sweden)

    Oxana Dobrovinskaya

    2016-08-01

    Full Text Available Various types of non-neuronal cells, including tumors, are able to produce acetylcholine (ACh, which acts as an autocrine/paracrine growth factor. T lymphocytes represent a key component of the non-neuronal cholinergic system. T cells-derived ACh is involved in a stimulation of their activation and proliferation, and acts as a regulator of immune response. The aim of the present work was to summarize the data about components of cholinergic machinery in T lymphocytes, with an emphasis on the comparison of healthy and leukemic T cells. Cell lines derived from acute lymphoblastic leukemias of T lineage (T-ALL were found to produce a considerably higher amount of ACh than healthy T lumphocytes. Additionally, ACh produced by T-ALL is not efficiently hydrolyzed, because acetylcholinesterase (AChE activity is drastically decreased in these cells. Up-regulation of muscarinic ACh receptors was also demonstrated at expression and functional level, whereas nicotinic ACh receptors seem to play a less important role and not form functional channels in cells derived from T-ALL. We hypothesized that ACh over-produced in T-ALL may act as an autocrine growth factor and play an important role in leukemic clonal expansion through shaping of intracellular Ca2+ signals. We suggest that cholinergic machinery may be attractive targets for new drugs against T-ALL. Specifically, testing of high affinity antagonists of muscarinic ACh receptors as well as antagomiRs, which interfere with miRNAs involved in the suppression of AChE expression, may be the first choice options.

  13. The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Moriyama, Takaya; Nishii, Rina; Lin, Ting-Nien

    2017-01-01

    Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow...... children with acute lymphoblastic leukemia, we simultaneously measured both thioguanine nucleotides (TGN) in red blood cells and DNA-incorporated thioguanine (DNA-TG) in white blood cells. TGN levels were significantly lower in patients with NUDT15 deficiency, likely because of toxicity-related MP dose...

  14. TREATMENT OF ADOLESCENT AND YOUNG ADULTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Josep-Maria Ribera

    2014-07-01

    Full Text Available The primary objective of this review was to update and discuss the current concepts andthe results of the treatment of acute lymphoblastic leukemia (ALL in adolescents and young adults(AYA. After a brief consideration of the epidemiologic and clinicobiologic characteristics of ALLin the AYA population, the main retrospective comparative studies stating the superiority ofpediatric over adult-based protocols were reviewed. The most important prospective studies inyoung adults using pediatric inspired or pediatric unmodified protocols were also reviewedemphasizing their feasibility at least up to the age of 40 yr and their promising results, with eventfreesurvival rates of 60-65% or greater. Results of trials from pediatric groups have shown that theunfavourable prognosis of adolescents is no more adequate. The majority of the older adolescentswith ALL can be cured with risk-adjusted and minimal residual disease-guided intensivechemotherapy, without stem cell transplantation. However, some specific subgroups, which aremore frequent in adolescents than in children (e.g., early pre-T, iAMP21, and BCR-ABL-like,deserve particular attention. In summary, the advances in treatment of ALL in adolescents havebeen translated to young adults, and that explains the significant improvement in survival of thesepatients in recent years.

  15. Prognostic significance of P2RY8-CRLF2 and CRLF2 overexpression may vary across risk subgroups of childhood B-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Dou, Hu; Chen, Xi; Huang, Yi; Su, Yongchun; Lu, Ling; Yu, Jie; Yin, Yibing; Bao, Liming

    2017-02-01

    The cytokine receptor-like factor 2 (CRLF2) gene plays an important role in early B-cell development. Aberrations in CRLF2 activate the JAK-STAT signaling pathway that contributes to B-cell acute lymphoblastic leukemia (B-ALL). The prognostic significance of CRLF2 overexpression and P2RY8-CRLF2 fusion in various B-ALL risk subgroups has not been well established. Two hundred seventy-one patients with newly diagnosed childhood B-ALL were enrolled from a Chinese population. The prevalence of CRLF2 overexpression, CRLF2-P2RY8 fusion, CRLF2 F232C mutation, and JAK2 and IL7R mutational status were analyzed, and the prognostic impact of CRLF2 overexpression and P2RY8-CRLF2 on B-ALL was evaluated by assessing their influence on overall survival and event-free survival. CRLF2 overexpression and P2RY8-CRLF2 were found in 19% and 10%, respectively, in the whole cohort. No correlation between CRLF2 overexpression and P2RY8-CRLF2 was observed. CRLF2 F322C and IL7R mutations were not detected in B-ALL cases overexpressing CRLF2, and no JAK2 mutations were found in the whole cohort either. The results showed that CRLF2 overexpression and P2RY8-CRLF2 were associated with a poor outcome in unselected B-ALL. Moreover, in an intermediate risk B-ALL subgroup P2RY8-CRLF2 was correlated with worse survival, whereas in high- and low-risk subgroups, CRLF2 overexpression predicted a poor outcome. Our findings suggest that P2RY8-CRLF2 is an independent prognostic indicator in intermediate risk B-ALL, while CRLF2 overexpression is correlated with an inferior outcome in high- or low-risk B-ALL. Our study demonstrates that the impact of P2RY8-CRLF2 and CRLF2 overexpression on B-ALL survival may differ across risk subgroups. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  16. 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...

  17. Establishment of a common acute lymphoblastic leukemia cell line (LC4-1) and effects of phorbol myristate acetate (PMA) on the surface antigen expression of the cell line.

    Science.gov (United States)

    Yoshimura, T; Mayumi, M; Yorifuji, T; Kim, K M; Heike, T; Miyanomae, T; Shinomiya, K; Mikawa, H

    1987-09-01

    A common acute lymphoblastic leukemia (ALL) cell line, designated LC4-1, was established from peripheral blood mononuclear cells of a patient with acute non-T-cell ALL. LC4-1 cells were characteristically positive for Ia, B4, and common ALL antigens (CALLA), but negative for B2, Tac, T3, T4, T8, T11, and M1 antigens and E-rosette formation. Approximately 30% of LC4-1 cells expressed detectable amounts of B1 antigens. LC4-1 cells expressed neither Epstein-Barr-virus-associated nuclear antigen (EBNA), cytoplasmic immunoglobulins (cIg) nor surface immunoglobulins (sIg). Gene rearrangements had already occurred in LC4-1 in the D-J region of immunoglobulin heavy chain genes, but not in T-cell receptor (beta-chain) genes, suggesting that LC4-1 is a progenitor cell line of B-cell lineage earlier than pre-B-cells. The expression of cell surface antigens of LC4-1 was changed by treatment with 4-phorbol 12-myristate 13-acetate (PMA) (0.1 ng/ml) for 2 days. Before treatment with PMA, about 98% of LC4-1 cells were positive for B4, CALLA, and Ia. However, following treatment they lost CALLA expression without any change in expression of Ia and B4. There was no change in B1-positive population. The change in surface antigens on LC4-1 cells seems to be due to differentiation induced in the cells by PMA. These results support the hypothesis that CALLA is a differentiation antigen and suggest one possible differentiation pathway for pre-B-cells.

  18. Acute lymphoblastic leukemia in children and adolescents: prognostic factors and analysis of survival

    Science.gov (United States)

    Lustosa de Sousa, Daniel Willian; de Almeida Ferreira, Francisco Valdeci; Cavalcante Félix, Francisco Helder; de Oliveira Lopes, Marcos Vinicios

    2015-01-01

    Objective To describe the clinical and laboratory features of children and adolescents with acute lymphoblastic leukemia treated at three referral centers in Ceará and evaluate prognostic factors for survival, including age, gender, presenting white blood cell count, immunophenotype, DNA index and early response to treatment. Methods Seventy-six under 19-year-old patients with newly diagnosed acute lymphoblastic leukemia treated with the Grupo Brasileiro de Tratamento de Leucemia da Infância – acute lymphoblastic leukemia-93 and -99 protocols between September 2007 and December 2009 were analyzed. The diagnosis was based on cytological, immunophenotypic and cytogenetic criteria. Associations between variables, prognostic factors and response to treatment were analyzed using the chi-square test and Fisher's exact test. Overall and event-free survival were estimated by Kaplan–Meier analysis and compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors. Results The average age at diagnosis was 6.3 ± 0.5 years and males were predominant (65%). The most frequently observed clinical features were hepatomegaly, splenomegaly and lymphadenopathy. Central nervous system involvement and mediastinal enlargement occurred in 6.6% and 11.8%, respectively. B-acute lymphoblastic leukemia was more common (89.5%) than T-acute lymphoblastic leukemia. A DNA index >1.16 was found in 19% of patients and was associated with favorable prognosis. On Day 8 of induction therapy, 95% of the patients had lymphoblast counts <1000/μL and white blood cell counts <5.0 × 109/L. The remission induction rate was 95%, the induction mortality rate was 2.6% and overall survival was 72%. Conclusion The prognostic factors identified are compatible with the literature. The 5-year overall and event-free survival rates were lower than those reported for developed countries. As shown by the multivariate analysis, age and baseline white

  19. Acute lymphoblastic leukemia in children and adolescents: prognostic factors and analysis of survival

    Directory of Open Access Journals (Sweden)

    Daniel Willian Lustosa de Sousa

    2015-08-01

    Full Text Available OBJECTIVE: To describe the clinical and laboratory features of children and adolescents with acute lymphoblastic leukemia treated at three referral centers in Ceará and evaluate prognostic factors for survival, including age, gender, presenting white blood cell count, immunophenotype, DNA index and early response to treatment.METHODS: Seventy-six under 19-year-old patients with newly diagnosed acute lymphoblastic leukemia treated with the Grupo Brasileiro de Tratamento de Leucemia da Infância - acute lymphoblastic leukemia-93 and -99 protocols between September 2007 and December 2009 were analyzed. The diagnosis was based on cytological, immunophenotypic and cytogenetic criteria. Associations between variables, prognostic factors and response to treatment were analyzed using the chi-square test and Fisher's exact test. Overall and event-free survival were estimated by Kaplan-Meier analysis and compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors.RESULTS: The average age at diagnosis was 6.3 ± 0.5 years and males were predominant (65%. The most frequently observed clinical features were hepatomegaly, splenomegaly and lymphadenopathy. Central nervous system involvement and mediastinal enlargement occurred in 6.6% and 11.8%, respectively. B-acute lymphoblastic leukemia was more common (89.5% than T-acute lymphoblastic leukemia. A DNA index >1.16 was found in 19% of patients and was associated with favorable prognosis. On Day 8 of induction therapy, 95% of the patients had lymphoblast counts <1000/µL and white blood cell counts <5.0 Ã- 109/L. The remission induction rate was 95%, the induction mortality rate was 2.6% and overall survival was 72%.CONCLUSION: The prognostic factors identified are compatible with the literature. The 5-year overall and event-free survival rates were lower than those reported for developed countries. As shown by the multivariate analysis, age

  20. A new recurrent inversion, inv(7)(p15q34), leads to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias.

    Science.gov (United States)

    Speleman, F; Cauwelier, B; Dastugue, N; Cools, J; Verhasselt, B; Poppe, B; Van Roy, N; Vandesompele, J; Graux, C; Uyttebroeck, A; Boogaerts, M; De Moerloose, B; Benoit, Y; Selleslag, D; Billiet, J; Robert, A; Huguet, F; Vandenberghe, P; De Paepe, A; Marynen, P; Hagemeijer, A

    2005-03-01

    Chromosomal translocations with breakpoints in T-cell receptor (TCR) genes are recurrent in T-cell malignancies. These translocations involve the TCRalphadelta gene (14q11), the TCRbeta gene (7q34) and to a lesser extent the TCRgamma gene at chromosomal band 7p14 and juxtapose T-cell oncogenes next to TCR regulatory sequences leading to deregulated expression of those oncogenes. Here, we describe a new recurrent chromosomal inversion of chromosome 7, inv(7)(p15q34), in a subset of patients with T-cell acute lymphoblastic leukemia characterized by CD2 negative and CD4 positive, CD8 negative blasts. This rearrangement juxtaposes the distal part of the HOXA gene cluster on 7p15 to the TCRbeta locus on 7q34. Real time quantitative PCR analysis for all HOXA genes revealed high levels of HOXA10 and HOXA11 expression in all inv(7) positive cases. This is the first report of a recurrent chromosome rearrangement targeting the HOXA gene cluster in T-cell malignancies resulting in deregulated HOXA gene expression (particularly HOXA10 and HOXA11) and is in keeping with a previous report suggesting HOXA deregulation in MLL-rearranged T- and B cell lymphoblastic leukemia as the key factor in leukaemic transformation. Finally, our observation also supports the previous suggested role of HOXA10 and HOXA11 in normal thymocyte development.

  1. Esophageal strictures during treatment for acute lymphoblastic leukemia.

    LENUS (Irish Health Repository)

    Kelly, Kevin

    2012-02-01

    Esophageal stricture is a rare complication of paediatric cancer treatment that usually occurs after esophageal exposure to radiotherapy. We describe 4 cases of esophageal stricture during chemotherapy for acute lymphoblastic leukemia. All patients presented with refractory vomiting and were diagnosed with radiologic contrast studies. None of the patients had received radiotherapy. Esophageal candidiasis was seen in 2 patients but the remaining 2 patients had earlier systemic candidiasis. High-dose dexamethasone may predispose these children to both esophageal candidiasis and peptic esophagitis. The etiology of esophageal strictures during treatment for acute leukemia is likely to be multifactorial but systemic candidiasis may play a significant role.

  2. EBV-associated post-transplantation B-cell lymphoproliferative disorder following allogenic stem cell transplantation for acute lymphoblastic leukaemia: tumor regression after reduction of immunosuppression - a case report

    Directory of Open Access Journals (Sweden)

    Niedobitek Gerald

    2010-03-01

    Full Text Available Abstract Epstein-Barr virus (EBV-associated B-cell post-transplantation lymphoproliferative disorder (PTLD is a severe complication following stem cell transplantation. This is believed to occur as a result of iatrogenic immunosuppression leading to a relaxation of T-cell control of EBV infection and thus allowing viral reactivation and proliferation of EBV-infected B-lymphocytes. In support of this notion, reduction of immunosuppressive therapy may lead to regression of PTLD. We present a case of an 18-year-old male developing a monomorphic B-cell PTLD 2 months after receiving an allogenic stem cell transplant for acute lymphoblastic leukemia. Reduction of immunosuppressive therapy led to regression of lymphadenopathy. Nevertheless, the patient died 3 months afterwards due to extensive graft-vs.-host-disease and sepsis. As a diagnostic lymph node biopsy was performed only after reduction of immunosuppressive therapy, we are able to study the histopathological changes characterizing PTLD regression. We observed extensive apoptosis of blast cells, accompanied by an abundant infiltrate comprising predominantly CD8-positive, Granzyme B-positive T-cells. This observation supports the idea that regression of PTLD is mediated by cytotoxic T-cells and is in keeping with the observation that T-cell depletion, represents a major risk factor for the development of PTLD.

  3. Exit of pediatric pre-B acute lymphoblastic leukaemia cells from the bone marrow to the peripheral blood is not associated with cell maturation or alterations in gene expression

    Directory of Open Access Journals (Sweden)

    Wiebe Thomas

    2008-08-01

    Full Text Available Abstract Background Childhood pre-B acute lymphoblastic leukemia (ALL is a bone marrow (BM derived disease, which often disseminates out of the BM cavity, where malignant cells to a variable degree can be found circulating in the peripheral blood (PB. Normal pre-B cells are absolutely dependent on BM stroma for survival and differentiation. It is not known whether transformed pre-B ALL cells retain any of this dependence, which possibly could impact on drug sensitivity or MRD measurements. Results Pre-B ALL cells, highly purified by a novel method using surface expression of CD19 and immunoglobulin light chains, from BM and PB show a very high degree of similarity in gene expression patterns, with differential expression of vascular endothelial growth factor (VEGF as a notable exception. In addition, the cell sorting procedure revealed that in 2 out of five investigated patients, a significant fraction of the malignant cells had matured beyond the pre-B cell stage. Conclusion The transition of ALL cells from the BM into the circulation does not demand, or result in, major changes of gene expression pattern. This might indicate an independence of BM stroma on the part of transformed pre-B cells, which contrasts with that of their normal counterparts.

  4. Treatment of refractory/relapsed adult acute lymphoblastic leukemia with bortezomib- based chemotherapy

    Directory of Open Access Journals (Sweden)

    Zhao J

    2015-06-01

    Full Text Available Junmei Zhao,* Chao Wang,* Yongping Song, Yuzhang Liu, Baijun FangHenan Key Lab of Experimental Haematology, Henan Institute of Haematology, Henan Tumor Hospital, Zhengzhou University, Zhengzhou, People’s Republic of China  *These authors contributed equally to this work Abstract: Nine pretreated patients aged >19 years with relapsed/refractory acute lymphoblastic leukemia (ALL were treated with a combination of bortezomib plus chemotherapy before allogeneic hematopoietic stem cell transplantation (allo-HSCT. Eight (88.9% patients, including two Philadelphia chromosome-positive ALL patients, achieved a complete remission. Furthermore, the evaluable patients have benefited from allo-HSCT after response to this reinduction treatment. We conclude that bortezomib-based chemotherapy was highly effective for adults with refractory/relapsed ALL before allo-HSCT. Therefore, this regimen deserves a larger series within prospective trials to confirm these results. Keywords: acute lymphoblastic leukemia, refractory, relapsed, bortezomib

  5. Family-based exome-wide assessment of maternal genetic effects on susceptibility to childhood B-cell acute lymphoblastic leukemia in Hispanics

    Science.gov (United States)

    Archer, Natalie P.; Perez-Andreu, Virginia; Scheurer, Michael E.; Rabin, Karen R.; Peckham-Gregory, Erin C.; Plon, Sharon E.; Zabriskie, Ryan C.; De Alarcon, Pedro A.; Fernandez, Karen S.; Najera, Cesar R.; Yang, Jun J.; Antillon-Klussmann, Federico; Lupo, Philip J.

    2016-01-01

    Background Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) than other ethnic groups, but the genetic basis for racial disparities remain incompletely understood. Genome-wide association studies (GWAS) of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of maternal genotype on offspring phenotype development) may also play a role in ALL susceptibility. Methods We conducted a family-based exome-wide association study (EXWAS) of maternal genetic effects among Hispanics with childhood B-cell ALL (B-ALL) using the Illumina Human Exome BeadChip. We used a discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families. Results Three maternal SNPs approached our threshold for significance, after correction for multiple testing (P<1.0×10−6): MTL5 rs12365708 (RR=2.62, 95% CI=1.61-4.27, P=1.8×10−5); ALKBH1 rs6494 (RR=3.77, 95% CI=1.84-7.74, P=3.7×10−5); NEUROG3 rs4536103 (RR=1.75, 95% CI=1.30-2.37, P=1.2×10−4). While effect sizes were similar, these SNPs were not nominally significant in our replication cohort. In a meta-analysis comprised of the discovery cohort and the replication cohort, these SNPs were still not statistically significant after correction for multiple comparisons (rs12365708: pooled RR=2.27, 95% CI=1.48-3.50, P=1.99×10−4; rs6494: pooled RR=2.31, 95% CI=1.38-3.85, P=0.001; rs4536103: pooled RR=1.67, 95% CI=1.29-2.16, P=9.23×10−5). Conclusions In the first family-based EXWAS to investigate maternal genotype effects associated with childhood ALL, our results did not implicate a strong role of maternal genotype on disease risk among Hispanics; however, we identified three maternal SNPs that may play a modest role in susceptibility. PMID:27529658

  6. The t(10;14)(q24;q11) of T-cell acute lymphoblastic leukemia juxtaposes the δT-cell receptor with TCL3, a conserved and activated locus at 10q24

    International Nuclear Information System (INIS)

    Zutter, M.; Hockett, R.D.; Roberts, C.W.M.; McGuire, E.A.; Bloomstone, J.; Korsmeyer, S.J.; Morton, C.C.; Deaven, L.L.; Crist, W.M.; Carroll, A.J.

    1990-01-01

    The authors cloned the t(10;14) recurrent translocation from CD3-negative T-cell acute lymphoblastic leukemia cells. The breakpoint at 14q11 involved an intermediate rearrangement of the δ T-cell receptor locus, suggesting that the translocation arose at the time of antigen receptor assemblage. Translocation introduced chromosome segment 10q24 as proven by hybridization of a breakpoint-derived probe to flow-sorted chromosomes and metaphase chromosomes. Two t(10;14) breakpoints were clustered within a 600-base-pair region of 10q24 but no heptamer-spacer-nonamer motifs resembling T-cell receptor/immunoglobulin rearrangement signals were noted at the breakpoint. A locus distinct from terminal deoxynucleotidyltransferase was found at 10q24. Evolutionarily conserved regions surrounding the 10q24 breakpoint were examined for transcriptional activity. A region telomeric to the 10q24 breakpoint, expected to translocate to the der(14) chromosome, recognized an abundant 2.9-kilobase RNA in a t(10;14) T-cell leukemia. This locus was not active in a variety of other normal and neoplastic T cells, arguing that it was deregulated by he introduction of the T-cell receptor. This locus is a candidate for a putative protooncogene, TCL3, involved in T-cell neoplasia

  7. Heterogeneity of genomic fusion of BCR and ABL in Philadelphia chromosome-positive acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Rubin, C.M.; Carrino, J.J.; Dickler, M.N.; Leibowitz, D.; Smith, S.D.; Westbrook, C.A.

    1988-01-01

    Philadelphia chromosome-positive acute lymphoblastic leukemia occurs in two molecular forms, those with and those without rearrangement of the breakpoint cluster region on chromosome 22. The molecular abnormality in the former group is similar to that found in chronic myelogenous leukemia. To characterize the abnormality in the breakpoint cluster region-unrearranged form, the authors have mapped a 9; 22 translocation from the Philadelphia chromosome-positive acute lymphoblastic leukemia cell line SUP-B13 by using pulsed-field gel electrophoresis and have cloned the DNA at the translocation junctions. They demonstrate a BCR-ABL fusion gene on the Philadelphia chromosome. The exons from ABL are the same. Analysis of leukemic cells from four other patients with breakpoint cluster region-unrearranged Philadelphia chromosome-positive acute lymphoblastic leukemia revealed a rearrangement on chromosome 22 close to the breakpoint in SUP-B13 in only one patient. These data indicate that breakpoints do not cluster tightly in this region but are scattered, possibly in a large intron. Given the large size of BCR and the heterogeneity in breakpoint location, detection of BCR rearrangement by standard Southern blot analysis is difficult. Pulsed-field gel electrophoresis should allow detection at the DNA level in every patient and thus will permit clinical correlation of the breakpoint location with prognosis

  8. Acute lymphoblastic leukemia mimicking Wilms tumor at presentation.

    Science.gov (United States)

    Singh, Amitabh; Mandal, Anirban; Guru, Vijay; Seth, Rachna

    2016-09-01

    Acute lymphoblastic leukemia (ALL), the commonest malignancy of childhood, is known to manifest with a myriad of atypical presentations. Nephromegaly is a rare presentation of childhood ALL with hepatic mass being even rarer. We present a 3 year-old child with unilateral renal mass and hepatic mass lesion with normal blood counts, initially suspected to have metastatic Wilms tumor based on clinical, radiological and WT1 positivity on immunocytochemistry of renal mass. He was later diagnosed as ALL with peripheral blood flowcytometry and bone marrow examination. Renomegaly at presentation of acute leukemia is not necessarily due to leukemic infiltration and rarely leads to renal impairment. The radiological differential of such a renal mass includes both benign and malignant entities including metastasis. Over-expression of WT1 mRNA has been found in a number of solid tumors and hematological malignancies and is far from being diagnostic of Wilms tumor. Again, a small number of children with acute leukemia may have a deceptively normal complete blood count at presentation. Though, initial all (clinical, radiological, hematological, and immunocytological) parameters pointed towards a diagnosis of Wilms tumor in our case, the subsequent development of thrombocytopenia and lymphocytic leukocytosis prompted further investigation and final diagnosis of ALL. WT1 positivity is a known phenomenon in childhood ALL and undifferentiated lymphoblasts may be positive for WT1 and negative for Leucocyte common antigen. Acute leukemia with renal and hepatic mass with normal blood counts at presentation is a diagnostic challenge.

  9. DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Borssén, Magnus; Haider, Zahra; Landfors, Mattias

    2016-01-01

    . In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T......: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD ≥0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ...... regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. CONCLUSIONS: CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further...

  10. IKZF1 deletion is associated with a poor outcome in pediatric B-cell precursor acute lymphoblastic leukemia in Japan

    International Nuclear Information System (INIS)

    Asai, Daisuke; Imamura, Toshihiko; Suenobu, So-ichi; Saito, Akiko; Hasegawa, Daiichiro; Deguchi, Takao; Hashii, Yoshiko; Matsumoto, Kimikazu; Kawasaki, Hirohide; Hori, Hiroki; Iguchi, Akihiro; Kosaka, Yoshiyuki; Kato, Koji; Horibe, Keizo; Yumura-Yagi, Keiko; Hara, Junichi; Oda, Megumi

    2013-01-01

    Genetic alterations of Ikaros family zinc finger protein 1 (IKZF1), point mutations in Janus kinase 2 (JAK2), and overexpression of cytokine receptor-like factor 2 (CRLF2) were recently reported to be associated with poor outcomes in pediatric B-cell precursor (BCP)-ALL. Herein, we conducted genetic analyses of IKZF1 deletion, point mutation of JAK2 exon 16, 17, and 21, CRLF2 expression, the presence of P2RY8-CRLF2 fusion and F232C mutation in CRLF2 in 202 pediatric BCP-ALL patients newly diagnosed and registered in Japan Childhood Leukemia Study ALL02 protocol to find out if alterations in these genes are determinants of poor outcome. All patients showed good response to initial prednisolone (PSL) treatment. Ph + , infantile, and Down syndrome–associated ALL were excluded. Deletion of IKZF1 occurred in 19/202 patients (9.4%) and CRLF2 overexpression occurred in 16/107 (15.0%), which are similar to previous reports. Patients with IKZF1 deletion had reduced event-free survival (EFS) and overall survival (OS) compared to those in patients without IKZF1 deletion (5-year EFS, 62.7% vs. 88.8%, 5-year OS, 71.8% vs. 90.2%). Our data also showed significantly inferior 5-year EFS (48.6% vs. 84.7%, log rank P = 0.0003) and 5-year OS (62.3% vs. 85.4%, log rank P = 0.009) in NCI-HR patients (n = 97). JAK2 mutations and P2RY8-CRLF2 fusion were rarely detected. IKZF1 deletion was identified as adverse prognostic factor even in pediatric BCP-ALL in NCI-HR showing good response to PSL

  11. Prognosis after acute lymphoblastic leukaemia. [Side effects of radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Howarth, C B

    1975-04-01

    Following chemotherapy of lymphoblastic leukemia in children with folic acid antagonists, remission is achieved in 94 percent of patients. After chemotherapy has been stopped the risk of relapse is greatest during the first year, but relapses do occur. Sequelae of radiotherapy include bone growth impairment, brain cell damage, radioinduced neoplasms, and immunosuppression. Adverse effects of chemotherapy include hepatic fibrosis, impaired gonadal development, and oncogenic effects. (HLW)

  12. Metaphyseal impaction fractures in acute lymphoblastic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Manson, D.; Cockshott, W.P.; Martin, R.F.

    1989-01-01

    Patients with acute lymphatic leukaemia frequently are osteoporotic. A small subset of these develop disabling metaphyseal transverse fractures, usually bilateral and in the lower limb. These impaction fractures have a characteristic appearance and develop in recently laid down bone. They may develop ab initio of during therapy, Magnesium deficiency is found in these patients.

  13. Metaphyseal impaction fractures in acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Manson, D.; Cockshott, W.P.; Martin, R.F.

    1989-01-01

    Patients with acute lymphatic leukaemia frequently are osteoporotic. A small subset of these develop disabling metaphyseal transverse fractures, usually bilateral and in the lower limb. These impaction fractures have a characteristic appearance and develop in recently laid down bone. They may develop ab initio of during therapy, Magnesium deficiency is found in these patients. (orig.)

  14. Pyomyositis During Induction Chemotherapy for Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Kai-Liang Kao

    2006-04-01

    Full Text Available Herein, we report on the correct diagnosis and effective treatment procedures for pyomyositis, a very rare complication that remains a diagnostic challenge in children being treated for acute lymphoblastic leukemia (ALL. We report the case of a 10-year-old girl suffering from pyomyositis with ALL. Correct diagnosis is usually delayed because the initial symptom of pyomyositis, usually local pain, is similar to the common side effect of vincristine, a drug necessary for ALL induction therapy. We summarize the procedures taken to reach a timely diagnosis and therapeutic success.

  15. Oral health of children with acute lymphoblastic leukemia: A review

    Directory of Open Access Journals (Sweden)

    Kadalagere Lakshmana Girish Babu

    2016-01-01

    Full Text Available Leukemia is a malignancy of the bone marrow and blood. It is the most common childhood cancer in India. Advances in the treatment regimens have greatly increased the chances of survival. Both the disease and its treatment change the oral environment. In some cases, oral manifestations are the presenting feature of the disease and it will be the dentist′s responsibility to identify the underlying disorder and guide the diagnosis of the patient. Hence, the aim of present article is to review the literature concerning the oral health of children with acute lymphoblastic leukemia (ALL.

  16. A rare case of acute lymphoblastic leukaemia with hemophilia A

    Directory of Open Access Journals (Sweden)

    John Biju

    2009-12-01

    Full Text Available Abstract A rare case of Acute lymphoblastic leukemia with hemophillia in a 12 year old boy is presented in the article. Patient was known case of hemophillia (factor VIII deficiency. He was diagnosed as a case of ALL based on bone marrow examination and immunophenotypic study. Patient was treated as per Children Cancer group guidelines. The main aim of reporting this rare association lies in developing treatment strategies in preventing life threatening bleeding due to this rare association which though may be accidental but need further research.

  17. Features of children temperament with acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    N. A. Kornetov

    2013-01-01

    Full Text Available The temperament characteristics were studied in 86 children with acute lymphoblastic leukemia (ALL at the age of 3–16 years. Research was conducted using standardized and adapted to the Russian-speaking population of parental questionnaires for children of different age groups (Kolpakov V.G. et al., 1993. Statistically significant differences in temperament ALL patients from healthy children installed and feature of temperament, which is most often seen in children with conduct disorder are installed. The need for psychological and/or psychiatric counseling this category of patients is substantiated.

  18. Collagen XVIII Mutation in Knobloch Syndrome with Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Mahajan, Vinit B.; Olney, Ann Haskins; Garrett, Penny; Chary, Ajit; Dragan, Ecaterina; Lerner, Gary; Murray, Jeffrey; Bassuk, Alexander G.

    2010-01-01

    Knobloch syndrome (KNO) is caused by mutations in the collagen XIII gene (COL18A1) and patients develop encephalocele and vitreoretinal degeneration. Here we report an El Salvadorian family where two sisters showed features of KNO. One of the siblings also developed acute lymphoblastic leukemia. DNA sequencing of COL18A1revealed a homozygous, 2-base pair deletion (c3514-3515delCT) in exon 41, which leads to abnormal collagen XVIII and deficiency of its proteolytic cleavage product endostatin. KNO patients with mutations in COL18A1 may be at risk for endostatin-related conditions including malignancy. PMID:20799329

  19. Technical relapsed testicular irradiation for acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Velazquez Miranda, S.; Delgado Gil, M. M.; Ortiz Siedel, M.; Munoz Carmona, D. M.; Gomez-Barcelona, J.

    2011-01-01

    Testicular irradiation in children suffering from acute lymphoblastic leukemia presents difficulties in relation to daily positioning, dosimetry for dose homogenization of complex geometry and volume change during irradiation thereof. This can lead to significant deviations from the prescribed doses. In addition, the usual techniques often associated with unnecessary irradiation of pelvic simphysis, anus and perineum. This, in the case of pediatric patients, is of great importance, since doses in the vicinity of 20 Gy are associated with a deviation of bone growth, low testosterone levels around 24 Gy and high rates of generation of second tumors. To overcome these problems we propose a special restraint in prone and non-coplanar irradiation.

  20. Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

    Science.gov (United States)

    Milone, Jorge H; Enrico, Alicia

    2009-12-01

    The presence of the Philadelphia chromosome is a poor prognosis factor in acute lymphoblastic leukemia (ALL), in both children and adults. Using molecular techniques of the gen bcr/abl, it is possible to detect the abnormality, in up to the 40% of adult patients. The unsatisfactory results with conventional chemotherapy schemes have determined the intensification of the treatments and the consideration of allogenic bone marrow transplants as the best therapeutic instance. The development of tyrosine kinase inhibitors have become a therapeutic improvement in the treatment of Philadelphia chromosome-positive ALL, being combined with chemotherapy schemes, only in a selected group of patients, even in therapeutic programs that include transplant.

  1. [Disseminated fusariosis in a patient with acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Hermansen, N.E.; Ralfkiaer, E.M.; Kjeldsen, L.

    2008-01-01

    Invasive mould infections are a major cause of infectious mortality in highly immunosuppressed patients. Incidence in this high risk group is 10-20% with a death rate in excess of 50%. Most invasive moulds are Aspergillus spp. We present a case of a 74-year-old woman with acute lymphoblastic...... leukaemia who developed a rare disseminated mould infection with Fusarium solani during induction chemotherapy. We present the case story and discuss the pathogenesis, clinical characteristics and treatment of invasive fusariosis Udgivelsesdato: 2008/9/8...

  2. Acute lymphoblastic leukemia in a patient with chronic granulomatous disease and a novel mutation in CYBB: First report

    NARCIS (Netherlands)

    Wolach, Baruch; Ash, Shifra; Gavrieli, Ronit; Stark, Batia; Yaniv, Isaac; Roos, Dirk

    2005-01-01

    We report for the first time a child with chronic granulomatous disease (CGD) who developed acute lymphoblastic leukemia (ALL). The diagnosis of CGD was made at the age of 4 months, by studies of his neutrophil functions. The superoxide production of the cells was negligible, as was the bactericidal

  3. The evolution of clinical trials for infant acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Kotecha, R S; Gottardo, N G; Kees, U R; Cole, C H

    2014-01-01

    Acute lymphoblastic leukemia (ALL) in infants has a significantly inferior outcome in comparison with older children. Despite initial improvements in survival of infants with ALL since establishment of the first pediatric cooperative group ALL trials, the poor outcome has plateaued in recent years. Historically, infants were treated on risk-adapted childhood ALL protocols. These studies were pivotal in identifying the need for infant-specific protocols, delineating prognostic categories and the requirement for a more unified approach between study groups to overcome limitations in accrual because of low incidence. This subsequently led to the development of collaborative infant-specific studies. Landmark outcomes have included the elimination of cranial radiotherapy following the discovery of intrathecal and high-dose systemic therapy as a superior and effective treatment strategy for central nervous system disease prophylaxis, with improved neurodevelopmental outcome. Universal prospective identification of independent adverse prognostic factors, including presence of a mixed lineage leukemia rearrangement and young age, has established the basis for risk stratification within current trials. The infant-specific trials have defined limits to which conventional chemotherapeutic agents can be intensified to optimize the balance between treatment efficacy and toxicity. Despite variations in therapeutic intensity, there has been no recent improvement in survival due to the equilibrium between relapse and toxicity. Ultimately, to improve the outcome for infants with ALL, key areas still to be addressed include identification and adaptation of novel prognostic markers and innovative therapies, establishing the role of hematopoietic stem cell transplantation in first complete remission, treatment strategies for relapsed/refractory disease and monitoring and timely intervention of late effects in survivors. This would be best achieved through a single unified

  4. Induction of a central memory and stem cell memory phenotype in functionally active CD4+ and CD8+ CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19+ acute lymphoblastic leukemia.

    Science.gov (United States)

    Blaeschke, Franziska; Stenger, Dana; Kaeuferle, Theresa; Willier, Semjon; Lotfi, Ramin; Kaiser, Andrew Didier; Assenmacher, Mario; Döring, Michaela; Feucht, Judith; Feuchtinger, Tobias

    2018-03-31

    Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4 + /CD8 + -separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector. The process was performed on a closed, automated device requiring additional manual/open steps under clean room conditions. The clinical situation of these critically ill and refractory patients with leukemia leads to inconsistent cellular compositions at start of the procedure including high blast counts and low T-cell numbers with exhausted phenotype. Nevertheless, a robust T-cell product was achieved (mean CD4 +  = 50%, CD8 +  = 39%, transduction = 27%, Tcm = 50%, Tscm = 46%). Strong proliferative potential (up to > 100-fold), specific cytotoxicity and low expression of co-inhibitory molecules were documented. CAR T cells significantly released TH1 cytokines IFN-γ, TNF-α and IL-2 upon target-recognition. In conclusion, partly automated GMP-generation of CAR T cells from critically small blood samples was feasible with a new stimulation protocol that leads to high functionality and expansion potential, balanced CD4/CD8 ratios and a conversion to a Tcm/Tscm phenotype.

  5. Association of ARID5B gene variants with acute lymphoblastic leukemia in Yemeni children.

    Science.gov (United States)

    Al-Absi, Boshra; Noor, Suzita M; Saif-Ali, Riyadh; Salem, Sameer D; Ahmed, Radwan H; Razif, Muhammad Fm; Muniandy, Sekaran

    2017-04-01

    Studies have shown an association between ARID5B gene polymorphisms and childhood acute lymphoblastic leukemia. However, the association between ARID5B variants and acute lymphoblastic leukemia among the Arab population still needs to be studied. The aim of this study was to investigate the association between ARID5B variants with acute lymphoblastic leukemia in Yemeni children. A total of 14 ARID5B gene single nucleotide polymorphisms (SNPs) were genotyped in 289 Yemeni children, of whom 136 had acute lymphoblastic leukemia and 153 were controls, using the nanofluidic Dynamic Array (Fluidigm 192.24 Dynamic Array). Using logistic regression adjusted for age and gender, the risks of acute lymphoblastic leukemia were presented as odds ratios and 95% confidence intervals. We found that nine SNPs were associated with acute lymphoblastic leukemia under additive genetic models: rs7073837, rs10740055, rs7089424, rs10821936, rs4506592, rs10994982, rs7896246, rs10821938, and rs7923074. Furthermore, the recessive models revealed that six SNPs were risk factors for acute lymphoblastic leukemia: rs10740055, rs7089424, rs10994982, rs7896246, rs10821938, and rs7923074. The gender-specific impact of these SNPs under the recessive genetic model revealed that SNPs rs10740055, rs10994982, and rs6479779 in females, and rs10821938 and rs7923074 in males were significantly associated with acute lymphoblastic leukemia risk. Under the dominant model, SNPs rs7073837, rs10821936, rs7896246, and rs6479778 in males only showed striking association with acute lymphoblastic leukemia. The additive model revealed that SNPs with significant association with acute lymphoblastic leukemia were rs10821936 (both males and females); rs7073837, rs10740055, rs10994982, and rs4948487 (females only); and rs7089424, rs7896246, rs10821938, and rs7923074 (males only). In addition, the ARID5B haplotype block (CGAACACAA) showed a higher risk for acute lymphoblastic leukemia. The haplotype (CCCGACTGC) was

  6. Predictive value of minimal residual disease in Philadelphia-chromosome-positive acute lymphoblastic leukemia treated with imatinib in the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia, based on immunoglobulin/T-cell receptor and BCR/ABL1 methodologies

    Science.gov (United States)

    Cazzaniga, Giovanni; De Lorenzo, Paola; Alten, Julia; Röttgers, Silja; Hancock, Jeremy; Saha, Vaskar; Castor, Anders; Madsen, Hans O.; Gandemer, Virginie; Cavé, Hélène; Leoni, Veronica; Köhler, Rolf; Ferrari, Giulia M.; Bleckmann, Kirsten; Pieters, Rob; van der Velden, Vincent; Stary, Jan; Zuna, Jan; Escherich, Gabriele; zur Stadt, Udo; Aricò, Maurizio; Conter, Valentino; Schrappe, Martin; Valsecchi, Maria Grazia; Biondi, Andrea

    2018-01-01

    The prognostic value of minimal residual disease (MRD) in Philadelphia-chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors is not fully established. We detected MRD by real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes (IG/TR) and/or BCR/ABL1 fusion transcript to investigate its predictive value in patients receiving Berlin-Frankfurt-Münster (BFM) high-risk (HR) therapy and post-induction intermittent imatinib (the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia (EsPhALL) study). MRD was monitored after induction (time point (TP)1), consolidation Phase IB (TP2), HR Blocks, reinductions, and at the end of therapy. MRD negativity progressively increased over time, both by IG/TR and BCR/ABL1. Of 90 patients with IG/TR MRD at TP1, nine were negative and none relapsed, while 11 with MRD<5×10−4 and 70 with MRD≥5×10−4 had a comparable 5-year cumulative incidence of relapse of 36.4 (15.4) and 35.2 (5.9), respectively. Patients who achieved MRD negativity at TP2 had a low relapse risk (5-yr cumulative incidence of relapse (CIR)=14.3[9.8]), whereas those who attained MRD negativity at a later date showed higher CIR, comparable to patients with positive MRD at any level. BCR/ABL1 MRD negative patients at TP1 had a relapse risk similar to those who were IG/TR MRD negative (1/8 relapses). The overall concordance between the two methods is 69%, with significantly higher positivity by BCR/ABL1. In conclusion, MRD monitoring by both methods may be functional not only for measuring response but also for guiding biological studies aimed at investigating causes for discrepancies, although from our data IG/TR MRD monitoring appears to be more reliable. Early MRD negativity is highly predictive of favorable outcome. The earlier MRD negativity is achieved, the better the prognosis. PMID

  7. Risk Groups for Childhood Acute Lymphoblastic Leukemia

    Science.gov (United States)

    ... cells in the blood at the time of diagnosis. Whether the leukemia cells began from B lymphocytes or T lymphocytes. ... How long it is between the time of diagnosis and when the leukemia comes back. Whether the leukemia comes back in ...

  8. Treatment Options for Childhood Acute Lymphoblastic Leukemia

    Science.gov (United States)

    ... cells in the blood at the time of diagnosis. Whether the leukemia cells began from B lymphocytes or T lymphocytes. ... How long it is between the time of diagnosis and when the leukemia comes back. Whether the leukemia comes back in ...

  9. General Information about Childhood Acute Lymphoblastic Leukemia

    Science.gov (United States)

    ... cells in the blood at the time of diagnosis. Whether the leukemia cells began from B lymphocytes or T lymphocytes. ... How long it is between the time of diagnosis and when the leukemia comes back. Whether the leukemia comes back in ...

  10. Imitation of Mb. perthes through acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Zaunschirm, A.; Muntean, W.; Kaulfersch, W.; Kurz, R.; Ritter, G.; Schneider, G.

    1983-01-01

    A two year old boy was seen in the orthopedic clinics because of typical symptoms of Legg-Perthes disease, a scintigraphy with Technetium sup(99m) showed a distinct deficiency of nuclear activity in the femoral head which is characteristic of the early stage of Legg-Perthes disease. A routine blood count lead to the diagnosis of acute lymphoblastic leukemia. The boy was treated according to the Austrian cooperative leukemia protocol and complete remission was achieved. No orthopedic treatment of the femur head necrosis was done, after eight weeks of treatment with multiagent chemotherapy the boy started to walk again and subsequently became free of all symptoms of Legg-Perthes disease. A scintigraphy done eight weeks after the initial scintigraphy showed that the deficiency of radionuclear activity of the femoral head was nearly vanished. This case illustrates the variability of bone involvement in acute lymphoblastic leukemia, which often is the most prominent symptom at an early stage of the disease. (Author)

  11. A case of acute lymphoblastic leukemia with an intracerebellar mass

    International Nuclear Information System (INIS)

    Oshima, Yukio; Shitara, Toshiji; Kuribayashi, Toshio; Noji, Takashi; Kuroume, Takayoshi

    1983-01-01

    A 3-year-old boy, who had a complaint of hemorrhagic diathesis, was diagnosed as having acute lymphoblastic leukemia. Remission was induced by a combination of vincristine and prednisolone. Prophylactic intrathecal methotrexate and cranial irradiation were administered. Two years later, he was hospitalized for CNS leukemia and treated with multiple doses of intrathecal methotrexate. At the time, the results of CT scanning were normal. Six months later, though, he developed vomiting and lethargy. CT scanning showed a mass of an increased density in the right cerebellar hemisphere that displaced the fourth ventricle to the left and resulted in an obstructive hydrocephalus. Decompression was done by means of Ommaya reservoir setting. Soon his consciousness returned to normal, and CT scanning revealed no abnormal mass three weeks later. A month later, though, the CNS leukemia returned. He developed vomiting and a headache, and CT scanning showed a high-density mass in the right cerebellar hemisphere. The mass was diagnosed as hematoma. He died one month later. In this case, the previous mass showed evidence of a relatively uniform contrast enhancement, which is consistent with the intracerebral leukemic mass reported by Wendling. In Japan, this is the first report of an intracerebellar mass of acute lymphoblastic leukemia as perceived by CT scanning. (author)

  12. First-line treatment of acute lymphoblastic leukemia with pegasparaginase

    Directory of Open Access Journals (Sweden)

    Riccardo Masetti

    2009-07-01

    Full Text Available Riccardo Masetti, Andrea PessionPediatric Oncology and Hematology Unit “Lalla Seràgnoli”, University of Bologna, Bologna, ItalyAbstract: Acute lymphoblastic leukemia (ALL accounts for almost 4000 cases annually in the United States, approximately two thirds of which are in children and adolescents. Treatment results of ALL have improved considerably in the past decade, due to an optimal stratification of patients and a rational use of different antileukemic agents among which L-asparaginase (L-ASNase plays a fundamental role. This drug has been used in pediatric ALL chemotherapy protocols for almost 3 decades. In the 1970s and 1980s a chemically modified form of this enzyme called pegasparaginase (PEG-ASNase was rationally synthesized to decrease immunogenicity of the enzyme and prolong its half-life. The different advantages of PEG-ASNase have been demonstrated in many clinical studies, the last of which underline the utility of this drug in front-line therapy of ALL. In this review, we discuss the pharmacological advantages and clinical potential of PEG-ASNase and its important use in first-line treatment of ALL.Keywords: pegasparaginase, acute, lymphoblastic leukemia, pegylation

  13. Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Lund, Bendik; Åsberg, Ann; Heyman, Mats

    2011-01-01

    -cell disease (HR: 1.9, 95% CI: 1.01-3.7), Down syndrome (HR: 7.3, 95% CI: 3.6-14.9) and haematopoietic stem cell transplantation in CR1 (HR: 8.0, 95% CI: 3.3-19.5) were identified as independent risk factors for TRD. CONCLUSION: Several TRDs were potentially preventable and future efforts should be directed......BACKGROUND: In spite of major improvements in the cure rate of childhood acute lymphoblastic leukaemia (ALL), 2-4% of patients still die from treatment related complications. PROCEDURE: We investigated the pattern of treatment related deaths (TRDs) and possible risk factors in the NOPHO ALL-92...

  14. Acute Activation of Metabolic Syndrome Components in Pediatric Acute Lymphoblastic Leukemia Patients Treated with Dexamethasone

    NARCIS (Netherlands)

    Warris, Lidewij T.; van den Akker, Erica L. T.; Bierings, Marc B.; van den Bos, Cor; Zwaan, Christian M.; Sassen, Sebastiaan D. T.; Tissing, Wim J. E.; Veening, Margreet A.; Pieters, Rob; van den Heuvel-Eibrink, Marry M.

    2016-01-01

    Although dexamethasone is highly effective in the treatment of pediatric acute lymphoblastic leukemia (ALL), it can cause serious metabolic side effects. Because studies regarding the effects of dexamethasone are limited by their small scale, we prospectively studied the direct effects of treating

  15. CDX2 gene expression in acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Arnaoaut, H.H.; Mokhtar, D.A.; Samy, R.M.; Omar, Sh.A.; Khames, S.A.

    2014-01-01

    CDX genes are classically known as regulators of axial elongation during early embryogenesis. An unsuspected role for CDX genes has been revealed during hematopoietic development. The CDX gene family member CDX2 belongs to the most frequent aberrantly expressed proto-oncogenes in human acute leukemias and is highly leukemogenic in experimental models. We used reversed transcriptase polymerase chain reaction (RT-PCR) to determine the expression level of CDX2 gene in 30 pediatric patients with acute lymphoblastic leukemia (ALL) at diagnosis and 30 healthy volunteers. ALL patients were followed up to detect minimal residual disease (MRD) on days 15 and 42 of induction. We found that CDX2 gene was expressed in 50% of patients and not expressed in controls. Associations between gene expression and different clinical and laboratory data of patients revealed no impact on different findings. With follow up, we could not confirm that CDX2 expression had a prognostic significance.

  16. Childhood acute lymphoblastic leukemia: from genome to patient

    International Nuclear Information System (INIS)

    Kolenova, A.

    2016-01-01

    Acute lymphoblastic leukemia is the most common malignant disease in childhood. During recent decades prognosis for children with acute leukemia has greatly improved, including the patients treated in the Slovak Republic. The prognosis for these patients has improved as a result of the systematic and well-organized international research efforts and clinical trials. The advent of new genomic technologies has provided new insights into leukemogenesis, identified many novel subtypes of leukemia, and triggered development of new therapeutic formulations. The success of treatment depends on stratifying patients into risk group and incorporating novel treatment strategies.The Slovak pediatric leukemia group is actively incorporated into these international clinical trials and the outcome for our patients is comparable to the results published in Western Europe. (author)

  17. Leydig cell damage after testicular irradiation for lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Shalet, S.M.; Horner, A.; Ahmed, S.R.; Morris-Jones, P.H.

    1985-01-01

    The effect of testicular irradiation on Leydig cell function has been studied in a group of boys irradiated between 1 and 5 years earlier for a testicular relapse of acute lymphoblastic leukemia. Six of the seven boys irradiated during prepubertal life had an absent testosterone response to HCG stimulation. Two of the four boys irradiated during puberty had an appropriate basal testosterone level, but the testosterone response to HCG stimulation was subnormal in three of the four. Abnormalities in gonadotropin secretion consistent with testicular damage were noted in nine of the 11 boys. Evidence of severe Leydig cell damage was present irrespective of whether the boys were studied within 1 year or between 3 and 5 years after irradiation, suggesting that recovery is unlikely. Androgen replacement therapy has been started in four boys and will be required by the majority of the remainder to undergo normal pubertal development

  18. High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients.

    Science.gov (United States)

    Pan, J; Yang, J F; Deng, B P; Zhao, X J; Zhang, X; Lin, Y H; Wu, Y N; Deng, Z L; Zhang, Y L; Liu, S H; Wu, T; Lu, P H; Lu, D P; Chang, A H; Tong, C R

    2017-12-01

    Refractory or relapsed B lymphoblastic leukemia (B-ALL) patients have a dismal outcome with current therapy. We treated 42 primary refractory/hematological relapsed (R/R) and 9 refractory minimal residual disease by flow cytometry (FCM-MRD + ) B-ALL patients with optimized second generation CD19-directed CAR-T cells. The CAR-T-cell infusion dosages were initially ranged from 0.05 to 14 × 10 5 /kg and were eventually settled at 1 × 10 5 /kg for the most recent 20 cases. 36/40 (90%) evaluated R/R patients achieved complete remission (CR) or CR with incomplete count recovery (CRi), and 9/9 (100%) FCM-MRD + patients achieved MRD - . All of the most recent 20 patients achieved CR/CRi. Most cases only experienced mild to moderate CRS. 8/51 cases had seizures that were relieved by early intervention. Twenty three of twenty seven CR/CRi patients bridged to allogeneic hematopoietic stem cell transplantation (allo-HCT) remained in MRD - with a median follow-up time of 206 (45-427) days, whereas 9 of 18 CR/CRi patients without allo-HCT relapsed. Our results indicate that a low CAR-T-cell dosage of 1 × 10 5 /kg, is effective and safe for treating refractory or relapsed B-ALL, and subsequent allo-HCT could further reduce the relapse rate.

  19. Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

    DEFF Research Database (Denmark)

    Schmiegelow, Kjeld; Müller, Klaus Gottlob; Mogensen, Signe Sloth

    2017-01-01

    During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal...... useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall...... obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically...

  20. Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

    Science.gov (United States)

    Schmiegelow, Kjeld; Müller, Klaus; Mogensen, Signe Sloth; Mogensen, Pernille Rudebeck; Wolthers, Benjamin Ole; Stoltze, Ulrik Kristoffer; Tuckuviene, Ruta; Frandsen, Thomas

    2017-01-01

    During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs. PMID:28413626

  1. Acute Pancreatitis and Diabetic Ketoacidosis following L-Asparaginase/Prednisone Therapy in Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Dania Lizet Quintanilla-Flores

    2014-01-01

    Full Text Available Acute pancreatitis and diabetic ketoacidosis are unusual adverse events following chemotherapy based on L-asparaginase and prednisone as support treatment for acute lymphoblastic leukemia. We present the case of a 16-year-old Hispanic male patient, in remission induction therapy for acute lymphoblastic leukemia on treatment with mitoxantrone, vincristine, prednisone, and L-asparaginase. He was hospitalized complaining of abdominal pain, nausea, and vomiting. Hyperglycemia, acidosis, ketonuria, low bicarbonate levels, hyperamylasemia, and hyperlipasemia were documented, and the diagnosis of diabetic ketoacidosis was made. Because of uncertainty of the additional diagnosis of acute pancreatitis as the cause of abdominal pain, a contrast-enhanced computed tomography was performed resulting in a Balthazar C pancreatitis classification.

  2. Inactivation of the P16INK4/MTS1 gene by a chromosome translocation t(9;14)(p21-22;q11) in an acute lymphoblastic leukemia of B-cell type.

    Science.gov (United States)

    Duro, D; Bernard, O; Della Valle, V; Leblanc, T; Berger, R; Larsen, C J

    1996-02-15

    We have reported previously a preliminary study of a t(9;14)(p21-22; q11) in B-cell acute lymphoblastic leukemia. This translocation had rearranged the TCRA/D locus on chromosome band 14q11 and the locus encoding the tumor suppressor gene P16INK4/MTS1 (P16) on band 9p21 (D. Duro et al., Oncogene, 11: 21-29, 1995). In the present report, the breakpoints were precisely localized on each chromosome partner. On the 14q- derivative, the sequence derived from chromosome 9 was interrupted at 1.0 kb upstream of the first exon of P16, close to a consensus recombination heptamer, CACTGTG. In addition, the chromosome 14 breakpoint was localized at the end of the TCRD2 (delta 2) segment, and 22 residues with unknown origin were present at the translocation junction. On the 9p+ derivative, chromosome 9 sequences were in continuity with those displaced onto chromosome 14, and the 14q11 breakpoint was located within TCRJA29 segment. These features are consistent with aberrant activity of the TCR gene recombinase complex. Although all three coding exons of P16 were displaced onto the chromosome 14q-derivative, no P16 transcript was detected in the leukemic cells. Because the region spanning the P16 exon 1 was not inactivated by methylation and because the other P16 allele was deleted, the implication is that the chromosome breakpoint was likely to disrupt regulatory elements involved in the normal expression of the gene. As a whole, then, our results show that translocations affecting band 9p21 can participate to the inactivation of P16, thus justifying a systematic survey of translocations of the 9p21 band in acute lymphoblastic leukemia.

  3. Association of Macroeconomic Factors With Nonrelapse Mortality After Allogeneic Hematopoietic Cell Transplantation for Adults With Acute Lymphoblastic Leukemia: An Analysis From the Acute Leukemia Working Party of the EBMT.

    Science.gov (United States)

    Giebel, Sebastian; Labopin, Myriam; Ibatici, Adalberto; Browne, Paul; Czerw, Tomasz; Socie, Gerard; Unal, Ali; Kyrcz-Krzemien, Slawomira; Bacigalupo, Andrea; Goker, Hakan; Potter, Mike; Furness, Caroline L; McQuaker, Grant; Beelen, Dietrich; Milpied, Noel; Campos, Antonio; Craddock, Charles; Nagler, Arnon; Mohty, Mohamad

    2016-03-01

    From a global perspective, the rates of allogeneic hematopoietic cell transplantation (alloHCT) are closely related to the economic status of a country. However, a potential association with outcome has not yet been documented. The goal of this study was to evaluate effects of health care expenditure (HCE), Human Development Index (HDI), team density, and center experience on nonrelapse mortality (NRM) after HLA-matched sibling alloHCT for adults with acute lymphoblastic leukemia (ALL). A total of 983 patients treated with myeloablative alloHCT between 2004 and 2008 in 24 European countries were included. In a univariate analysis, the probability of day 100 NRM was increased for countries with lower current HCE (8% vs. 3%; p = .06), countries with lower HDI (8% vs. 3%; p = .02), and centers with less experience (8% vs. 5%; p = .04). In addition, the overall NRM was increased for countries with lower current HCE (21% vs. 17%; p = .09) and HDI (21% vs. 16%; p = .03) and for centers with lower activity (21% vs. 16%; p = .07). In a multivariate analysis, the strongest predictive model for day 100 NRM included current HCE greater than the median (hazard ratio [HR], 0.39; p = .002). The overall NRM was mostly predicted by HDI greater than the median (HR, 0.65; p = .01). Both lower current HCE and HDI were associated with decreased probability of overall survival. Both macroeconomic factors and the socioeconomic status of a country strongly influence NRM after alloHCT for adults with ALL. Our findings should be considered when clinical studies in the field of alloHCT are interpreted. ©AlphaMed Press.

  4. Comparable results of autologous and allogeneic haematopoietic stem cell transplantation for adults with Philadelphia-positive acute lymphoblastic leukaemia in first complete molecular remission: An analysis by the Acute Leukemia Working Party of the EBMT.

    Science.gov (United States)

    Giebel, Sebastian; Labopin, Myriam; Potter, Michael; Poiré, Xavier; Sengeloev, Henrik; Socié, Gerard; Huynh, Anne; Afanasyev, Boris V; Schanz, Urs; Ringden, Olle; Kalhs, Peter; Beelen, Dietrich W; Campos, Antonio M; Masszi, Tamás; Canaani, Jonathan; Mohty, Mohamad; Nagler, Arnon

    2018-06-01

    Allogeneic haematopoietic stem cell transplantation (alloHSCT) is considered a standard treatment for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) achieving complete remission after induction containing tyrosine kinase inhibitors (TKIs). We retrospectively compared results of myeloablative alloHSCT from either matched sibling donor (MSD) or unrelated donor (URD) with autologous (auto) HSCT for adults with Ph+ ALL in molecular remission, treated between 2007 and 2014. In univariate analysis, the incidence of relapse at 2 years was 47% after autoHSCT, 28% after MSD-HSCT and 19% after URD-HSCT (P = 0.0002). Respective rates of non-relapse mortality were 2%, 18%, and 22% (P = 0.001). The probabilities of leukaemia-free survival were 52%, 55% and 60% (P = 0.69), while overall survival rates were 70%, 70% and 69% (P = 0.58), respectively. In multivariate analysis, there was a trend towards increased risk of overall mortality after MSD-HSCT (hazard ratio [HR], 1.5, P = 0.12) and URD-HSCT (HR, 1.6, P = 0.08) when referred to autoHSCT. The use of total body irradiation (TBI)-based regimens was associated with reduced risk of relapse (HR, 0.65, P = 0.02) and overall mortality (HR, 0.67, P = 0.01). In the era of TKIs, outcomes of myeloablative autoHSCT and alloHSCT for patients with Ph+ ALL in first molecular remission are comparable. Therefore, autoHSCT appears to be an attractive treatment option potentially allowing for circumvention of alloHSCT sequelae. Irrespective of the type of donor, TBI-based regimens should be considered the preferable type of conditioning for Ph+ ALL. Copyright © 2018 Elsevier Ltd. All rights reserved.

  5. Characterization of the CDR3 structure of the Vβ21 T cell clone in patients with P210(BCR-ABL)-positive chronic myeloid leukemia and B-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Zha, Xianfeng; Chen, Shaohua; Yang, Lijian; Li, Bo; Chen, Yu; Yan, Xiaojuan; Li, Yangqiu

    2011-10-01

    The clonally expanded T cells identified in most cancer patients that respond to tumor-associated antigen such as P210(BCR-ABL) protein have definite, specific antitumor cytotoxicity. T cell receptor (TCR) Vβ CDR3 repertoire diversity was analyzed in patients with chronic myeloid leukemia (CML) and BCR-ABL(+) B-cell acute lymphoblastic leukemia (B-ALL) by GeneScan. A high frequency of oligoclonal expansion of the TCR Vβ21 subfamily was observed in the peripheral blood of CML and B-ALL patients. These clonally expanded Vβ21 T cells were correlated with the pathophysiologic process of CML. A conserved amino acid motif (SLxxV) was observed within the CDR3 region in only 3 patients with CML. Preferential usage of the Jβ segments was also observed in a minority of patients. The 3-dimensional structures of the CDR3 region containing the same motif or using the same Jβ segment displayed low similarity; on the contrary, the conformation of the CDR3 region containing no conserved motif in some T cell clones was highly similar. In conclusion, our findings indicate a high frequency of TCR Vβ21 subfamily expansion in p210(BCR-ABL)-positive CML and B-ALL patients. The characterization of the CDR3 structure was complex. Regrettably, at this time it was not possible to confirm that the Vβ21 T cell clones were derived from the stimulation of p210(BCR-ABL) protein. Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  6. CD26: A Prognostic Marker of Acute Lymphoblastic Leukemia in Children in the Post Remission Induction Phase.

    Science.gov (United States)

    Mehde, Atheer Awad; Yusof, Faridah; Adel Mehdi, Wesen; Zainulabdeen, Jwan Abdulmohsin

    2015-01-01

    ALL is an irredeemable disease due to the resistance to treatment. There are several influences which are involved in such resistance to chemotherapy, including oxidative stress as a result of the generation of reactive oxygen species (ROS) and presence of hypodiploid cells. Cluster of differentiation 26 (CD26), also known as dipeptidyl peptidase-4, is a 110 kDa, multifunctional, membrane-bound glycoprotein. The aim of this study was to evaluate the clinical significance of serum CD26 in patients with acute lymphoblastic leukaemia patients in the post remission induction phase, as well as the relationship between CD26 activity and the oxidative stress status. CD26, total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI), in addition to activity of related enzymes myeloperoxidase, glutathione- s-transferase and xanthine oxidase, were analysed in sixty children with acute lymphoblastic leukaemia in the post remission induction phase. The study showed significant elevation in CD26, TOS and OSI levels in patients with acute lymphoblastic leukaemia in the post remission induction phase in comparison to healthy control samples. In contrast, myeloperoxidase, glutathione-s-transferase and xanthine oxidase activities were decreased significantly. A significant correlation between CD26 concentration and some oxidative stress parameters was evident in ALL patients. Serum levels of CD26 appear to be useful as a new biomarker of oxidative stress in children with acute lymphoblastic leukaemia in the post remission induction phase, and levels of antioxidants must be regularly estimated during the treatment of children with ALL.

  7. Allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia who had central nervous system involvement: a study from the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation.

    Science.gov (United States)

    Shigematsu, Akio; Kako, Shinichi; Mitsuhashi, Kenjiro; Iwato, Koji; Uchida, Naoyuki; Kanda, Yoshinobu; Fukuda, Takahiro; Sawa, Masashi; Senoo, Yasushi; Ogawa, Hiroyasu; Miyamura, Koichi; Takada, Satoru; Nagamura-Inoue, Tokiko; Morishima, Yasuo; Ichinohe, Tatsuo; Atsuta, Yoshiko; Mizuta, Shuichi; Tanaka, Junji

    2017-06-01

    The prognosis for adult acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement (CNS+) who received allogeneic hematopoietic stem cell transplantation (allo-SCT) remains unclear. We retrospectively compared the outcomes of allo-SCT for patients with CNS involvement and for patients without CNS involvement (CNS-) using a database in Japan. The eligibility criteria for this study were as follows: diagnosis of ALL, aged more than 16 years, allo-SCT between 2005 and 2012, and first SCT. Data for 2582 patients including 136 CNS+ patients and 2446 CNS- patients were used for analyses. As compared with CNS- patients, CNS+ patients were younger, had worse disease status at SCT and had poorer performance status (PS) at SCT (P < 0.01). Incidence of relapse was higher in CNS+ patients (P = 0.02), and incidence of CNS relapse was also higher (P < 0.01). The probability of 3-year overall survival (OS) was better in CNS- patients (P < 0.01) by univariate analysis. However, in patients who received SCT in CR, there was no difference in the probability of OS between CNS+ and CNS- patients (P = 0.38) and CNS involvement did not have an unfavorable effect on OS by multivariate analysis. CNS+ patients who achieved CR showed OS comparable to that of CNS- patients.

  8. DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Nordlund, Jessica; Bäcklin, Christofer L; Zachariadis, Vasilios

    2015-01-01

    BACKGROUND: We present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA...... in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant...

  9. Acute lymphoblastic leukemia with multiple cytogenetic abnormalities secondary to treatment of Ewing's sarcoma

    Energy Technology Data Exchange (ETDEWEB)

    Al-Homaidhi, A.M. [Department of Medicine, Princess Margaret Hospital and The University of Toronto, 610 University Ave, Rm. 4-429, Toronto, Ont. M5G 2M9 (Canada); Patterson, B. [Department of Pathology, Princess Margaret Hospital and The University of Toronto, 610 University Ave, Rm. 4-429, Toronto, Ont. M5G 2M9 (Canada); Rubin, S. [Moncton Hospital, Moncton, New Brunswick (Canada); Lipton, J.H. [Department of Medicine, Princess Margaret Hospital and The University of Toronto, 610 University Ave, Rm. 4-429, Toronto, Ont. M5G 2M9 (Canada)

    1999-06-01

    We report the case of a 22-year-old man with Ewing's sarcoma who attained a complete remission (CR) after combination radiotherapy and chemotherapy. Secondary acute lymphoblastic leukemia with multiple cytogenetic abnormalities involving chromosome 5 and 7 developed 16 years later. The patient underwent induction chemotherapy and entered a CR. Peripheral blood stem cell transplantation from a matched sibling was performed successfully and he is in complete remission of both ALL and Ewing's sarcoma. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)

  10. Acute lymphoblastic leukemia with multiple cytogenetic abnormalities secondary to treatment of Ewing's sarcoma

    International Nuclear Information System (INIS)

    Al-Homaidhi, A.M.; Patterson, B.; Rubin, S.; Lipton, J.H.

    1999-01-01

    We report the case of a 22-year-old man with Ewing's sarcoma who attained a complete remission (CR) after combination radiotherapy and chemotherapy. Secondary acute lymphoblastic leukemia with multiple cytogenetic abnormalities involving chromosome 5 and 7 developed 16 years later. The patient underwent induction chemotherapy and entered a CR. Peripheral blood stem cell transplantation from a matched sibling was performed successfully and he is in complete remission of both ALL and Ewing's sarcoma. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)

  11. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia | Office of Cancer Genomics

    Science.gov (United States)

    Publication Abstract:  Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL.

  12. CLINICAL AND IMMUNO-METABOLIC PECULIARITIES OF THE PRIMARY ATTACK OF ACUTE LYMPHOBLASTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Olga Valentinovna Smirnova

    2017-12-01

    Full Text Available The authors studied the characteristics of the clinical condition, cellular, humoral immunity and metabolism of lymphocytes in patients with acute lymphoblastic leukemia at the onset of the disease, with the primary attack. The disease usually begins with the combined symptoms appearance in the clinical picture. Fever, fatigue, decreased performance, dizziness, the accompanying infection process were recorded in most patients. Reduction of T-lymphocytes and a decrease in the ratio of CD4+ to CD8+ contributed to the debut appearance of ALL and T-cell immunodeficiency development. Changed metabolomics of energy, plastic processes in lymphocytes. The authors proposed an immunometabolic own concept of the disease.

  13. Cytogenetic Profile and Gene Mutations of Childhood Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Nawaf Alkhayat

    2017-07-01

    Full Text Available Background: Childhood acute lymphoblastic leukemia (ALL is characterized by recurrent genetic aberrations. The identification of those abnormalities is clinically important because they are considered significant risk-stratifying markers. Aims: There are insufficient data of cytogenetic profiles in Saudi Arabian patients with childhood ALL leukemia. We have examined a cohort of 110 cases of ALL to determine the cytogenetic profiles and prevalence of FLT3 mutations and analysis of the more frequently observed abnormalities and its correlations to other biologic factors and patient outcomes and to compare our results with previously published results. Materials and methods: Patients —We reviewed all cases from 2007 to 2016 with an established diagnosis of childhood ALL. Of the 110 patients, 98 were B-lineage ALL and 12 T-cell ALL. All the patients were treated by UKALL 2003 protocol and risk stratified according previously published criteria. Cytogenetic analysis —Chromosome banding analysis and fluorescence in situ hybridization were used to detect genetic aberrations. Analysis of FLT3 mutations —Bone marrow or blood samples were screened for FLT3 mutations (internal tandem duplications, and point mutations, D835 using polymerase chain reaction methods. Result: Cytogenetic analysis showed chromosomal anomalies in 68 out of 102 cases with an overall incidence 66.7%. The most frequent chromosomal anomalies in ALL were hyperdiploidy, t(9;22, t(12;21, and MLL gene rearrangements. Our data are in accordance with those published previously and showed that FLT3 mutations are not common in patients with ALL (4.7% and have no prognostic relevance in pediatric patients with ALL. On the contrary, t(9;22, MLL gene rearrangements and hypodiploidy were signs of a bad prognosis in childhood ALL with high rate of relapse and shorter overall survival compared with the standard-risk group ( P  = .031.The event-free survival was also found to be worse ( P

  14. Bacteremia due to Aeromonas hydrophila in Acute Lymphoblastic Leukemia

    International Nuclear Information System (INIS)

    Fatima, A.; Afridi, F.I.; Farooqi, B.J.; Qureshi, A.; Hussain, A.

    2013-01-01

    Aeromonas hydrophila (A. hydrophila) is a low virulent organism but may cause devastating fatal infections in immunocompromised host especially in liver cirrhosis. It is rarely reported to cause septicemia in a patient with Acute Lymphoblastic Leukemia (ALL). The mortality rate of septicemia due to A. hydrophila is 29% to 73%. We report a case of 59-year-old female patient who was a known case of ALL, presented with the complaints of fever, lethargy and generalized weakness for one month. After taking blood samples for investigations, empirical antimicrobial therapy was started. She did not improve after 48 hours of therapy. Meanwhile blood culture revealed pure growth of A. hydrophila. After sensitivity report was available, ciprofloxacin was started. Patient became afebrile after 48 hours of treatment with ciprofloxacin. It is very vital to correctly identified and treat bacteremia due to A. hydrophila especially in the underlying leukemic patient. (author)

  15. Prediction of intellectual deficits in children with acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Trautman, P.D.; Erickson, C.; Shaffer, D.; O'Connor, P.A.; Sitarz, A.; Correra, A.; Schonfeld, I.S.

    1988-01-01

    Possible predictors of reported lower cognitive functioning in irradiated children with acute lymphoblastic leukemia (ALL) were investigated. Thirty-four subjects, 5-14 years old, with ALL in continuous complete remission and without evidence of current or past central nervous system disease, were examined 9-110 months after diagnosis, using standard measures of intelligence and academic achievement. Subjects with a history of post-irradiation somnolence syndrome were significantly older at diagnosis than nonsomnolent subjects. Intelligence (IQ) was found to be unrelated to history of somnolence syndrome. IQ and achievement were unrelated to age at irradiation, irradiation-examination interval, and radiation dosages. The strongest predictor of IQ by far is parental social class. The importance of controlling for social class differences when searching for treatment effects on IQ and achievement is stressed

  16. [Acute lymphoblastic leukemia of T progenitors: from biology to clinics].

    Science.gov (United States)

    Genescà, Eulàlia; Ribera, Jordi; Ribera, Josep-Maria

    2015-03-09

    Acute lymphoblastic leukemia (ALL) is the most common cancer in children and the main cause of morbidity among childhood blood disorders. There are 2 subtypes according to the affected lymphoid progenitor: B-ALL and T-ALL. The T-ALL is the less common and, although historically was associated with poor prognosis in both adults and children, at present, treatment outcomes do not differ significantly between the 2 types of ALL. The T-ALL subtype is the most complex and heterogeneous at the genetic level and currently the one with less new therapeutic alternatives available. This trend is changing thanks to the remarkable progress upon understanding its biology. This review summarizes the most recent and important biological findings in T-ALL and their possible therapeutic implications. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

  17. Childhood Acute Lymphoblastic Leukemia: Integrating Genomics into Therapy

    Science.gov (United States)

    Tasian, Sarah K; Loh, Mignon L; Hunger, Stephen P

    2015-01-01

    Acute lymphoblastic leukemia (ALL), the most common malignancy of childhood, is a genetically complex entity that remains a major cause of childhood cancer-related mortality. Major advances in genomic and epigenomic profiling during the past decade have appreciably enhanced knowledge of the biology of de novo and relapsed ALL and have facilitated more precise risk stratification of patients. These achievements have also provided critical insights regarding potentially targetable lesions for development of new therapeutic approaches in the era of precision medicine. This review delineates the current genetic landscape of childhood ALL with emphasis upon patient outcomes with contemporary treatment regimens, as well as therapeutic implications of newly identified genomic alterations in specific subsets of ALL. PMID:26194091

  18. Childhood vaccinations and risk of acute lymphoblastic leukaemia in children

    DEFF Research Database (Denmark)

    Søegaard, Signe Holst; Rostgaard, Klaus; Schmiegelow, Kjeld

    2017-01-01

    information on ALL subtypes. Using Cox regression, we estimated hazard ratios (HRs) comparing vaccinated with unvaccinated children.Results: Childhood ALL was diagnosed in 490 children during 10 829 194 person-years of follow-up. Neither the total number of vaccine doses received nor exposure to each......Background: It has been proposed that childhood vaccinations protect against acute lymphoblastic leukaemia (ALL) in children by modulation of future responses to common infections in childhood. However, the available studies provide inconsistent findings, and population-based cohort studies...... with longitudinal information on vaccinations are lacking.Methods: In a register-based cohort of all children born in Denmark from 1 January 1990 to 31 December 2008, followed up until age 15 years or 31 December 2009 (n=1 225 404), we evaluated exposure to childhood vaccination and risk of childhood ALL, including...

  19. Acute lymphoblastic leukemia in adolescents and young adults.

    Science.gov (United States)

    Ribera, Josep-Maria; Oriol, Albert

    2009-10-01

    Today, long-term survival is achieved in more than 80% of children 1 to 10 years old with acute lymphoblastic leukemia (ALL). However, cure rates for adults and adolescents and young adults (AYA) with ALL remain relatively low, at only 40% to 50%. Age is a continuous prognostic variable in ALL, with no single age at which prognosis deteriorates markedly. Within childhood ALL populations, older children have shown inferior outcomes, whereas younger adults have shown superior outcomes among adult ALL patients. The type of treatment (pediatric-based versus adult-based) for AYA has recently been a matter of debate. In this article the biology and treatment of ALL in AYA is reviewed.

  20. Remission rate of acute lymphoblastic leukemia (all) in adolescents and young adults (aya)

    International Nuclear Information System (INIS)

    Vallacha, A.; Haider, G.; Kumar, D.

    2018-01-01

    To determine the remission rate in adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL). Study Design:Descriptive study. Place and Duration of Study:Department of Oncology, Jinnah Postgraduate Medical Centre (JPMC), Karachi from January, 2016 to March, 2017. Methodology:Adolescent and young adult (AYA) patients aged 15-39 years, newly diagnosed with acute lymphoblastic leukemia from January, 2016 to March, 2017. Diagnosis was confirmed by bone marrow trephine biopsy and immuno-phenotyping. All the patients were treated with daunorubicin, vincristine, prednisone, and L-asparaginase in the induction phase. The response evaluation was done on day 35 of the induction phase and the remission rate was assessed by the bone marrow examination. Results:Of the total 50 AYA patients diagnosed with ALL, 41 patients could complete induction phase and 9 patients died during the first week of induction, therefore excluded from the study. Forty (97.8%) patients were <35years of age, 28 (68.3%) were male, of female 10 (24.4%) were housewives, 33 (80.5%) patients belonged to Sindh, 28 (68.3%) presented with fever and body ache, 17 (41.5%) patients had precursor B cell type ALL, with 7 (17.1%) patients had hemoglobin of <7 g/dL,11 (26.8%) patients had white cell count of >30x10/sup 9//L, platelet count of <20x103/mu L in 6 (14.6%) patients and complete morphological remission was reported in 29 (70.7%) patients. Conclusion:The remission induction rate was 70.7% in the adolescents and young adults with acute lymphoblastic leukemia at the study centre. (author)

  1. Molecular discrimination between relapsed and secondary acute lymphoblastic leukemia : Proposal for an easy strategy

    NARCIS (Netherlands)

    Szczepanski, T; Willemse, MJ; Kamps, WA; van Wering, ER; Langerak, AW; van Dongen, JJM

    Background. Discrimination between late relapse of acute lymphoblastic leukemia (ALL) and secondary ALL might be clinically important, because the former might still respond favorably to chemotherapy and/or bone marrow transplantation, whereas secondary ALL is associated with poor prognosis.

  2. Host genome variations and risk of infections during induction treatment for childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Lund, Bendik; Wesolowska-Andersen, Agata; Lausen, Birgitte

    2014-01-01

    Objectives: To investigate association of host genomic variation and risk of infections during treatment for childhood acute lymphoblastic leukaemia (ALL). Methods: We explored association of 34 000 singlenucleotide polymorphisms (SNPs) related primarily to pharmacogenomics and immune function...

  3. The controversy of varicella vaccination in children with acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Caniza, Miguela A; Hunger, Stephen P; Schrauder, Andre

    2012-01-01

    The available guidelines for varicella vaccination of susceptible children with acute lymphoblastic leukemia (ALL) have become increasingly conservative. However, vaccination of those who have remained in continuous complete remission for 1 year and are receiving chemotherapy is still considered...

  4. Predicting the neurobehavioral side effects of dexamethasone in pediatric acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Warris, Lidewij T.; van den Akker, Erica L. T.; Aarsen, Femke K.; Bierings, Marc B.; van den Bos, Cor; Tissing, Wim J. E.; Sassen, Sebastiaan D. T.; Veening, Margreet A.; Zwaan, Christian M.; Pieters, Rob; van den Heuvel-Eibrink, Marry M.

    2016-01-01

    Although dexamethasone is an effective treatment for acute lymphoblastic leukemia (ALL), it can induce a variety of serious neurobehavioral side effects. We hypothesized that these side effects are influenced by glucocorticoid sensitivity at the tissue level. We therefore prospectively studied

  5. Hepatotoxicity During Maintenance Therapy and Prognosis in Children With Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Ebbesen, Maria S.; Nygaard, Ulrikka; Rosthøj, Susanne

    2017-01-01

    Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine...

  6. Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients

    NARCIS (Netherlands)

    Sassen, Sebastiaan D. T.; Mathôt, Ron A. A.; Pieters, Rob; Kloos, Robin Q. H.; de Haas, Valérie; Kaspers, Gertjan J. L.; van den Bos, Cor; Tissing, Wim J. E.; te Loo, Maroeska; Bierings, Marc B.; Kollen, Wouter J. W.; Zwaan, Christian M.; van der Sluis, Inge M.

    2017-01-01

    Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough

  7. Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients

    NARCIS (Netherlands)

    Sassen, Sebastiaan D. T.; Mathot, Ron A. A.; Pieters, Rob; Kloos, Robin Q. H.; de Haas, Valerie; Kaspers, Gertjan J. L.; van den Bos, Cor; Tissing, Wim J. E.; te Loo, D. Maroeska W. M.; Bierings, Marc B.; Kollen, Wouter J. W.; Zwaan, Christian M.; van der Sluis, Inge M.

    Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough

  8. Effect of azole antifungal therapy on vincristine toxicity in childhood acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Schie, R.M. van; Bruggemann, R.J.M.; Hoogerbrugge, P.M.; Loo, D.M. te

    2011-01-01

    BACKGROUND: Vincristine is one of the cornerstones of the treatment of children with acute lymphoblastic leukaemia (ALL). Constipation, and peripheral and central neurotoxicities are the most common side effects. A comparative study exploring vincristine toxicity in individual patients receiving

  9. Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Cyclophosphamide, Total-Body Irradiation and Donor Bone Marrow Transplant in Treating Patients With Advanced Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or High-Risk Myelodysplastic Syndrome

    Science.gov (United States)

    2018-05-14

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; CD45-Positive Neoplastic Cells Present; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Refractory Anemia With Excess Blasts; Refractory Anemia With Ring Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts

  10. Imaging findings of the brain abnormalities in acute lymphoblastic leukemia of children during and after treatment

    International Nuclear Information System (INIS)

    Lee, Kyung Joo; Lee, Seung Rho; Park, Dong Woo; Joo, Kyung Bin; Kim, Jang Wook; Hahm, Chang Kok; Kim, Ki Joong; Lee, Hahng

    2001-01-01

    We evaluated the imaging abnormalities of the brain observed during and after treatment of acute childhood lymphoblastic leukemia. The study group consisted of 30 patients (male : female=19 : 11 ; mean age, 64 months) with acute childhood lymphoblastic leukemia during the previous ten-year period who had undergone prophylaxis of the central nervous system. Irrespective of the CNS symptoms, base-line study of the brain involving CT and follow-up CT or MRI was undertaken more than once. We retrospectively evaluated the imaging findings, methods of treatment, associated CNS symptoms, and the interval between diagnosis and the time at which brain abnormalities were revealed by imaging studies. In 15 (50% ; male : female=9 : 6 ; mean age, 77 months) of 30 patients, brain abnormalities that included brain atrophy (n=9), cerebral infarctions (n=4), intracranial hemorrhage (n=1), mineralizing microangiopathy (n=2), and periventricular leukomalacia (n=3) were seen on follow-up CT or MR images. In four of nine patients with brain atrophy, imaging abnormalities such as periventricular leukomalacia (n=2), infarction (n=1) and microangiopathy (n=1) were demonstrated. Fourteen of the 15 patients underwent similar treatment ; the one excluded had leukemic cells in the CSF. Six patients had CNS symptoms. In the 15 patients with abnormal brain imaging findings, the interval between diagnosis and the demonstration of brain abnormalities was between one month and four years. After the cessation of treatment, imaging abnormalities remained in all patients except one with brain atrophy. Various imaging abnormalities of the brain may be seen during and after the treatment of acute childhood lymphoblastic leukemia and persist for a long time. In children with this condition, the assessment of brain abnormalities requires follow-up study of the brain

  11. Imaging findings of the brain abnormalities in acute lymphoblastic leukemia of children during and after treatment

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Kyung Joo; Lee, Seung Rho; Park, Dong Woo; Joo, Kyung Bin; Kim, Jang Wook; Hahm, Chang Kok; Kim, Ki Joong; Lee, Hahng [College of Medicine, Hanyang Univ., Seoul (Korea, Republic of)

    2001-09-01

    We evaluated the imaging abnormalities of the brain observed during and after treatment of acute childhood lymphoblastic leukemia. The study group consisted of 30 patients (male : female=19 : 11 ; mean age, 64 months) with acute childhood lymphoblastic leukemia during the previous ten-year period who had undergone prophylaxis of the central nervous system. Irrespective of the CNS symptoms, base-line study of the brain involving CT and follow-up CT or MRI was undertaken more than once. We retrospectively evaluated the imaging findings, methods of treatment, associated CNS symptoms, and the interval between diagnosis and the time at which brain abnormalities were revealed by imaging studies. In 15 (50% ; male : female=9 : 6 ; mean age, 77 months) of 30 patients, brain abnormalities that included brain atrophy (n=9), cerebral infarctions (n=4), intracranial hemorrhage (n=1), mineralizing microangiopathy (n=2), and periventricular leukomalacia (n=3) were seen on follow-up CT or MR images. In four of nine patients with brain atrophy, imaging abnormalities such as periventricular leukomalacia (n=2), infarction (n=1) and microangiopathy (n=1) were demonstrated. Fourteen of the 15 patients underwent similar treatment ; the one excluded had leukemic cells in the CSF. Six patients had CNS symptoms. In the 15 patients with abnormal brain imaging findings, the interval between diagnosis and the demonstration of brain abnormalities was between one month and four years. After the cessation of treatment, imaging abnormalities remained in all patients except one with brain atrophy. Various imaging abnormalities of the brain may be seen during and after the treatment of acute childhood lymphoblastic leukemia and persist for a long time. In children with this condition, the assessment of brain abnormalities requires follow-up study of the brain.

  12. The pyrrolo-1,5-benzoxazepine, PBOX-15, enhances TRAIL-induced apoptosis by upregulation of DR5 and downregulation of core cell survival proteins in acute lymphoblastic leukaemia cells

    Science.gov (United States)

    NATHWANI, SEEMA-MARIA; GREENE, LISA M.; BUTINI, STEFANIA; CAMPIANI, GIUSEPPE; WILLIAMS, D. CLIVE; SAMALI, AFSHIN; SZEGEZDI, EVA; ZISTERER, DANIELA M.

    2016-01-01

    Apoptotic defects are frequently associated with poor outcome in pediatric acute lymphoblastic leukaemia (ALL) hence there is an ongoing demand for novel strategies that counteract apoptotic resistance. The death ligand TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) and its selective tumour receptor system has attracted exceptional clinical interest. However, many malignancies including ALL are resistant to TRAIL monotherapy. Tumour resistance can be overcome by drug combination therapy. TRAIL and its agonist antibodies are currently undergoing phase II clinical trials with established chemotherapeutics. Herein, we present promising therapeutic benefits in combining TRAIL with the selective anti-leukaemic agents, the pyrrolo-1,5-benzoxazepines (PBOXs) for the treatment of ALL. PBOX-15 synergistically enhanced apoptosis induced by TRAIL and a DR5-selective TRAIL variant in ALL-derived cells. PBOX-15 enhanced TRAIL-induced apoptosis by dual activation of extrinsic and intrinsic apoptotic pathways. The specific caspase-8 inhibitor, Z-IETD-FMK, identified the extrinsic pathway as the principal mode of apoptosis. We demonstrate that PBOX-15 can enhance TRAIL-induced apoptosis by upregulation of DR5, reduction of cellular mitochondrial potential, activation of the caspase cascade and downregulation of PI3K/Akt, c-FLIP, Mcl-1 and IAP survival pathways. Of note, the PI3K pathway inhibitor LY-294002 significantly enhanced the apoptotic potential of TRAIL and PBOX-15 validating the importance of Akt downregulation in the TRAIL/PBOX-15 synergistic combination. Considering the lack of cytotoxicity to normal cells and ability to downregulate several survival pathways, PBOX-15 may represent an effective agent for use in combination with TRAIL for the treatment of ALL. PMID:27176505

  13. ATF5 polymorphisms influence ATF function and response to treatment in children with childhood acute lymphoblastic leukemia

    OpenAIRE

    Rousseau, Julie; Gagné, Vincent; Labuda, Malgorzata; Beaubois, Cyrielle; Sinnett, Daniel; Laverdière, Caroline; Moghrabi, Albert; Sallan, Stephen E.; Silverman, Lewis B.; Neuberg, Donna; Kutok, Jeffery L.; Krajinovic, Maja

    2011-01-01

    Asparaginase is a standard and critical component in the therapy of childhood acute lymphoblastic leukemia. Asparagine synthetase (ASNS) and the basic region leucine zipper activating transcription factor 5 (ATF5) and arginosuccinate synthase 1 (ASS1) have been shown to mediate the antileukemic effect of asparaginase and to display variable expression between leukemia cells that are resistant and sensitive to treatment. Fourteen polymorphisms in the regulatory and coding regions of these gene...

  14. Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Wojtuszkiewicz, Anna; Peters, Godefridus J; van Woerden, Nicole L

    2015-01-01

    BACKGROUND: Methotrexate (MTX) eradicates leukemic cells by disrupting de novo nucleotide biosynthesis and DNA replication, resulting in cell death. Since its introduction in 1947, MTX-containing chemotherapeutic regimens have proven instrumental in achieving curative effects in acute lymphoblast...... resistant to MTX at diagnosis may allow for tailoring novel treatment strategies to individual leukemia patients....... leukemia (ALL). However, drug resistance phenomena pose major obstacles to efficacious ALL chemotherapy. Moreover, clinically relevant molecular mechanisms underlying chemoresistance remain largely obscure. Several alterations in MTX metabolism, leading to impaired accumulation of this cytotoxic agent...... in tumor cells, have been classified as determinants of MTX resistance. However, the relation between MTX resistance and long-term clinical outcome of ALL has not been shown previously. METHODS: We have collected clinical data for 235 childhood ALL patients, for whom samples taken at the time of diagnosis...

  15. Metabolomics of the tumor microenvironment in pediatric acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Stefano Tiziani

    Full Text Available The tumor microenvironment is emerging as an important therapeutic target. Most studies, however, are focused on the protein components, and relatively little is known of how the microenvironmental metabolome might influence tumor survival. In this study, we examined the metabolic profiles of paired bone marrow (BM and peripheral blood (PB samples from 10 children with acute lymphoblastic leukemia (ALL. BM and PB samples from the same patient were collected at the time of diagnosis and after 29 days of induction therapy, at which point all patients were in remission. We employed two analytical platforms, high-resolution magnetic resonance spectroscopy and gas chromatography-mass spectrometry, to identify and quantify 102 metabolites in the BM and PB. Standard ALL therapy, which includes l-asparaginase, completely removed circulating asparagine, but not glutamine. Statistical analyses of metabolite correlations and network reconstructions showed that the untreated BM microenvironment was characterized by a significant network-level signature: a cluster of highly correlated lipids and metabolites involved in lipid metabolism (p<0.006. In contrast, the strongest correlations in the BM upon remission were observed among amino acid metabolites and derivatives (p<9.2 × 10(-10. This study provides evidence that metabolic characterization of the cancer niche could generate new hypotheses for the development of cancer therapies.

  16. The molecular genetic makeup of acute lymphoblastic leukemia.

    Science.gov (United States)

    Mullighan, Charles G

    2012-01-01

    Genomic profiling has transformed our understanding of the genetic basis of acute lymphoblastic leukemia (ALL). Recent years have seen a shift from microarray analysis and candidate gene sequencing to next-generation sequencing. Together, these approaches have shown that many ALL subtypes are characterized by constellations of structural rearrangements, submicroscopic DNA copy number alterations, and sequence mutations, several of which have clear implications for risk stratification and targeted therapeutic intervention. Mutations in genes regulating lymphoid development are a hallmark of ALL, and alterations of the lymphoid transcription factor gene IKZF1 (IKAROS) are associated with a high risk of treatment failure in B-ALL. Approximately 20% of B-ALL cases harbor genetic alterations that activate kinase signaling that may be amenable to treatment with tyrosine kinase inhibitors, including rearrangements of the cytokine receptor gene CRLF2; rearrangements of ABL1, JAK2, and PDGFRB; and mutations of JAK1 and JAK2. Whole-genome sequencing has also identified novel targets of mutation in aggressive T-lineage ALL, including hematopoietic regulators (ETV6 and RUNX1), tyrosine kinases, and epigenetic regulators. Challenges for the future are to comprehensively identify and experimentally validate all genetic alterations driving leukemogenesis and treatment failure in childhood and adult ALL and to implement genomic profiling into the clinical setting to guide risk stratification and targeted therapy.

  17. Acute lymphoblastic leukemia in adolescents and young adults.

    Science.gov (United States)

    Burke, Patrick W; Douer, Dan

    2014-01-01

    The cure rate of acute lymphoblastic leukemia (ALL) in children is 80%, compared to less than half in adults. A major proportion of this cure rate drop occurs in adolescents and young adults (AYAs). The age range defining this population varies between studies, biological characteristics are different from both younger children and older adults, and AYAs are treated either by pediatric or adult oncologists, who often apply different treatment approaches to the same ALL patient population. The outcome of AYAs aged 15-21 years treated by more contemporary pediatric protocols is similar to that of younger children but is inferior when using adult regimens. This motivated studying AYA patients, including those above the age of 21 years, with pediatric or 'pediatrics-inspired' regimens that intensified nonmyelosuppressive drugs such as vincristine, steroids and asparaginase, with very promising preliminary results. Discovering new mutations in AYA ALL will help stratify patients into risk subgroups and identify targets for novel agents. This, together with fine-tuning pediatric chemotherapy principles will hopefully finally decrease the cure rate gap between children and AYAs - and even older adults. © 2014 S. Karger AG, Basel.

  18. L-asparaginase induced hyperlipidaemia in acute lymphoblastic leukaemia

    International Nuclear Information System (INIS)

    Nesheli, H. M.; Tamaddoni, A.; Hosseinzadeh, F.; Moghaddam, T. G.

    2013-01-01

    Objective: To evaluate hyperlipidaemia in patients with acute lymphoblastic leukaemia (ALL) receiving L-asparaginase. Methods: A case-control study carried out between October 2007 and October 2010 with 77 patients undergoing chemotherapy at a teaching children hospital in Babol, Iran. Patients were treated with anti-leukaemic agents according to the protocols for standard-risk and high-risk ALL. Those patients who received asparaginase represented the cases and those who did not receive it were the controls. Biochemical markers were checked during the induction phase chemotherapy. Lipid profile of patients was recorded. Data was analysed using SPSS 16. Results: Of the 77 patients, 37 (48.05%) received asparaginase therapy and 40 (51.94%) patients did not. The mean peak triglyceride and cholesterol levels during asparaginase therapy in the first group were significantly higher than the levels in the second group. Conclusion: Severe hyperlipidaemia may be the cause of some morbidity in children receiving asparaginase. Asparaginase-induced hyperlipidaemia should be monitored in ALL patients during the induction phase of treatment. (author)

  19. Outcome following late marrow relapse in childhood acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Chessells, J.; Leiper, A.; Rogers, D.

    1984-01-01

    Thirty-four children with acute lymphoblastic leukemia, who developed bone marrow relapse after treatment was electively stopped, received reinduction, consolidation, continuing therapy, and intrathecal (IT) methotrexate (MTX). Sixteen children who relapsed within six months of stopping treatment had a median second-remission duration of 26 weeks; all next relapses occurred in the bone marrow. In 18 children who relapsed later, the median duration of second remission was in excess of two years, but after a minimum of four years follow-up, 16 patients have so far relapsed again (six in the CNS). CNS relapse occurred as a next event in four of 17 children who received five IT MTX injections only and in two of 14 children who received additional regular IT MTX. Although children with late marrow relapses may achieve long second remissions, their long-term out-look is poor, and regular IT MTX does not afford adequate CNS prophylaxis. It remains to be seen whether more intensive chemotherapy, including high-dose chemoradiotherapy and bone marrow transplantation, will improve the prognosis in this group of patients

  20. Suppressed neutrophil function in children with acute lymphoblastic leukemia.

    Science.gov (United States)

    Tanaka, Fumiko; Goto, Hiroaki; Yokosuka, Tomoko; Yanagimachi, Masakatsu; Kajiwara, Ryosuke; Naruto, Takuya; Nishimaki, Shigeru; Yokota, Shumpei

    2009-10-01

    Infection is a major obstacle in cancer chemotherapy. Neutropenia has been considered to be the most important risk factor for severe infection; however, other factors, such as impaired neutrophil function, may be involved in susceptibility to infection in patients undergoing chemotherapy. In this study, we analyzed neutrophil function in children with acute lymphoblastic leukemia (ALL). Whole blood samples were obtained from 16 children with ALL at diagnosis, after induction chemotherapy, and after consolidation chemotherapy. Oxidative burst and phagocytic activity of neutrophils were analyzed by flow cytometry. Oxidative burst of neutrophils was impaired in ALL patients. The percentage of neutrophils with normal oxidative burst after PMA stimulation was 59.0 +/- 13.2 or 70.0 +/- 21.0% at diagnosis or after induction chemotherapy, respectively, which was significantly lower compared with 93.8 +/- 6.1% in healthy control subjects (P = 0.00004, or 0.002, respectively); however, this value was normal after consolidation chemotherapy. No significant differences were noted in phagocytic activity in children with ALL compared with healthy control subjects. Impaired oxidative burst of neutrophils may be one risk factor for infections in children with ALL, especially in the initial periods of treatment.

  1. SIGNIFICANCE OF ETV6-RUNX1 FUSION GENE TRANSCRIPT DETECTION IN PEDIATRIC B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA WITH TRANSLOCATION t(12;21(p13;q22

    Directory of Open Access Journals (Sweden)

    G. A. Tsaur

    2017-01-01

    Full Text Available Introduction. Translocation t(12;21(p13;q22 is one of the most common structural genetic abnormalities in childhood acute lymphoblastic leukemia (ALL. It cannot be detected by conventional G-banding, so a reverse-transcriptase polymerase chain reaction (RT-PCR or fluorescent in situ hybridization are used for this purpose.The aim of the study was to evaluate the prognostic significance of qualitative and quantitative detection of ETV6-RUNX1 fusion gene transcript at various time points in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL patients.Materials and methods. ETV6-RUNX1 fusion gene transcript was revealed by both reverse-transcriptase PCR and quantitative real-time PCR (RQ-PCR in 34 out of 166 (20.5 % children with BCP-ALL. Qualitative ETV6-RUNX1-positivity at days 36 and 85 led to unfavorable outcome (lower event-free survival –EFS and higher cumulative incidence of relapse – CIR. While ETV6-RUNX1 status at day 15 did not allow to divide patients with different outcomes. By ROC curve analysis we determined threshold levels (TL for ETV6-RUNX1/ABL1 ratio at days 0, 15, 36 and 85. Afterwards we adjusted obtained results to 10-fold scale.Results. So practically applicable TL were as follows 500.0 %, 1 %, 0.1 % и 0.01 % for days 0, 15, 36 and 85, respectively. EFS and CIR were both worse in patients with ETV6-RUNX1/ABL1 ratio equal or above defined TL. Moreover, initial ratio ≥500,0 % corresponded to delayed blast clearance at days 15 and 36. We showed good qualitative (84.8 % and quantitative (R2 = 0.953 concordance between ETV6-RUNX1/ABL1 ratio and MRD data obtained by flow cytometry at days 15, 36, 85. Of note, defined TL for ETV6-RUNX1/ABL1 at days 15, 36, 85 were equal to prognostically important levels for flow cytometry MRD.Conclusion. Thus, qualitative detection and quantitative value of ETV6-RUNX1 fusion gene transcript showed prognostic significance in the course of treatment in children with BCP-ALL. Based

  2. Duration of adrenal insufficiency during treatment for childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Vestergaard, Therese Risom; Juul, Anders; Lausten-Thomsen, Ulrik

    2011-01-01

    Children with acute lymphoblastic leukemia (ALL) recive high doses of glucocorticosteroid as part of their treatment. This may lead to suppression of the hypothalamic-pituitary-adrenal axis, acute adrenal insufficiency, and ultimately to life-threatening conditions. This study explores the adrena...

  3. Serial Ultrasound Monitoring for Early Recognition of Asparaginase Associated Pancreatitis in Children With Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Raja, Raheel Altaf; Schmiegelow, K.; Henriksen, Birthe Merete

    2015-01-01

    BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common cancer in children and L-asparaginase is an essential component of the treatment. Cessation of L-asparaginase decreases event free survival. Acute pancreatitis is the toxicity that most commonly results in cessation of L...

  4. High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome

    DEFF Research Database (Denmark)

    Lundin, Catarina; Hjorth, Lars; Behrendtz, Mikael

    2012-01-01

    Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS...

  5. Genetic loss of SH2B3 in acute lymphoblastic leukemia.

    Science.gov (United States)

    Perez-Garcia, Arianne; Ambesi-Impiombato, Alberto; Hadler, Michael; Rigo, Isaura; LeDuc, Charles A; Kelly, Kara; Jalas, Chaim; Paietta, Elisabeth; Racevskis, Janis; Rowe, Jacob M; Tallman, Martin S; Paganin, Maddalena; Basso, Giuseppe; Tong, Wei; Chung, Wendy K; Ferrando, Adolfo A

    2013-10-03

    The SH2B adaptor protein 3 (SH2B3) gene encodes a negative regulator of cytokine signaling with a critical role in the homeostasis of hematopoietic stem cells and lymphoid progenitors. Here, we report the identification of germline homozygous SH2B3 mutations in 2 siblings affected with developmental delay and autoimmunity, one in whom B-precursor acute lymphoblastic leukemia (ALL) developed. Mechanistically, loss of SH2B3 increases Janus kinase-signal transducer and activator of transcription signaling, promotes lymphoid cell proliferation, and accelerates leukemia development in a mouse model of NOTCH1-induced ALL. Moreover, extended mutation analysis showed homozygous somatic mutations in SH2B3 in 2 of 167 ALLs analyzed. Overall, these results demonstrate a Knudson tumor suppressor role for SH2B3 in the pathogenesis of ALL and highlight a possible link between genetic predisposition factors in the pathogenesis of autoimmunity and leukemogenesis.

  6. The use of optical microscope equipped with multispectral detector to distinguish different types of acute lymphoblastic leukemia

    Science.gov (United States)

    Pronichev, A. N.; Polyakov, E. V.; Tupitsyn, N. N.; Frenkel, M. A.; Mozhenkova, A. V.

    2017-01-01

    The article describes the use of a computer optical microscopy with multispectral camera to characterize the texture of blasts bone marrow of patients with different variants of acute lymphoblastic leukemia: B- and T- types. Specific characteristics of the chromatin of the nuclei of blasts for different types of acute lymphoblastic leukemia were obtained.

  7. Assessing Compliance With Mercaptopurine Treatment in Younger Patients With Acute Lymphoblastic Leukemia in First Remission | Division of Cancer Prevention

    Science.gov (United States)

    This randomized phase III trial studies compliance to a mercaptopurine treatment intervention compared to standard of care in younger patients with acute lymphoblastic leukemia in remission. Assessing ways to help patients who have acute lymphoblastic leukemia to take their medications as prescribed may help them in taking their medications more consistently and may improve

  8. Paediatric B-cell precursor acute lymphoblastic leukaemia with t(1;19)(q23;p13): clinical and cytogenetic characteristics of 47 cases from the Nordic countries treated according to NOPHO protocols

    DEFF Research Database (Denmark)

    Andersen, Mette Klarskov; Autio, Kirsi; Barbany, Gisela

    2011-01-01

    The translocation t(1;19)(q23;p13)/der(19)t(1;19) is a risk stratifying aberration in childhood B-cell precursor acute lymphoblastic leukaemia (BCP ALL) in the Nordic countries. We have identified 47 children/adolescents with t(1;19)/der(19)t(1;19)-positive BCP ALL treated on two successive Nordic...... Society of Paediatric Haematology and Oncology (NOPHO) protocols between 1992 and 2007 and have reviewed the clinical and cytogenetic characteristics of these cases, comprising 1·8% of all cases. The translocation was balanced in 15 cases (32%) and unbalanced in 29 cases (62%). The most common additional...... and 10 years was 0·85 and 0·82, respectively. Nine patients had a bone marrow relapse after a median of 23 months; no patient had a central nervous system relapse. Additional cytogenetic abnormalities, age, gender, WBC count or whether the t(1;19) was balanced or unbalanced did not influence EFS or OS...

  9. The clinical characteristics and prognostic significance of AID, miR-181b, and miR-155 expression in adult patients with de novo B-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Zhou, Guangquan; Cao, Yang; Dong, Weimin; Lin, Yan; Wang, Qi; Wu, Wei; Hua, Xiaoying; Ling, Yun; Xie, Xiaobao; Hu, Shaoyan; Cen, Jiannong; Gu, Weiying

    2017-09-01

    This study aimed to investigate clinical characteristics and prognostic significance of activation-induced cytidine deaminase (AID) gene, miR-181b and miR-155 expression in de novo adult B-cell acute lymphoblastic leukemia (B-ALL) patients. Results showed that AID and miR-155 expression were higher in B-ALL patients than healthy controls, while miR-181b expression was lower in B-ALL patients. In addition, Ph + B-ALLs had higher AID expression than Ph - B-ALLs, and its high expression was associated with BCR-ABL. Moreover, B-ALL patients with AID high or miR-181b low expression had a shorter overall survival (OS). AID high with miR-181b low , AID high with miR-155 low , miR-181b low , miR-155 low , AID high with miR-181b low and miR-155 low expression were associated with shorter OS. Combination of the three molecules are more accurate predictors for unfavorable OS compared with univariate group. Therefore, AID, miR-181b and miR-155 provide clinical prognosis of adult de novo B-ALL patients and may refine their molecular risk classification.

  10. Primitive neuroectodermal tumor arising 8 years after chemotherapy and radiotherapy for acute lymphoblastic leukemia. Case report

    International Nuclear Information System (INIS)

    Yoshida, Yuya; Toma, Yasuo; Arai, Masayuki; Higashi, Ryo; Kashihara, Kengo; Kaizaki, Yasuharu

    2005-01-01

    We report a case of primitive neuroectodermal tumor (PNET) arising 8 years after chemotherapy and radiotherapy for acute lymphoblastic leukemia. A 15-year-old boy with a history of acute lymphoblastic leukemia, at the age of 7, underwent chemotherapy and 14 Gy of radiotherapy to the whole brain. He was admitted to our department due to the development of aphasia, right hemiparesis and generalized convulsive seizure. MRI showed an irregularly enhanced mass in the left frontal lobe. A gross total removal of the tumor was performed and histological examination showed it to be PNET. Postoperatively, the patient underwent 20 Gy of radiotherapy to the whole brain and 42 Gy of local radiotherapy. Follow-up MRI showed no evidence of recurrent tumor 4 months after the radiotherapy. This tumor was thought to be a secondary brain tumor arising in this survivor of childhood acute lymphoblastic leukemia and it is a rare complication of successful leukemia treatment. (author)

  11. ZFX Controls Propagation and Prevents Differentiation of Acute T-Lymphoblastic and Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Stuart P. Weisberg

    2014-02-01

    Full Text Available Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML and acute T-lymphoblastic leukemia (T-ALL originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem-cell-related genetic regulator.

  12. Pictorial essay: Acute neurological complications in children with acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Seema A Kembhavi

    2012-01-01

    Full Text Available Acute lymphoblastic leukemia (ALL is the commonest childhood malignancy with high cure rates due to recent advances in central nervous system (CNS prophylaxis. The disease per se, as well as the prophylactic therapy, predisposes the child to complications such as cerebrovascular events, infections, drug toxicities, etc. The purpose of this study is to highlight the pathophysiology and the imaging features (with appropriate examples of these complications and to propose a diagnostic algorithm based on MRI. Interpreting these scans in the light of clinical inputs very often helps the radiologist reach an appropriate diagnosis and help treatment and management.

  13. Pictorial essay: Acute neurological complications in children with acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Kembhavi, Seema A.; Somvanshi, Snehal; Banavali, Shripad; Kurkure, Purna; Arora, Brijesh

    2012-01-01

    Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy with high cure rates due to recent advances in central nervous system (CNS) prophylaxis. The disease per se, as well as the prophylactic therapy, predisposes the child to complications such as cerebrovascular events, infections, drug toxicities, etc. The purpose of this study is to highlight the pathophysiology and the imaging features (with appropriate examples) of these complications and to propose a diagnostic algorithm based on MRI. Interpreting these scans in the light of clinical inputs very often helps the radiologist reach an appropriate diagnosis and help treatment and management

  14. Severe Hypertriglyceridemia During Therapy For Childhood Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Bhojwani, Deepa; Darbandi, Rashid; Pei, Deqing; Ramsey, Laura B.; Chemaitilly, Wassim; Sandlund, John T.; Cheng, Cheng; Pui, Ching-Hon; Relling, Mary V.; Jeha, Sima; Metzger, Monika L.

    2014-01-01

    Background Asparaginase and steroids can cause hypertriglyceridemia in children with acute lymphoblastic leukemia (ALL). There are no guidelines for screening or management of patients with severe hypertriglyceridemia (>1000 mg/dL) during ALL therapy. Patients and Methods Fasting lipid profiles were obtained prospectively at 4 time-points for 257 children consecutively enrolled on a frontline ALL study. Risk factors were evaluated by the exact chi-square test. Details of adverse events and management of hypertriglyceridemia were extracted retrospectively. Results Eighteen of 257 (7%) patients developed severe hypertriglyceridemia. Older age and treatment with higher doses of asparaginase and steroids on the standard/high-risk arm were significant risk factors. Severe hypertriglyceridemia was not associated with pancreatitis after adjustment for age and treatment arm or with osteonecrosis after adjustment for age. However, patients with severe hypertriglyceridemia had a 2.5 to 3 times higher risk of thrombosis compared to patients without, albeit the difference was not statistical significant. Of the 30 episodes of severe hypertriglyceridemia in 18 patients, 7 were managed conservatively while the others with pharmacotherapy. Seventeen of 18 patients continued to receive asparaginase and steroids. Triglyceride levels normalized after completion of ALL therapy in all 12 patients with available measurements. Conclusion Asparaginase- and steroid-induced transient hypertriglyceridemia can be adequately managed with dietary modifications and close monitoring without altering chemotherapy. Patients with severe hypertriglyceridemia were not at increased risk of adverse events, with a possible exception of thrombosis. The benefit of pharmacotherapy in decreasing symptoms and potential complications requires further investigation. PMID:25087182

  15. Lipid and lipoprotein abnormalities in acute lymphoblastic leukemia survivors.

    Science.gov (United States)

    Morel, Sophia; Leahy, Jade; Fournier, Maryse; Lamarche, Benoit; Garofalo, Carole; Grimard, Guy; Poulain, Floriane; Delvin, Edgard; Laverdière, Caroline; Krajinovic, Maja; Drouin, Simon; Sinnett, Daniel; Marcil, Valérie; Levy, Emile

    2017-05-01

    Survivors of acute lymphoblastic leukemia (ALL), the most common cancer in children, are at increased risk of developing late cardiometabolic conditions. However, the mechanisms are not fully understood. This study aimed to characterize the plasma lipid profile, Apo distribution, and lipoprotein composition of 80 childhood ALL survivors compared with 22 healthy controls. Our results show that, despite their young age, 50% of the ALL survivors displayed dyslipidemia, characterized by increased plasma triglyceride (TG) and LDL-cholesterol, as well as decreased HDL-cholesterol. ALL survivors exhibited lower plasma Apo A-I and higher Apo B-100 and C-II levels, along with elevated Apo C-II/C-III and B-100/A-I ratios. VLDL fractions of dyslipidemic ALL survivors contained more TG, free cholesterol, and phospholipid moieties, but less protein. Differences in Apo content were found between ALL survivors and controls for all lipoprotein fractions except HDL 3 HDL 2 , especially, showed reduced Apo A-I and raised Apo A-II, leading to a depressed Apo A-I/A-II ratio. Analysis of VLDL-Apo Cs disclosed a trend for higher Apo C-III 1 content in dyslipidemic ALL survivors. In conclusion, this thorough investigation demonstrates a high prevalence of dyslipidemia in ALL survivors, while highlighting significant abnormalities in their plasma lipid profile and lipoprotein composition. Special attention must, therefore, be paid to these subjects given the atherosclerotic potency of lipid and lipoprotein disorders. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  16. Acute lymphoblastic leukemia: Are Egyptian children adherent to maintenance therapy?

    Directory of Open Access Journals (Sweden)

    Elhamy Rifky Abdel Khalek

    2015-01-01

    Full Text Available Background, Aims, Settings and Design: Poor adherence to oral maintenance chemotherapy can cause relapse of acute lymphoblastic leukemia (ALL. A multicenter study for the evaluation of adherence to oral 6-mercaptopurine (6-MP maintenance chemotherapy for childhood ALL in Egypt to identify contributing factors and possible steps to promote adherence. Materials and Methods: The study included 129 children with ALL in complete remission receiving 6-MP single daily oral dose in the evening. Evaluation was done through specific questionnaires for the patients as well as serum 6-MP measurements. Results: Nonadherence was detected in around 56% by questionnaires and around 50% by serum 6-MP level measurement. There was a highly significant correlation between nonadherence as found by the questionnaire and 6-MP level (P - 0.001. Nonadherence was significantly associated with low socioeconomic standard, noneducation and low educational level and large family size by both methods. High cost to come for follow-up visits was significant by questionnaire but not by 6-MP measurement. Adolescent age, the higher number of siblings, lack of written instructions, long time spent per visit, were all associated with higher rates of nonadherence, although none reached statistical significance. Conclusions: Nonadherence is a real problem in pediatric patients. Specific questionnaires can be an excellent reliable method for the routine follow-up of these children, and drug level assay can be requested only for confirmation. This protocol is especially effective in developing countries where financial resources may be limited. Every effort should be made to uncover its true incidence, contributing factors, and best methods of intervention.

  17. Growth and puberty after treatment for acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Alves Claudia Helena Bastos da Silva

    2004-01-01

    Full Text Available Over the last 20 years, after combining treatment of chemotherapy and radiotherapy, there has been an improvement in the survival rate of acute lymphoblastic leukemia patients, with a current cure rate of around 70%. Children with the disease have been enrolled into international treatment protocols designed to improve survival and minimize the serious irreversible late effects. Our oncology unit uses the international protocol: GBTLI LLA-85 and 90, with the drugs methotrexate, cytosine, arabinoside, dexamethasone, and radiotherapy. However, these treatments can cause gonadal damage and growth impairment. PATIENTS AND METHOD: The authors analyzed 20 children off therapy in order to determine the role of the various doses of radiotherapy regarding endocrinological alterations. They were divided into 3 groups according to central nervous system prophylaxis: Group A underwent chemotherapy, group B underwent chemotherapy plus radiotherapy (18 Gy, and group C underwent chemotherapy plus radiotherapy (24 Gy. Serum concentrations of LH, FSH, GH, and testosterone were determined. Imaging studies included bone age, pelvic ultrasound and scrotum, and skull magnetic resonance imaging. RESULTS: Nine of the patients who received radiotherapy had decreased pituitary volume. There was a significant difference in the response to GH and loss of predicted final stature (Bayley-Pinneau between the 2 irradiated groups and the group that was not irradiated, but there was no difference regarding the radiation doses used (18 or 24 Gy. The final predicted height (Bayley-Pinneau was significantly less (P = 0.0071 in both groups treated with radiotherapy. Two girls had precocious puberty, and 1 boy with delayed puberty presented calcification of the epididymis. CONCLUSION: Radiotherapy was been responsible for late side effects, especially related to growth and puberty.

  18. Bilateral knee and right ankle osteonecrosis in an adolescent girl with acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Ülker Koçak

    2009-03-01

    Full Text Available Although rare, avascular necrosis of bone is a serious and incapacitating complication seen in children with acute lymphoblastic leukemia receiving high dose steroids. Here we present a 16 year-old girl who developed bilateral knee and right ankle avascular osteonecrosis one year after intensive chemotherapy for medium risk acute lymphoblastic leukemia. Indirect curettage of necrotic tissue and bone grafting were performed for both knees whereas conservative measures had been sufficient for the ankle. Early recognition of this condition is important in prevention of disabling sequela in skeletal system.

  19. Aplastic anaemia preceding acute lymphoblastic leukaemia in an adult with isolated deletion of chromosome 9q.

    LENUS (Irish Health Repository)

    Kelly, Kevin

    2008-12-01

    Aplastic anaemia (AA) can precede acute lymphoblastic leukaemia (ALL) in 2% of children but this is rarely reported to occur in adults. A 21-year-old male presented with bone marrow failure and bone marrow biopsy showed a profoundly hypocellular marrow. He recovered spontaneously but represented 2 months later when he was diagnosed with pre-B acute lymphoblastic leukaemia. Chromosomal examination revealed 46,XY,del(9)(q13q34). To the best of our knowledge this is the first case to be reported of aplasia preceding ALL with 9q minus as the sole chromosomal abnormality.

  20. Up-regulation of asparagine synthetase expression is not linked to the clinical response to L-asparaginase in pediatric acute lymphoblastic leukemia

    NARCIS (Netherlands)

    I.M. Appel (Inge); M.L. den Boer (Monique); J.P.P. Meijerink (Jules); A.J.P. Veerman (Anjo); N.C.M. Reniers (N. C M); R. Pieters (Rob)

    2006-01-01

    textabstractL-asparaginase (L-Asp) is an effective drug for treatment of children with acute lymphoblastic leukemia (ALL). The effectiveness is generally thought to result from a rapid depletion of asparagine in serum and cells. Asparagine synthetase (AS) opposes the action of L-Asp by resynthesis

  1. Outcome After First Relapse in Children With Acute Lymphoblastic Leukemia : A Report Based on the Dutch Childhood Oncology Group (DCOG) Relapse ALL 98 Protocol

    NARCIS (Netherlands)

    van den Berg, H.; de Groot-Kruseman, H. A.; Damen-Korbijn, C. M.; de Bont, E. S. J. M.; Schouten-van Meeteren, A. Y. N.; Hoogerbrugge, P. M.

    Background. We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse. The protocol focused on: (1) Intensive chemotherapy preceding allogeneic stem cell transplantation (SCT) in early bone marrow relapse; (2) Rotational chemotherapy in late

  2. Outcome after first relapse in children with acute lymphoblastic leukemia: a report based on the Dutch Childhood Oncology Group (DCOG) relapse all 98 protocol

    NARCIS (Netherlands)

    Berg, H. van den; Groot-Kruseman, H.A. de; Damen-Korbijn, C.M.; Bont, E.S. de; Schouten-van Meeteren, A.Y.; Hoogerbrugge, P.M.

    2011-01-01

    BACKGROUND: We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse. The protocol focused on: (1) Intensive chemotherapy preceding allogeneic stem cell transplantation (SCT) in early bone marrow relapse; (2) Rotational chemotherapy in late

  3. Outcome After First Relapse in Children With Acute Lymphoblastic Leukemia: A Report Based on the Dutch Childhood Oncology Group (DCOG) Relapse ALL 98 Protocol

    NARCIS (Netherlands)

    van den Berg, H.; de Groot-Kruseman, H. A.; Damen-Korbijn, C. M.; de Bont, E. S. J. M.; Schouten-van Meeteren, A. Y. N.; Hoogerbrugge, P. M.

    2011-01-01

    Background. We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse. The protocol focused on: (1) Intensive chemotherapy preceding allogeneic stem cell transplantation (SCT) in early bone marrow relapse; (2) Rotational chemotherapy in late

  4. Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Nordlund, Jessica; Bäcklin, Christofer L; Wahlberg, Per

    2013-01-01

    BACKGROUND: Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic...... background, drug resistance and relapse in ALL is poorly understood. RESULTS: We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared...... cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status. CONCLUSIONS: Our results suggest an important...

  5. Case report of acute lymphoblastic leukemia with multiple soft tissue mass

    International Nuclear Information System (INIS)

    Jang, Jung Yong; Huh, Kyung Hoe; Yi, Won Jin; Heo, Min Suk; Lee, Sam Sun; Choi, Soon Chul

    2005-01-01

    A 15-year-old patient, who had been diagnosed and treated as Burkitt cell type acute lymphoblastic leukemia (ALL-L3) already, visited our department. He complained of gingival enlargement and loosening teeth 1 month ago. The clinical examination revealed anterior open bite, gingival enlargement, and non tender swelling particularly in molar regions of both jaws. Deep periodontal pockets and severe mobility was shown on most of the teeth. The panoramic radiographs showed severe bone destruction and extrusion of the molars. The contrast enhanced CT showed multiple enhanced mass and bone marrow obliteration in both jaws. Chemotherapy was done the swelling was subsided at 1 month later. In conclusion, radiologic findings of leukemia with soft tissue mass, known as chloroma or granulocytic sarcoma, mimic those of lymphoma, so blood test may be needed for the final diagnosis.

  6. RBP2 Promotes Adult Acute Lymphoblastic Leukemia by Upregulating BCL2.

    Directory of Open Access Journals (Sweden)

    Xiaoming Wang

    Full Text Available Despite recent increases in the cure rate of acute lymphoblastic leukemia (ALL, adult ALL remains a high-risk disease that exhibits a high relapse rate. In this study, we found that the histone demethylase retinoblastoma binding protein-2 (RBP2 was overexpressed in both on-going and relapse cases of adult ALL, which revealed that RBP2 overexpression was not only involved in the pathogenesis of ALL but that its overexpression might also be related to relapse of the disease. RBP2 knockdown induced apoptosis and attenuated leukemic cell viability. Our results demonstrated that BCL2 is a novel target of RBP2 and supported the notion of RBP2 being a regulator of BCL2 expression via directly binding to its promoter. As the role of RBP2 in regulating apoptosis was confirmed, RBP2 overexpression and activation of BCL2 might play important roles in ALL development and progression.

  7. Case report of acute lymphoblastic leukemia with multiple soft tissue mass

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Jung Yong; Huh, Kyung Hoe; Yi, Won Jin; Heo, Min Suk; Lee, Sam Sun; Choi, Soon Chul [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2005-06-15

    A 15-year-old patient, who had been diagnosed and treated as Burkitt cell type acute lymphoblastic leukemia (ALL-L3) already, visited our department. He complained of gingival enlargement and loosening teeth 1 month ago. The clinical examination revealed anterior open bite, gingival enlargement, and non tender swelling particularly in molar regions of both jaws. Deep periodontal pockets and severe mobility was shown on most of the teeth. The panoramic radiographs showed severe bone destruction and extrusion of the molars. The contrast enhanced CT showed multiple enhanced mass and bone marrow obliteration in both jaws. Chemotherapy was done the swelling was subsided at 1 month later. In conclusion, radiologic findings of leukemia with soft tissue mass, known as chloroma or granulocytic sarcoma, mimic those of lymphoma, so blood test may be needed for the final diagnosis.

  8. Body composition and phase angle in Russian children in remission from acute lymphoblastic leukemia

    Science.gov (United States)

    Tseytlin, G. Ja; Khomyakova, I. A.; Nikolaev, D. V.; Konovalova, M. V.; Vashura, A. Yu; Tretyak, A. V.; Godina, E. Z.; Rudnev, S. G.

    2010-04-01

    Elevated degree of body fatness and changes in other body composition parameters are known to be common effects of treatment for acute lymphoblastic leukemia (ALL) in children. In order to study peculiarities of somatic growth and development in ALL survivors, we describe the results of BIA body composition analysis of 112 boys and 108 girls aged 5-18 years in remission from ALL (remission time range 1-13 years) compared to data from the same number of age- and sex-matched healthy controls (n=220). Detrimental effect on height in ALL boys was observed, whereas girls experienced additional weight gain compared to healthy subjects. In ALL patients, resistance, body fat, and percent body fat were significantly increased. The reactance, phase angle, absolute and relative values of skeletal muscle and body cell mass were significantly decreased. Principal component analysis revealed an early prevalence of adiposity traits in the somatic growth and development of ALL girls compared to healthy controls.

  9. The biology, pathogenesis and clinical aspects of acute lymphoblastic leukemia in children with Down syndrome.

    Science.gov (United States)

    Lee, P; Bhansali, R; Izraeli, S; Hijiya, N; Crispino, J D

    2016-09-01

    Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (DS-ALL). Although the etiology of this higher risk of developing leukemia remains largely unclear, the recent identification of CRLF2 (cytokine receptor like factor 2) and JAK2 mutations and study of the effect of trisomy of Hmgn1 and Dyrk1a (dual-specificity tyrosine phosphorylation-regulated kinase 1A) on B-cell development have shed significant new light on the disease process. Here we focus on the clinical features, biology and genetics of ALL in children with DS. We review the unique characteristics of DS-ALL on both the clinical and molecular levels and discuss the differences in treatments and outcomes in ALL in children with DS compared with those without DS. The identification of new biological insights is expected to pave the way for novel targeted therapies.

  10. New insights into Notch1 regulation of the PI3K-AKT-mTOR1 signaling axis: targeted therapy of γ-secretase inhibitor resistant T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Hales, Eric C; Taub, Jeffrey W; Matherly, Larry H

    2014-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is characterized as a high-risk stratified disease associated with frequent relapse, chemotherapy resistance, and a poorer prognostic outlook than B-precursor ALL. Many of the challenges in treating T-ALL reflect the lack of prognostic cytogenetic or molecular abnormalities on which to base therapy, including targeted therapy. Notch1 activating mutations were identified in more than 50% of T-ALL cases and can be therapeutically targeted with γ-secretase inhibitors (GSIs). Mutant Notch1 can activate cMyc and PI3K-AKT-mTOR1 signaling in T-ALL. In T-ALLs with wild-type phosphatase and tensin homolog deleted on chromosome ten (PTEN), Notch1 transcriptionally represses PTEN, an effect reversible by GSIs. Notch1 also promotes growth factor receptor (IGF1R and IL7Rα) signaling to PI3K-AKT. Loss of PTEN is common in primary T-ALLs due to mutation or posttranslational inactivation and results in chronic activation of PI3K-AKT-mTOR1 signaling, GSI-resistance, and repression of p53-mediated apoptosis. Notch1 itself might regulate posttranslational inactivation of PTEN. PP2A is activated by Notch1 in PTEN-null T-ALL cells, and GSIs reduce PP2A activity and increase phosphorylation of AKT, AMPK, and p70S6K. This review focuses on the central role of the PI3K-AKT-mTOR1 signaling in T-ALL, including its regulation by Notch1 and potential therapeutic interventions, with emphasis on GSI-resistant T-ALL. © 2013.

  11. Charcot-Marie-Tooth Disease in a Child with Acute Lymphoblastic ...

    African Journals Online (AJOL)

    Results: Facial nerve palsy, increasing lower extremities muscle weakness and abnormal gait were noticed 4 weeks into vincristine therapy in a ten year old male on treatment for acute lymphoblastic leukaemia (ALL). On a suspicion of vincristine neurotoxicity, vincristine was excluded from his chemotherapy regimen.

  12. Cytokines, growth, and environment factors in bone marrow plasma of acute lymphoblastic leukemia pediatric patients

    Czech Academy of Sciences Publication Activity Database

    Kováč, M.; Vášková, M.; Petráčková, Denisa; Pelková, V.; Mejstříková, E.; Kalina, T.; Žaliová, M.

    2014-01-01

    Roč. 25, č. 1 (2014), s. 8-13 ISSN 1148-5493 R&D Projects: GA MZd NR9531 Institutional support: RVO:61388971 Keywords : pediatric acute lymphoblastic leukemia * bone marrow plasma * cytokine Subject RIV: CE - Biochemistry Impact factor: 1.960, year: 2014

  13. Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)—Health Professional Version

    Science.gov (United States)

    For acute lymphoblastic leukemia (ALL), the 5-year survival rate has improved significantly since 1975. Get information about risk factors, signs, diagnosis, molecular features, survival, risk-based treatment assignment, and induction and postinduction therapy for children and adolescents with newly diagnosed and recurrent ALL.

  14. Prediction of immunophenotype, treatment response, and relapse in childhood acute lymphoblastic leukemia using DNA microarrays

    DEFF Research Database (Denmark)

    Willenbrock, Hanni; Juncker, Agnieszka; Schmiegelow, K.

    2004-01-01

    Gene expression profiling is a promising tool for classification of pediatric acute lymphoblastic leukemia ( ALL). We analyzed the gene expression at the time of diagnosis for 45 Danish children with ALL. The prediction of 5-year event-free survival or relapse after treatment by NOPHO-ALL92 or 2000...

  15. High concordance of subtypes of childhood acute lymphoblastic leukemia within families

    DEFF Research Database (Denmark)

    Schmiegelow, K.; Thomsen, U Lautsen; Baruchel, A

    2012-01-01

    Polymorphic genes have been linked to the risk of acute lymphoblastic leukemia (ALL). Surrogate markers for a low burden of early childhood infections are also related to increased risk for developing childhood ALL. It remains uncertain, whether siblings of children with ALL have an increased risk...

  16. Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia | Office of Cancer Genomics

    Science.gov (United States)

    NCI's TARGET Initiative reported the discovery of a novel genetic marker for children with acute lymphoblastic leukemia (ALL) in the January 7, 2009, advance online edition of The New England Journal of Medicine. The genetic alteration identified, IKZF1, should improve clinicians' ability to identify high-risk patients and better assign these patients to appropriate therapy.

  17. Challenges in implementing individualized medicine illustrated by antimetabolite therapy of childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Nersting, Jacob; Borst, Louise; Schmiegelow, Kjeld

    2011-01-01

    illustrated by studies involving childhood acute lymphoblastic leukemia (ALL), where each patient may receive up to 13 different anticancer agents over a period of 2-3 years. The challenges include i) addressing important, but low-frequency outcomes, ii) difficulties in interpreting the impact of single drug...

  18. Tracheoesophageal fistula resulting from invasive aspergillosis in acute lymphoblastic leukemia: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Si Won [Daejeon St. Mary' s Hospital, College of Medicine, Catholic University, Daejeon (Korea, Republic of)

    2006-04-15

    Tracheoesophageal fistula (TEF) in adult patients is an uncommon complication in leukemia. We present here on a case of TEF in a 46-year-old woman with ALL. The patient was asymptomatic and TEF is resulted from aspergillus bronchitis during the chemotherapy for acute lymphoblastic leukemia (ALL)

  19. Osteonecrosis in children treated for acute lymphoblastic leukemia: a magnetic resonance imaging study after treatment

    Energy Technology Data Exchange (ETDEWEB)

    Ojala, A.; Lanning, F.; Paakko, E.; Lanning, B. [Oulu Univ. (Finland)

    1998-02-01

    The purpose of this study was to find out the prevalence of osteonecrosis in children with acute lymphoblastic leukaemia (ALL) in complete bone marrow remission at the end of the treatment. Finally, the study suggests that the intensification phase of the treatment protocols with intensive dexamethasone medication might be responsible for the development of osteonecrosis. (N.C.)

  20. Delayed Neurotoxicity Associated with Therapy for Children with Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Cole, Peter D.; Kamen, Barton A.

    2006-01-01

    Most children diagnosed today with acute lymphoblastic leukemia (ALL) will be cured. However, treatment entails risk of neurotoxicity, causing deficits in neurocognitive function that can persist in the years after treatment is completed. Many of the components of leukemia therapy can contribute to adverse neurologic sequelae, including…

  1. An Initial Reintegration Treatment of Children with Acute Lymphoblastic Leukemia (ALL).

    Science.gov (United States)

    Lurie, Michelle; Kaufman, Nadeen

    2001-01-01

    Evaluated the cognitive, psychological, and social adjustment of pediatric acute lymphoblastic leukemia (ALL) patients and assessed how their needs could best be met through reintegration programs focusing on learning/ educational needs. Findings from three case studies highlight the need for ALL patients to be provided with comprehensive programs…

  2. PEG-asparaginase allergy in children with acute lymphoblastic leukemia in the NOPHO ALL2008 protocol

    DEFF Research Database (Denmark)

    Henriksen, Louise Tram; Harila-Saari, Arja; Ruud, Ellen

    2014-01-01

    BACKGROUND: L-Asparaginase is an effective drug in the treatment of childhood acute lymphoblastic leukemia (ALL). The use of L-asparaginase may be limited by serious adverse events of which allergy is the most frequent. The objective of this study was to describe the clinical aspects of PEG...

  3. Tracheoesophageal fistula resulting from invasive aspergillosis in acute lymphoblastic leukemia: a case report

    International Nuclear Information System (INIS)

    Kang, Si Won

    2006-01-01

    Tracheoesophageal fistula (TEF) in adult patients is an uncommon complication in leukemia. We present here on a case of TEF in a 46-year-old woman with ALL. The patient was asymptomatic and TEF is resulted from aspergillus bronchitis during the chemotherapy for acute lymphoblastic leukemia (ALL)

  4. Erroneous Exchange of Asparaginase Forms in the Treatment of Acute Lymphoblastic Leukemia

    NARCIS (Netherlands)

    Cheung, Ka-Chun; van den Bemt, Patricia M. L. A.; Torringa, Maarten L. J.; Tamminga, Rienk Y. J.; Pieters, Rob; de Smet, Peter A. G. M.

    For the treatment of children with acute lymphoblastic leukemia (ALL), Dutch pediatric oncologists use the Dutch Childhood Oncology Group ALL 10 protocol. This protocol is complex, as it comprises many different drug regimens. One of the drugs is asparaginase which is available in different forms

  5. Efficacy and Toxicity of Asparaginases During Prospective Drug Monitoring in Patients With Childhood Acute Lymphoblastic Leukemia

    NARCIS (Netherlands)

    W.H. Tong (Wing)

    2014-01-01

    markdownabstract__Abstract__ Intensified and effective asparaginase therapy is very important in modern treatment of childhood acute lymphoblastic leukemia. The use of native E.coli asparaginase in induction leads to a high rate of hypersensitivity reactions to PEGasparaginase in the

  6. Erroneous exchange of asparaginase forms in the treatment of acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Cheung, K.C.; Bemt, P.M. van den; Torringa, M.L.; Tamminga, R.Y.; Pieters, R.; Smet, P.A. de

    2011-01-01

    For the treatment of children with acute lymphoblastic leukemia (ALL), Dutch pediatric oncologists use the Dutch Childhood Oncology Group ALL 10 protocol. This protocol is complex, as it comprises many different drug regimens. One of the drugs is asparaginase which is available in different forms

  7. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment

    DEFF Research Database (Denmark)

    Schmiegelow, K.; Attarbaschi, Andishe; Barzilai, Shlomit

    2016-01-01

    Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi ...

  8. Karyotyping, FISH, and PCR in acute lymphoblastic leukemia: competing or complementary diagnostics?

    NARCIS (Netherlands)

    Olde Nordkamp, Louise; Mellink, Clemens; van der Schoot, Ellen; van den Berg, Henk

    2009-01-01

    BACKGROUND: Chromosomal abnormalities, such as t(9;22)(q34;q11) (ABL/BCR), t(12;21)(p13;q22) (TEL/AML1), and t(11q23) (MLL) are independent prognostic indicators in childhood acute lymphoblastic leukemia resulting in risk adapted therapy. Accurate and rapid detection of these abnormalities is

  9. Osteonecrosis in children treated for acute lymphoblastic leukemia: a magnetic resonance imaging study after treatment

    International Nuclear Information System (INIS)

    Ojala, A.; Lanning, F.; Paakko, E.; Lanning, B.

    1998-01-01

    The purpose of this study was to find out the prevalence of osteonecrosis in children with acute lymphoblastic leukaemia (ALL) in complete bone marrow remission at the end of the treatment. Finally, the study suggests that the intensification phase of the treatment protocols with intensive dexamethasone medication might be responsible for the development of osteonecrosis. (N.C.)

  10. Acute lymphoblastic leukemia and obesity : increased energy intake or decreased physical activity?

    NARCIS (Netherlands)

    Jansen, H.; Postma, A.; Stolk, R. P.; Kamps, W. A.

    Background Obesity is a well-known problem in children with acute lymphoblastic leukemia ( ALL), and it might be the result of an excess in energy intake, reduced energy expenditure, or both. The aim of this study is to describe energy intake and physical activity during treatment for ALL with

  11. Late cardiac effects of anthracycline containing therapy for childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Rathe, Mathias; Carlsen, Niels L T; Oxhøj, Henrik

    2007-01-01

    At present about 80% of children with acute lymphoblastic leukemia (ALL) will be cured following treatment with multi-drug chemotherapy. A major concern for this growing number of survivors is the risk of late effects of treatment. The aim of this study was to determine whether signs...

  12. Handwriting and fine motor problems after treatment for acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Reinders-Messelink, H.A.; Schoemaker, M.M.; Goeken, L.N H; van den Briel, M.M.; Kamps, W.A; Simner, M L; Leedham, C G; Thomassen, A J W M

    1996-01-01

    Fine motor skills and handwriting performance were investigated in 17 children at least two years after treatment for acute lymphoblastic leukemia. It was hypothesized that as a late effect of vincristine neuropathy, children would still have fine motor and/or handwriting problems. Gross and fine

  13. The effect of central nervous system involvement and irradiation in childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Taskinen, Mervi; Oskarsson, Trausti; Levinsen, Mette

    2017-01-01

    BACKGROUND: Central nervous system irradiation (CNS-RT) has played a central role in the cure of acute lymphoblastic leukemia (ALL), but due to the risk of long-term toxicity, it is now considered a less-favorable method of CNS-directed therapy. PROCEDURES: Retrospectively, we estimated the effect...

  14. Bilateral cytomegalovirus retinitis in a child with acute lymphoblastic leukemia while on maintenance chemotherapy

    Directory of Open Access Journals (Sweden)

    Vaidehi S. Dedania

    2016-08-01

    Full Text Available We report a case of bilateral cytomegalovirus retinitis in a 12 year-old with neutropenic fever after maintenance chemotherapy for acute lymphoblastic leukemia. Ophthalmologic examination for photophobia prompted a diagnosis of cytomegalovirus retinitis. With early diagnosis and prompt treatment, this patient had a favorable visual outcome.

  15. Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries

    DEFF Research Database (Denmark)

    Lundin, Catarina; Forestier, Erik; Klarskov Andersen, Mette

    2014-01-01

    BACKGROUND: Children with Down syndrome (DS) have an increased risk for acute lymphoblastic leukemia (ALL). Although previous studies have shown that DS-ALL differs clinically and genetically from non-DS-ALL, much remains to be elucidated as regards genetic and prognostic factors in DS-ALL. METHODS...

  16. Physicians compliance during maintenance therapy in children with Down syndrome and acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Bohnstedt, C; Levinsen, M; Rosthøj, S

    2013-01-01

    Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have an inferior prognosis compared with non-DS ALL patients. We reviewed methotrexate (MTX)/mercaptopurine (6MP) maintenance therapy data for children with DS treated according to the Nordic Society of Pediatric Hematology...

  17. Prognostic factors in children with acute lymphoblastic leukemia: a ten year study

    Directory of Open Access Journals (Sweden)

    Oloomi yazdi Z.

    2008-06-01

    Full Text Available Background: Acute lymphoblastic leukemia (ALL is the most common cancer in the pediatric population. With modern treatments, the chance of the complete recovery is nearly 100%. The most important prognostic factors are appropriate treatment protocol and determination of patient risk factors based on clinical, morphological, immunological and cytological characteristics. In this study we reviewed frequency of these factors, like as age, gender, the primary white blood cell number, sub- group on the base of FAB classification, immunophenotype and the clinical progress. Methods: In this retrospective study, we reviewed 877 pediatric patients with the diagnosis of ALL between the years of 1994 and 2004. In these patients the age, gender, primary WBC count, sub-group based on the FAB classification, immunophenotype and the clinical progress in 177 patient with acute lymphoblastic leukemia at Imam Khomeini Hospital between the years of 1994 to 2004 were determined. Results: Of these patients, 1.6% was younger than one year, 24.8% more than ten years old and 73.6% were between the ages of one and ten years; 63.8% were male. WBC counts were above 50,000/ul in 28.8% of the patients. FAB classifications included L1 in 80.2%, L2 in 17.5% and L3 in 2.3% of the patients. Immunophenotypes included pre-B cell in 63.8%, early pre-B cell in 23.1%, T cell in 12.3% and mature B cell in 0.8% of the patients. Marker CD10+ was detected in 88.1% of the B cell cases. In this study group, 74% of the patients recovered, 16.3% died and 16.5% relapsed.Conclusions: The prevalence of FAB-L1 and pre-B cell cases in this study is greater than a previous study, while the prevalence of FAB-L2 and early pre-B cell cases is less than that of the previous study.

  18. Implications of infectious diseases and the adrenal hypothesis for the etiology of childhood acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    F. Azevedo-Silva

    2010-03-01

    Full Text Available Acute leukemia is the most frequent cancer in children. Recently, a new hypothesis was proposed for the pathogenesis of childhood acute lymphoblastic leukemia (ALL. The so-called "adrenal hypothesis" emphasized the role of endogenous cortisol in the etiology of B-cell precursor ALL. The incidence peak of ALL in children between 3 to 5 years of age has been well documented and is consistent with this view. The adrenal hypothesis proposes that the risk of childhood B-cell precursor ALL is reduced when early childhood infections induce qualitative and quantitative changes in the hypothalamus-pituitary-adrenal axis. It suggests that the increased plasma cortisol levels would be sufficient to eliminate all clonal leukemic cells originating during fetal life. Because Brazil is a continental and tropical country, the exposure to infections is diversified with endemic viral and regionally non-viral infections, with some characteristics that support the recent adrenal hypothesis. Here we discuss this new hypothesis in terms of data from epidemiological studies and the possible implications of the diversity of infections occurring in Brazilian children.

  19. Imatinib use immediately before stem cell transplantation in children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Results from Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Study Ph(+) ALL04.

    Science.gov (United States)

    Manabe, Atsushi; Kawasaki, Hirohide; Shimada, Hiroyuki; Kato, Itaru; Kodama, Yuichi; Sato, Atsushi; Matsumoto, Kimikazu; Kato, Keisuke; Yabe, Hiromasa; Kudo, Kazuko; Kato, Motohiro; Saito, Tomohiro; Saito, Akiko M; Tsurusawa, Masahito; Horibe, Keizo

    2015-05-01

    Incorporation of imatinib into chemotherapeutic regimens has improved the prognosis of children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). We investigated a role of imatinib immediately before hematopoietic stem cell transplantation (HSCT). Children with Ph(+) ALL were enrolled on JPLSG Ph(+) ALL 04 Study within 1 week of initiation of treatment for ALL. Treatment regimen consisted of Induction phase, Consolidation phase, Reinduction phase, 2 weeks of imatinib monotherapy phase, and HSCT phase (Etoposide+CY+TBI conditioning). Minimal residual disease (MRD), the amount of BCR-ABL transcripts, was measured with the real-time PCR method. The study was registered in UMIN-CTR: UMIN ID C000000290. Forty-two patients were registered and 36 patients (86%) achieved complete remission (CR). Eight of 17 patients (47%) who had detectable MRD at the beginning of imatinib monotherapy phase showed disappearance or decrease in MRD after imatinib treatment. Consequently, 26 patients received HSCT in the first CR and all the patients had engraftment and no patients died because of complications of HSCT. The 4-year event-free survival rates and overall survival rates among all the 42 patients were 54.1 ± 7.8% and 78.1 ± 6.5%, respectively. Four of six patients who did achieve CR and three of six who relapsed before HSCT were salvaged with imatinib-containing chemotherapy and subsequently treated with HSCT. The survival rate was excellent in this study although all patients received HSCT. A longer use of imatinib concurrently with chemotherapy should eliminate HSCT in a subset of patients with a rapid clearance of the disease. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  20. HLA-DPβ1 Asp84-Lys69 antigen-binding signature predicts event-free survival in childhood B-cell precursor acute lymphoblastic leukaemia: results from the MRC UKALL XI childhood ALL trial.

    Science.gov (United States)

    Taylor, G M; Wade, R; Hussain, A; Thompson, P; Hann, I; Gibson, B; Eden, T; Richards, S

    2012-07-01

    We previously reported that children in the UKALL XI ALL trial with HLA-DP 1 and -DP 3 supertypes had significantly worse event-free survival (EFS) than children with other DP supertypes. As DP 1 and DP 3 share two of four key antigen-binding amino-acid polymorphisms (aspartic acid84-lysine69), we asked whether Asp84-Lys69 or Asp84 alone were independent prognostic indicators in childhood acute lymphoblastic leukemia (ALL). We analysed EFS in 798 UKALL XI patients, stratified by Asp84-Lys69 vs non-Asp84-Lys69, for a median follow-up of 12.5 years. Asp84-Lys69 was associated with a significantly worse EFS than non-Asp84-Lys69 (5-year EFS: Asp84-Lys69: 58.8% (95% CI (confidence of interval): 52.7-64.9%); non-Asp84-Lys69: 67.3% (63.4-71.2%); 2P=0.007). Post-relapse EFS was 10% less in Asp84-Lys69 than non-Asp84-Lys69 patients. EFS was significantly worse (P=0.03) and post-relapse EFS marginally worse (P=0.06) in patients with Asp84 compared with Gly84. These results suggest that Asp84-Lys69 predicted adverse EFS in the context of UKALL XI because of Asp84, and may have influenced post-relapse EFS. We speculate that this may be due to the recruitment of Asp84-Lys69-restricted regulatory T cells in the context of this regimen, leading to the re-emergence of residual disease. However, functional and molecular studies of the prognostic value of this and other HLA molecular signatures in other childhood ALL trials are needed.

  1. Sinonasal Lymphoma Presenting as a Probable Sanctuary Site for Relapsed B Acute Lymphoblastic Leukaemia: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    W. Y. Lim

    2015-01-01

    Full Text Available Sinonasal lymphoma is a non-Hodgkin lymphoma (NHL representing 1.5% of all lymphomas. It presents as an unremitting ulceration with progressive destruction of midline sinonasal and surrounding structures. Poor prognosis warrants early treatment although diagnosis is challenging and frequently delayed. It is usually primary in origin and to our knowledge the sinonasal region has never been reported as a sanctuary site in leukaemia/lymphoma relapse. We present a unique case of B-cell ALL (acute lymphoblastic leukaemia with late relapse to the nasal septum as a sinonasal lymphoblastic lymphoma and with genetic support for this as a sanctuary site.

  2. Sinonasal Lymphoma Presenting as a Probable Sanctuary Site for Relapsed B Acute Lymphoblastic Leukaemia: A Case Report and Review of the Literature.

    Science.gov (United States)

    Lim, W Y; Care, R; Lau, M; Chiruka, S; Dawes, P J D

    2015-01-01

    Sinonasal lymphoma is a non-Hodgkin lymphoma (NHL) representing 1.5% of all lymphomas. It presents as an unremitting ulceration with progressive destruction of midline sinonasal and surrounding structures. Poor prognosis warrants early treatment although diagnosis is challenging and frequently delayed. It is usually primary in origin and to our knowledge the sinonasal region has never been reported as a sanctuary site in leukaemia/lymphoma relapse. We present a unique case of B-cell ALL (acute lymphoblastic leukaemia) with late relapse to the nasal septum as a sinonasal lymphoblastic lymphoma and with genetic support for this as a sanctuary site.

  3. Profile of blinatumomab and its potential in the treatment of relapsed/refractory acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Ribera JM

    2015-06-01

    Full Text Available Josep-Maria Ribera, Albert Ferrer, Jordi Ribera, Eulàlia GenescàClinical Hematology Department, ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Universitat Autònoma de Barcelona, Badalona, SpainAbstract: The CD19 marker is expressed on the surface of normal and malignant immature or mature B-cells. On the other hand, immunotherapy involving T-cells is a promising modality of treatment for many neoplastic diseases including leukemias and lymphomas. The CD19/CD3-bispecific T-cell-engaging (BiTE® monoclonal antibody blinatumomab can transiently engage cytotoxic T-cells to CD19+ target B-cells inducing serial perforin-mediated lysis. In the first clinical trial, blinatumomab showed efficacy in non-Hodgkin’s lymphomas, but the most important trials have been conducted in relapsed/refractory (R/R acute lymphoblastic leukemia (ALL and in ALL with minimal residual disease. Encouraging reports on the activity of blinatumomab in R/R Philadelphia chromosome-negative B-cell precursor ALL led to its approval by the US Food and Drug Administration on December 3, 2014 after an accelerated review process. This review focuses on the profile of blinatumomab and its activity in R/R ALL.Keywords: acute lymphoblastic leukemia, relapsed/refractory, BiTE® monoclonal antibodies, blinatumomab

  4. Risk-adapted stratification and treatment of childhood acute lymphoblastic leukaemia

    International Nuclear Information System (INIS)

    Schrappe, M.

    2008-01-01

    Systematic enrolment of children and adolescents with acute lymphoblastic leukaemia (ALL) into clinical trials has allowed the establishment of prognostic parameters derived from initial diagnostic findings. More important, these trials have significantly contributed to the reduction of disease recurrence as much as to the reduction of acute and late side effects. Some problems that are related to the specificity of the parameters used for risk assessment were not overcome: high tumour load by white blood cell count (WBC), age and (rare) cytogenetic subtypes (e.g. t9;22) may characterise a significant proportion of children and adolescents with high-risk ALL. Most patients who will eventually relapse do not present with characteristic features at initial diagnosis. It appears feasible through careful response assessment to identify these patients at risk of relapse, who present initially without specific features. Earlier trials of the ALL-BFM (Berlin/Frankfurt/Muenster) study group and others have demonstrated that inadequate leukaemic blast reduction in the peripheral blood or bone marrow after the first few days of therapy is highly predictive of treatment failure. Using clone-specific polymerase chain reaction-based detection of minimal residual disease (MRD) as done in trial AIEOP-BFM ALL 2000 allowed a close surveillance of specific treatment elements when applied in MRD positive patients. This may facilitate innovative chemotherapy approaches and a more rational use of allogeneic haematopoietic stem cell transplantation. In addition, genetic signatures of treatment response or failure have been identified. (authors)

  5. Molecular cloning of the common acute lymphoblastic leukemia antigen (CALLA) identifies a type II integral membrane protein

    International Nuclear Information System (INIS)

    Shipp, M.A.; Richardson, N.E.; Sayre, P.H.; Brown, N.R.; Masteller, E.L.; Clayton, L.K.; Ritz, J.; Reinherz, E.L.

    1988-01-01

    Common acute lymphoblastic leukemia antigen (CALLA) is a 100-kDa cell-surface glycoprotein expressed on most acute lymphoblastic leukemias and certain other immature lymphoid malignancies and on normal lymphoid progenitors. The latter are either uncommitted to B- or T-cell lineage or committed to only the earliest stages of B- or T-lymphocyte maturation. To elucidate the primary structure of CALLA, the authors purified the protein to homogeneity, obtained the NH 2 -terminal sequence from both the intact protein and derived tryptic and V8 protease peptides and isolated CALLA cDNAs from a Nalm-6 cell line λgt10 library using redundant oligonucleotide probes. The CALLA cDNA sequence predicts a 750-amino acid integral membrane protein with a single 24-amino acid hydrophobic segment that could function as both a transmembrane region and a signal peptide. The COOH-terminal 700 amino acids, including six potential N-linked glycosylation sites compose the extracellular protein segment, whereas the 25 NM 2 -terminal amino acids remaining after cleavage of the initiation methionine form the cytoplasmic tail. CALLA + cells contain CALLA transcripts of 2.7 to 5.7 kilobases with the major 5.7- and 3.7-kilobase mRNAs being preferentially expressed in specific cell types

  6. Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Schmiegelow, Kjeld; Björk, Olle; Glomstein, Anders

    2003-01-01

    by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E......-MTX (pharmacology group), or by WBC only (control group). RESULTS: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P =.00003), high WBC at diagnosis (P =.03), pharmacology arm (6.6 times increased relapse hazard for girls), high...

  7. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia | Office of Cancer Genomics

    Science.gov (United States)

    Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN).

  8. Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Kjeld Schmiegelow

    2017-04-01

    Full Text Available During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both, bone toxicities (including osteonecrosis, thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia, high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs.

  9. A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Tong, Wing H.; Pieters, Rob; Kaspers, Gertjan J. L.; te Loo, D. Maroeska W. M.; Bierings, Marc B.; van den Bos, Cor; Kollen, Wouter J. W.; Hop, Wim C. J.; Lanvers-Kaminsky, Claudia; Relling, Mary V.; Tissing, Wim J. E.; van der Sluis, Inge M.

    2014-01-01

    This study prospectively analyzed the efficacy of very prolonged courses of pegylated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2500 IU/m(2) every 2 weeks) in

  10. Gene Dose Effects of GSTM1, GSTT1 and GSTP1 Polymorphisms on Outcome in Childhood Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Borst, Louise; Buchard, Anders; Rosthoj, Susanne

    2012-01-01

    Children with acute lymphoblastic leukemia (ALL) react very differently to chemotherapy. One explanation for this is inherited genetic variation. The glutathione S-transferase (GST) enzymes inactivate a number of chemotherapeutic drugs administered in childhood ALL therapy. Two multiplexing methods...

  11. Efficacy and Toxicity of Intrathecal Liposomal Cytarabine in First-line Therapy of Childhood Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Levinsen, Mette; Harila-Saari, Arja; Grell, Kathrine

    2016-01-01

    We investigated efficacy and toxicity of replacing conventional triple (cytarabine, methotrexate, and hydrocortisone) intrathecal therapy (TIT) with liposomal cytarabine during maintenance therapy among 40 acute lymphoblastic leukemia patients. Twenty-eight of 29 patients in the TIT arm received...

  12. A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia

    NARCIS (Netherlands)

    W.H. Tong (Wing); R. Pieters (Rob); G.J. Kaspers (Gertjan); D.M.W.M. Te Loo (D. Maroeska W.); M. Bierings (Marc); C. van den Bos (Cor); W.J.W. Kollen (Wouter); W.C.J. Hop (Wim); C. Lanvers-Kaminsky (Claudia); M.V. Relling (Mary); W.J.E. Tissing (Wim); I.M. van der Sluis (Inge)

    2014-01-01

    textabstractThis study prospectively analyzed the efficacy of very prolonged courses of pegylated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2500 IU/m2 every 2

  13. Prognostic significance of primary bone changes in children with acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Rajantie, J.; Jaeaeskelaeinen, J.; Perkkioe, M.; Siimes, M.A.

    1985-01-01

    In a period of 6.5 years, acute leukaemia was diagnosed in 140 children at our hospital: 137 children had long bone radiographs and 45 patients had bone lesions. Eleven of the 115 patients who had skull radiographs had osteolytic lesions and another four had wide sutures. No patients had bone changes at relapse or at cessation of 3 years' successful therapy. In acute lymphoblastic leukemia, the frequence of osseous lesions tended to be higher in patients in sub-groups with a more favourable prognosis. The duration of remission and survival times were higher in patients with ''leukemic'' long bones than in those without them (p<0.10 and <0.05, respectively). Changes in the skull could not be related to the outcome. We found no abnormalities in the bones of the eight patients with acute non-lymphoblastic leukemia. (orig.)

  14. Constitutional abnormalities of IDH1 combined with secondary mutations predispose a patient with Maffucci syndrome to acute lymphoblastic leukemia.

    Science.gov (United States)

    Hirabayashi, Shinsuke; Seki, Masafumi; Hasegawa, Daisuke; Kato, Motohiro; Hyakuna, Nobuyuki; Shuo, Takuya; Kimura, Shunsuke; Yoshida, Kenichi; Kataoka, Keisuke; Fujii, Yoichi; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Kiyokawa, Nobutaka; Miyano, Satoru; Ogawa, Seishi; Takita, Junko; Manabe, Atsushi

    2017-12-01

    Maffucci syndrome is a nonhereditary disorder caused by somatic mosaic isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations and is characterized by multiple enchondromas along with hemangiomas. Malignant transformation of enchondromas to chondrosarcomas and secondary neoplasms, such as brain tumors or acute myeloid leukemia, are serious complications. A 15-year-old female with Maffucci syndrome developed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). A somatic mutation in IDH1 was detected in hemangioma and leukemic cells. KRAS mutation and deletion of IKZF1 were detected in leukemic cells. Patients with Maffucci syndrome may, therefore, be at risk of BCP-ALL associated with secondary genetic events that affect lymphocyte differentiation. © 2017 Wiley Periodicals, Inc.

  15. Recent advances in acute lymphoblastic leukemia in children and adolescents: an expert panel discussion.

    Science.gov (United States)

    Asselin, Barbara L; Gaynon, Paul; Whitlock, James A

    2013-12-01

    Acute lymphoblastic leukemia (ALL) is the most common form of childhood leukemia, representing 75% to 80% of cases of acute leukemia among children. Dramatic improvements in the cure rates and survival outcomes for children with ALL have been seen over the past several decades; currently the 5-year survival rate for childhood ALL is more than 80%. These improvements have come about because of advances in the understanding of the molecular genetics and pathogenesis of the disease, incorporation of risk-adapted therapy, and the advent of new targeted agents. Scientific advances have provided new insights into leukemogenesis, drug resistance, and host pharmacogenomics, identified novel subtypes of leukemia, and suggested potential targets for therapy. At the same time novel monoclonal antibodies, small molecule inhibitors, chemotherapeutics, and cell-based treatment strategies have been developed and investigated. In this article, experts will discuss some of the current challenges and future directions in the treatment of pediatric ALL. The authors will offer expert guidance to practicing oncologists on how to best incorporate newer treatment approaches into the care of children and adolescents with ALL. The most important ongoing clinical trials in the area will also be reviewed.

  16. Multiple drug resistance protein (MDR-1, multidrug resistance-related protein (MRP and lung resistance protein (LRP gene expression in childhood acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Elvis Terci Valera

    Full Text Available CONTEXT: Despite the advances in the cure rate for acute lymphoblastic leukemia, approximately 25% of affected children suffer relapses. Expression of genes for the multiple drug resistance protein (MDR-1, multidrug resistance-related protein (MRP, and lung resistance protein (LRP may confer the phenotype of resistance to the treatment of neoplasias. OBJECTIVE: To analyze the expression of the MDR-1, MRP and LRP genes in children with a diagnosis of acute lymphoblastic leukemia via the semiquantitative reverse transcription polymerase chain reaction (RT-PCR, and to determine the correlation between expression and event-free survival and clinical and laboratory variables. DESIGN: A retrospective clinical study. SETTING: Laboratory of Pediatric Oncology, Department of Pediatrics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brazil. METHODS: Bone marrow aspirates from 30 children with a diagnosis of acute lymphoblastic leukemia were assessed for the expression of messenger RNA for the MDR-1, MRP and LRP genes by semi-quantitative RT-PCR. RESULTS: In the three groups studied, only the increased expression of LRP was related to worsened event-free survival (p = 0.005. The presence of the common acute lymphoblastic leukemia antigen (CALLA was correlated with increased LRP expression (p = 0.009 and increased risk of relapse or death (p = 0.05. The relative risk of relapse or death was six times higher among children with high LRP expression upon diagnosis (p = 0.05, as confirmed by multivariate analysis of the three genes studied (p = 0.035. DISCUSSION: Cell resistance to drugs is a determinant of the response to chemotherapy and its detection via RT-PCR may be of clinical importance. CONCLUSIONS: Evaluation of the expression of genes for resistance to antineoplastic drugs in childhood acute lymphoblastic leukemia upon diagnosis, and particularly the expression of the LRP gene, may be of clinical relevance, and should be the

  17. Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group.

    Science.gov (United States)

    Oriol, Albert; Vives, Susana; Hernández-Rivas, Jesús-María; Tormo, Mar; Heras, Inmaculada; Rivas, Concepción; Bethencourt, Concepción; Moscardó, Federico; Bueno, Javier; Grande, Carlos; del Potro, Eloy; Guardia, Ramon; Brunet, Salut; Bergua, Juan; Bernal, Teresa; Moreno, Maria-José; Calvo, Carlota; Bastida, Pilar; Feliu, Evarist; Ribera, Josep-Maria

    2010-04-01

    About one half of adults with acute lymphoblastic leukemia are not cured of the disease and ultimately die. The objective of this study was to explore the factors influencing the outcome of adult patients with relapsed acute lymphoblastic leukemia. We analyzed the characteristics, the outcome and the prognostic factors for survival after first relapse in a series of 263 adult patients with acute lymphoblastic leukemia (excluding those with mature B-cell acute lymphoblastic leukemia) prospectively enrolled in four consecutive risk-adapted PETHEMA trials. The median overall survival after relapse was 4.5 months (95% CI, 4-5 months) with a 5-year overall survival of 10% (95% CI, 8%-12%); 45% of patients receiving intensive second-line treatment achieved a second complete remission and 22% (95% CI, 14%-30%) of them remained disease free at 5 years. Factors predicting a good outcome after rescue therapy were age less than 30 years (2-year overall survival of 21% versus 10% for those over 30 years old; P<0.022) and a first remission lasting more than 2 years (2-year overall survival of 36% versus 17% among those with a shorter first remission; P<0.001). Patients under 30 years old whose first complete remission lasted longer than 2 years had a 5-year overall survival of 38% (95% CI, 23%-53%) and a 5-year disease-free survival of 53% (95% CI, 34%-72%). The prognosis of adult patients with acute lymphoblastic leukemia who relapse is poor. Those aged less than 30 years with a first complete remission lasting longer than 2 years have reasonable possibilities of becoming long-term survivors while patients over this age or those who relapse early cannot be successfully rescued using the therapies currently available.

  18. A fatal case of acute pulmonary embolism caused by right ventricular masses of acute lymphoblastic lymphoma-leukemia in a 13 year old girl

    Directory of Open Access Journals (Sweden)

    Yu Mi Ko Ko

    2012-07-01

    Full Text Available We report a case of a 13-year-old girl with acute lymphoblastic lymphoma- leukemia, who presented with a cardiac metastasis in the right ventricle, resulting in a pulmonary embolism. At the time of her leukemia diagnosis, a cardiac mass was incidentally found. The differential diagnosis for this unusual cardiac mass included cardiac tumor, metastasis, vegetation, and thrombus. Empirical treatment was initiated, including anticoagulation and antibiotics. She underwent plasmapheresis and was administered oral prednisolone for her leukemia. Five days later, she experienced sudden hemodynamic collapse and required extracorporeal membrane oxygenation insertion and emergency surgery. These interventions proved futile, and the patient died. Pathology revealed that the cardiac mass comprised an aggregation of small, round, necrotic cells consistent with leukemia. This is the first known case of acute lymphoblastic leukemia presenting as a right ventricular mass, with consequent fatal acute pulmonary embolism. A cardiac mass in a child with acute leukemia merits investigation to rule out every possible etiology, including vegetation, thrombus, and even a mass of leukemic cells, which could result in the fatal complication of pulmonary embolism.

  19. Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children’s Oncology Group Study AALL03N1

    Science.gov (United States)

    Landier, Wendy; Hageman, Lindsey; Chen, Yanjun; Kornegay, Nancy; Evans, William E.; Bostrom, Bruce C.; Casillas, Jacqueline; Dickens, David S.; Angiolillo, Anne L.; Lew, Glen; Maloney, Kelly W.; Mascarenhas, Leo; Ritchey, A. Kim; Termuhlen, Amanda M.; Carroll, William L.; Relling, Mary V.; Wong, F. Lennie

    2017-01-01

    Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 ± 107.1 v 220.6 ± 121.6; P = .5), with dairy versus without (220.1 ± 87.8 v 216.3 ± 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 ± 119.7 v 195.5 ± 82.3 v 174.8 ± 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for

  20. Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1.

    Science.gov (United States)

    Landier, Wendy; Hageman, Lindsey; Chen, Yanjun; Kornegay, Nancy; Evans, William E; Bostrom, Bruce C; Casillas, Jacqueline; Dickens, David S; Angiolillo, Anne L; Lew, Glen; Maloney, Kelly W; Mascarenhas, Leo; Ritchey, A Kim; Termuhlen, Amanda M; Carroll, William L; Relling, Mary V; Wong, F Lennie; Bhatia, Smita

    2017-05-20

    Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 ± 107.1 v 220.6 ± 121.6; P = .5), with dairy versus without (220.1 ± 87.8 v 216.3 ± 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 ± 119.7 v 195.5 ± 82.3 v 174.8 ± 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for

  1. Identification of prognostic genetic factors in pediatric T-cell acute lymphoblastic leukemia: prognostic genetic factors in pediatric T-ALL

    NARCIS (Netherlands)

    M. van Grotel (Martine)

    2008-01-01

    textabstractHematopoiesis is a complex process in which primitive and undifferentiated stem cells multiply (self-renewal) and differentiate into many different blood cell types. Hematopoiesis primarily takes place in the bone marrow that is composed of stromal cells and a microvascular network,

  2. Acute lymphoblastic leukemia in adolescents and young adults – from genomics to the clinics

    Directory of Open Access Journals (Sweden)

    Kenderian SS

    2013-04-01

    Full Text Available Saad Sirop Kenderian, Mark R Litzow Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA Abstract: Acute lymphoblastic leukemia (ALL in adolescents and young adults (AYA represents a unique and challenging disease entity. Despite the recent improvement of survival in this population over the last decade, it is still lagging behind the excellent cure rates obtained in pediatric ALL. This special population of AYA receives care from pediatric as well as adult hematologists and can be treated on pediatric or adult protocols. There is a substantial difference in disease biology, response to chemotherapy, and allogeneic stem cell transplantation between pediatric and AYA patients. This review discusses current controversies in the management of AYA, outcomes following treatment with pediatric and adult protocols, and the role of allogeneic stem cell transplantation. It focuses on the unique clinical, biological, and socioeconomic characteristics of this population that might partly explain the inferior outcomes. This review also explores recent advances in genomic profiling and emerging treatments in ALL. Keywords: novel agents, monoclonal antibodies, stem cell transplantation, bone marrow transplantation, Philadelphia positive ALL, genomic profile

  3. Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia

    Science.gov (United States)

    Vesely, C; Frech, C; Eckert, C; Cario, G; Mecklenbräuker, A; zur Stadt, U; Nebral, K; Kraler, F; Fischer, S; Attarbaschi, A; Schuster, M; Bock, C; Cavé, H; von Stackelberg, A; Schrappe, M; Horstmann, M A; Mann, G; Haas, O A; Panzer-Grümayer, R

    2017-01-01

    Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1’s critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias. PMID:27899802

  4. Clonal heterogeneity and chromosomal instability at disease presentation in high hyperdiploid acute lymphoblastic leukemia.

    Science.gov (United States)

    Talamo, Anna; Chalandon, Yves; Marazzi, Alfio; Jotterand, Martine

    2010-12-01

    Although aneuploidy has many possible causes, it often results from underlying chromosomal instability (CIN) leading to an unstable karyotype with cell-to-cell variation and multiple subclones. To test for the presence of CIN in high hyperdiploid acute lymphoblastic leukemia (HeH ALL) at diagnosis, we investigated 20 patients (10 HeH ALL and 10 non-HeH ALL), using automated four-color interphase fluorescence in situ hybridization (I-FISH) with centromeric probes for chromosomes 4, 6, 10, and 17. In HeH ALL, the proportion of abnormal cells ranged from 36.3% to 92.4%, and a variety of aneuploid populations were identified. Compared with conventional cytogenetics, I-FISH revealed numerous additional clones, some of them very small. To investigate the nature and origin of this clonal heterogeneity, we determined average numerical CIN values for all four chromosomes together and for each chromosome and patient group. The CIN values in HeH ALL were relatively high (range, 22.2-44.7%), compared with those in non-HeH ALL (3.2-6.4%), thus accounting for the presence of numerical CIN in HeH ALL at diagnosis. We conclude that numerical CIN may be at the origin of the high level of clonal heterogeneity revealed by I-FISH in HeH ALL at presentation, which would corroborate the potential role of CIN in tumor pathogenesis. Copyright © 2010 Elsevier Inc. All rights reserved.

  5. Challenges faced in the treatment of acute lymphoblastic leukemia in adolescents and young adults

    Directory of Open Access Journals (Sweden)

    Levine SR

    2016-02-01

    Full Text Available Selena R Levine,1 Jennifer L McNeer,2 Michael S Isakoff1 1Center for Cancer and Blood Disorders, Connecticut Children’s Medical Center and University of Connecticut School of Medicine, Hartford, CT, 2Section of Pediatric Hematology/Oncology, University of Chicago Comer Children's Hospital, Chicago, IL, USA Abstract: The survival rate for children with acute lymphoblastic leukemia (ALL has dramatically improved over the last 50 years. However, for those in the adolescent and young adult (AYA age-group of 15–30 years with ALL, there has not been the same degree of improvement. Historically, pediatric and adult providers have utilized different treatment approaches based on clinical trials. However, studies that have compared the outcome of AYA patients with ALL treated on pediatric or adult clinical trials have generally shown substantially better outcomes for this patient population treated with the pediatric trials. Additionally, hematopoietic stem cell transplantation has been considered as part of intensified therapy for AYA patients with ALL. Herein, we review the outcomes with chemotherapy alone and with hematopoietic stem cell transplantation, and explore the challenges faced in determining the ideal therapy for the AYA population of patients. Keywords: adolescent young adult oncology, leukemia, hematopoietic stem cell transplantation

  6. Successful Treatment of Disseminated Cryptococcal Infection in a Pediatric Acute Lymphoblastic Leukemia Patient During Induction

    Science.gov (United States)

    Heath, Jessica L.; Yin, Dwight E.; Wechsler, Daniel S.; Turner, David A.

    2015-01-01

    Disseminated cryptococcal infection is rarely reported in the setting of pediatric acute leukemia, despite the immunocompromised state of these patients. However, when present, disseminated cryptococcal infection poses treatment challenges and is associated with significant morbidity and mortality. Treatment of invasive fungal disease in a child with acute leukemia requires a delicate balance between anti-fungal and anti-neoplastic therapy. This balance is particularly important early in the course of leukemia, since both the underlying disease and overwhelming infection can be life threatening. We describe the successful management of life-threatening disseminated cryptococcosis in a child with acute lymphoblastic leukemia during induction therapy. PMID:22258349

  7. Prolonged Survival of Acute Lymphoblastic Leukemia with Intrathecal Treatments for Isolated Central Nervous System Relapse

    Directory of Open Access Journals (Sweden)

    Elan Gorshein

    2018-01-01

    Full Text Available Acute lymphoblastic leukemia is commonly cured when diagnosed in the pediatric population. It portends a poorer prognosis if present in adult patients. Although adults frequently achieve complete remission, relapse rates are substantial, particularly among the elderly and high-risk populations. In the absence of prophylactic intrathecal chemotherapy, more than half of patients may develop CNS involvement or relapse, which is associated with significant risk for systemic illness. This report describes a patient with acute lymphoblastic leukemia with repeated isolated CNS relapses. This case should remind clinicians that isolated CNS disease in the absence of systemic recurrence could successfully respond to intrathecal therapy and offer patients a favorable quality of life.

  8. [Copy number alterations in adult patients with mature B acute lymphoblastic leukemia treated with specific immunochemotherapy].

    Science.gov (United States)

    Ribera, Jordi; Zamora, Lurdes; García, Olga; Hernández-Rivas, Jesús-María; Genescà, Eulàlia; Ribera, Josep-Maria

    2016-12-02

    Unlike Burkitt lymphoma, molecular abnormalities other than C-MYC rearrangements have scarcely been studied in patients with mature B acute lymphoblastic leukemia (B-ALL). The aim of this study was to analyze the frequency and prognostic significance of copy number alterations (CNA) in genes involved in lymphoid differentiation, cell cycle and tumor suppression in adult patients with B-ALL. We have analyzed by multiplex ligation-dependent probe amplification the genetic material from bone marrow at diagnosis from 25 adult B-ALL patients treated with rituximab and specific chemotherapy. The most frequent CNA were alterations in the 14q32.33 region (11 cases, 44%) followed by alterations in the cell cycle regulator genes CDKN2A/B and RB1 (16%). No correlation between the presence of specific CNA and the clinical-biologic features or the response to therapy was found. The high frequency of CNA in the 14q32.33 region, CDKN2A/B and RB1 found in our study could contribute to the aggressiveness and invasiveness of mature B-ALL. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  9. Subgroups of Paediatric Acute Lymphoblastic Leukaemia Might Differ Significantly in Genetic Predisposition to Asparaginase Hypersensitivity.

    Directory of Open Access Journals (Sweden)

    Nóra Kutszegi

    Full Text Available L-asparaginase (ASP is a key element in the treatment of paediatric acute lymphoblastic leukaemia (ALL. However, hypersensitivity reactions (HSRs to ASP are major challenges in paediatric patients. Our aim was to investigate genetic variants that may influence the risk to Escherichia coli-derived ASP hypersensitivity. Sample and clinical data collection was carried out from 576 paediatric ALL patients who were treated according to protocols from the Berlin-Frankfurt-Münster Study Group. A total of 20 single nucleotide polymorphisms (SNPs in GRIA1 and GALNT10 genes were genotyped. Patients with GRIA1 rs4958351 AA/AG genotype showed significantly reduced risk to ASP hypersensitivity compared to patients with GG genotype in the T-cell ALL subgroup (OR = 0.05 (0.01-0.26; p = 4.70E-04, while no such association was found in pre-B-cell ALL. In the medium risk group two SNPs of GRIA1 (rs2055083 and rs707176 were associated significantly with the occurrence of ASP hypersensitivity (OR = 0.21 (0.09-0.53; p = 8.48E-04 and OR = 3.02 (1.36-6.73; p = 6.76E-03, respectively. Evaluating the genders separately, however, the association of rs707176 with ASP HSRs was confined only to females. Our results suggest that genetic variants of GRIA1 might influence the risk to ASP hypersensitivity, but subgroups of patients can differ significantly in this respect.

  10. The association of folate pathway and DNA repair polymorphisms with susceptibility to childhood acute lymphoblastic leukemia.

    Science.gov (United States)

    Goričar, Katja; Erčulj, Nina; Faganel Kotnik, Barbara; Debeljak, Maruša; Hovnik, Tinka; Jazbec, Janez; Dolžan, Vita

    2015-05-15

    Genetic factors may play an important role in susceptibility to childhood acute lymphoblastic leukemia (ALL). The aim of our study was to evaluate the associations of genetic polymorphisms in folate pathway and DNA repair genes with susceptibility to ALL. In total, 121 children with ALL and 184 unrelated healthy controls of Slovenian origin were genotyped for 14 polymorphisms in seven genes of folate pathway, base excision repair and homologous recombination repair (TYMS, MTHFR, OGG1, XRCC1, NBN, RAD51, and XRCC3). In addition, the exon 6 of NBN was screened for the presence of mutations using denaturing high performance liquid chromatography. Twelve polymorphisms were in Hardy-Weinberg equilibrium in controls and their genotype frequencies were in agreement with those reported in other Caucasian populations. Among the investigated polymorphisms and mutations, NBN Glu185Gln significantly decreased susceptibility to B-cell ALL (p=0.037), while TYMS 3R allele decreased susceptibility to T-cell ALL (p=0.011). Moreover, significantly decreased susceptibility to ALL was observed for MTHFR TA (p=0.030) and RAD51 GTT haplotypes (p=0.016). Susceptibility to ALL increased with the increasing number of risk alleles (ptrend=0.007). We also observed significant influence of hOGG-RAD51 and NBN-RAD51 interactions on susceptibility to ALL. Our results suggest that combination of several polymorphisms in DNA repair and folate pathways may significantly affect susceptibility to childhood ALL. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers

    DEFF Research Database (Denmark)

    Nielsen, Stine N; Eriksson, Frank; Rosthøj, Susanne

    2017-01-01

    BACKGROUND: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. PROCEDURE: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology......], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard...

  12. Clinical features and early treatment response of central nervous system involvement in childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Levinsen, Mette; Taskinen, Mervi; Abrahamsson, Jonas

    2014-01-01

    BACKGROUND: Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) remains a therapeutic challenge. PROCEDURE: To explore leukemia characteristics of patients with CNS involvement at ALL diagnosis, we analyzed clinical features and early treatment response of 744...... leukemia and patients without such characteristics (0.50 vs. 0.61; P = 0.2). CONCLUSION: CNS involvement at diagnosis is associated with adverse prognostic features but does not indicate a less chemosensitive leukemia....

  13. The molecular genetic makeup of acute lymphoblastic leukemia | Office of Cancer Genomics

    Science.gov (United States)

    Abstract: Genomic profiling has transformed our understanding of the genetic basis of acute lymphoblastic leukemia (ALL). Recent years have seen a shift from microarray analysis and candidate gene sequencing to next-generation sequencing. Together, these approaches have shown that many ALL subtypes are characterized by constellations of structural rearrangements, submicroscopic DNA copy number alterations, and sequence mutations, several of which have clear implications for risk stratification and targeted therapeutic intervention.

  14. Imaging findings of recurrent acute lymphoblastic leukemia in children and young adults, with emphasis on MRI

    International Nuclear Information System (INIS)

    Porter, Rosalyn P.; Kaste, Sue C.

    2004-01-01

    Acute lymphoblastic leukemia (ALL) is the most common of all childhood malignancies. Current remission rates approach 80%. Recurrent disease can present in a wide variety of ways. MR imaging plays a crucial role in the detection of disease relapse. Because other disorders can mimic recurrence of leukemia, it is important for the radiologist to judge recurrence from non-recurrence accurately in order to avoid unnecessary testing and emotional stress on the patient and family. (orig.)

  15. Imaging findings of recurrent acute lymphoblastic leukemia in children and young adults, with emphasis on MRI

    Energy Technology Data Exchange (ETDEWEB)

    Porter, Rosalyn P. [Department of Diagnostic Imaging, St. Jude Children' s Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794 (United States); Kaste, Sue C. [Department of Diagnostic Imaging, St. Jude Children' s Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794 (United States); Department of Radiology, University of Tennessee, College of Medicine, Memphis, Tennessee (United States)

    2004-05-01

    Acute lymphoblastic leukemia (ALL) is the most common of all childhood malignancies. Current remission rates approach 80%. Recurrent disease can present in a wide variety of ways. MR imaging plays a crucial role in the detection of disease relapse. Because other disorders can mimic recurrence of leukemia, it is important for the radiologist to judge recurrence from non-recurrence accurately in order to avoid unnecessary testing and emotional stress on the patient and family. (orig.)

  16. Adrenocortical function and reserve in children treated for acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Pawlaczyk, B.; Malecka, E.H.; Krause, W.

    1993-01-01

    Serum cortisol and 17 OHS, 17 KS and DHA levels in 24-hour urine were determined in 30 children (22 girls and boys) 0.5 to 4 years after completion of therapy (radio- and chemotherapy) for acute lymphoblastic leukemia (ALL). Serum cortisol after Syncthen (adrenocortical reserve) was determined in 15 girls and 4 boys. The results show that therapy for ALL depresses glucocorticosteroid synthesis; however, it does not disturb the adrenal reserve or androgenesis. (author)

  17. Psychological Impact of Chemotherapy for Childhood Acute Lymphoblastic Leukemia on Patients and Their Parents

    OpenAIRE

    Sherief, Laila M.; Kamal, Naglaa M.; Abdalrahman, Hadel M.; Youssef, Doaa M.; Alhady, Mohamed A Abd; Ali, Adel SA; Elbasset, Maha Aly Abd; Hashim, Hiatham M.

    2015-01-01

    Abstract To assess the self-esteem of pediatric patients on chemotherapy for acute lymphoblastic leukemia (ALL) and psychological status of their parents. The psychological status of 178 children receiving chemotherapy for ALL and their parents was assessed using parenting stress index (PSI) to determine the degree of stress the parents are exposed to using parent's and child's domains. Self-esteem Scale was used to determine the psychological status of patients. The study revealed significan...

  18. Considerations in the design of clinical trials for pediatric acute lymphoblastic leukemia

    OpenAIRE

    Devidas, Meenakshi; Anderson, James R

    2013-01-01

    Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although outcomes for children with ALL have improved dramatically over the last 50 years, ALL remains the leading cause of childhood cancer death. In addition, high-risk patient subsets can be identified with significantly inferior survival. In the current era of therapies directed at specific molecular targets, the use of conventional randomized Phase III trials to show benefit from a new treatment regimen may not b...

  19. Dental Anomalies and Dental Age Assessment in Treated Children with Acute Lymphoblastic Leukemia

    OpenAIRE

    Khojastepour, L; Zareifar, S; Ebrahimi, M

    2014-01-01

    Background This cross sectional study was performed to evaluate dental ages and incidence of dental anomalies in children treated for acute lymphoblastic leukemia (ALL). Methods and materials A total of 25 ALL patient who passed at least 2 years of chemotherapy and 25 healthy sex and age matched children were evaluated. Dental age as well as dental anomalies in shape, size, number, and structure was recorded based on their panoramic radiographies which were taken for dental purposes. Results ...

  20. Valosin-Containing Protein/p97 as a Novel Therapeutic Target in Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Gabriele Gugliotta

    2017-10-01

    Full Text Available B acute lymphoblastic leukemia (B-ALL cells are distinctively vulnerable to endoplasmic reticulum (ER stress. Recently, inhibition of p97 was shown to induce ER stress and subsequently cell death in solid tumors and in multiple myeloma. We investigated the role of a novel, orally available, p97 inhibitor (CB-5083; Cleave Biosciences in B-ALL. CB-5083 induced a significant reduction in viability in 10 human B-ALL cell lines, harboring the most common fusion-genes involved in pediatric and adult B-ALL, with IC50s ranging from 0.34 to 0.76 μM. Moreover, CB-5083 significantly reduced the colony formation of OP1 and NALM6 cells. Early and strong induction of apoptosis was demonstrated in BALL1 and OP1 cells, together with a robust cleavage of PARP. CB-5083 induced ER stress, as documented through: 1 prominent expression of chaperones (GRP78, GRP94, PDI, DNAJC3, and DNAJB9; 2 increased activation of IRE1-alpha, as demonstrated by the splicing of XBP1; and 3 activation of PERK, which resulted in a significant overexpression of CHOP, and its downstream genes. CB-5083 reduced the viability also in GRP78−/−, GRP94−/−, and XBP1−/− cells, suggesting that none of these proteins alone was strictly required for CB-5083 activity. Moreover, we showed that the absence of XBP1 (XBP1−/− increased the sensitivity to CB-5083, leading to the hypothesis that XBP1 splicing counteracts the activity of CB-5083, probably mitigating ER stress. Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 cells. In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL.

  1. Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome

    DEFF Research Database (Denmark)

    Nyvold, Charlotte; Madsen, Hans O; Ryder, Lars P

    2002-01-01

    The postinduction level of minimal residual disease (MRD) was quantified with a competitive polymerase chain reaction (PCR) technique in 104 children with acute lymphoblastic leukemia (ALL) diagnosed between June 1993 and January 1998 and followed for a median of 4.2 years. A significant correlat......The postinduction level of minimal residual disease (MRD) was quantified with a competitive polymerase chain reaction (PCR) technique in 104 children with acute lymphoblastic leukemia (ALL) diagnosed between June 1993 and January 1998 and followed for a median of 4.2 years. A significant......-free survival for patients with higher MRD levels was 0.52 (P =.0007). The group of patients with a D29 MRD less than 0.01% included patients with T-cell disease, white blood cell count more than 50 x 10(9)/L at diagnosis, or age 10 years or older, and could not be identified by up-front criteria. The best...

  2. Inferring a role for methylation of intergenic DNA in the regulation of genes aberrantly expressed in precursor B-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Almamun, Md; Kholod, Olha; Stuckel, Alexei J; Levinson, Benjamin T; Johnson, Nathan T; Arthur, Gerald L; Davis, J Wade; Taylor, Kristen H

    2017-09-01

    A complete understanding of the mechanisms involved in the development of pre-B ALL is lacking. In this study, we integrated DNA methylation data and gene expression data to elucidate the impact of aberrant intergenic DNA methylation on gene expression in pre-B ALL. We found a subset of differentially methylated intergenic loci that were associated with altered gene expression in pre-B ALL patients. Notably, 84% of these regions were also bound by transcription factors (TF) known to play roles in differentiation and B-cell development in a lymphoblastoid cell line. Further, an overall downregulation of eRNA transcripts was observed in pre-B ALL patients and these transcripts were associated with the downregulation of putative target genes involved in B-cell migration, proliferation, and apoptosis. The identification of novel putative regulatory regions highlights the significance of intergenic DNA sequences and may contribute to the identification of new therapeutic targets for the treatment of pre-B ALL.

  3. Common acute lymphoblastic leukemia antigen: partial characterization by in vivo labeling and isolation of its messenger RNA

    International Nuclear Information System (INIS)

    Heinsohn, S.; Kabisch, H.

    1987-01-01

    Common acute lymphoblastic leukemia (ALL) antigen (CALLA)-like proteins were detected by in vivo labeling experiments carried out with human lymphoblastoid cell line KM3 and also in cell-free translation, directed by CALLA-specific mRNA prepared from immunoadsorbed KM3 polysomes. The CALLA-like structure found in both systems shows an Mr of 95kDa. Additional CALLA-like proteins could be identified in the in vivo experiments with calculated Mrs of 40kDa in the cells and 85 and 38kDa in the culture medium. In the cell-free translation system, an additional product of Mr 80kDa could be detected

  4. A case of acute lymphoblastic leukemia with abnormal brain CT scan after cranial irradiation for central nervous system leukemia

    International Nuclear Information System (INIS)

    Sato, Junko; Abe, Takanori; Watanabe, Tsutomu

    1988-01-01

    A 21-year-old woman with acute lymphoblastic leukemia presented with central neurologic symptoms immediately after the second irradiation (20 Gy to the brain and 10 Gy to the spinal cord) for central nervous system (CNS)-leukemia 3 years and 2 months after the first cranial irradiation with 20 Gy. White matter was depicted as diffusely high density area on CT; histology revealed necrosis of leukemic cells. In the present patient with repeated recurrent CNS-leukemia, leukemic cells seemed to have been damaged simultaneously after irradiation because of parenchymal widespread involvement of leukemic cells, resulting in brain edema, an increased intracranial pressure and parenchymal disturbance. This finding may have an important implication for the risk of cranial irradiation in the case of widespread involvement of leukemic cells. Re-evaluation of cranial irradiation in such cases is suggested. (Namekawa, K.)

  5. Primary orbital precursor T-cell lymphoblastic lymphoma

    DEFF Research Database (Denmark)

    Stenman, Lisa; Persson, Marta; Enlund, Fredrik

    2016-01-01

    Primary T-cell lymphoblastic lymphoma (T-LBL) in the eye region is very rare. The present study described a unique case of T-LBL involving the extraocular muscles. A 22-year-old male patient presented with a 3-week history of headache, reduced visual acuity and edema of the left eye. Clinical...... knowledge, this is the first report of a case of T-LBL involving the extraocular muscles. Although primary T-LBL in the eye region is very rare, our findings demonstrate that lymphoma should be considered in the differential diagnosis of patients with similar symptoms....

  6. New Challenges in Targeting Signaling Pathways in Acute Lymphoblastic Leukemia by NGS Approaches: An Update

    Science.gov (United States)

    Hernández-Rivas, Jesús María

    2018-01-01

    The identification and study of genetic alterations involved in various signaling pathways associated with the pathogenesis of acute lymphoblastic leukemia (ALL) and the application of recent next-generation sequencing (NGS) in the identification of these lesions not only broaden our understanding of the involvement of various genetic alterations in the pathogenesis of the disease but also identify new therapeutic targets for future clinical trials. The present review describes the main deletions, amplifications, sequence mutations, epigenetic lesions, and new structural DNA rearrangements detected by NGS in B-ALL and T-ALL and their clinical importance for therapeutic procedures. We reviewed the molecular basis of pathways including transcriptional regulation, lymphoid differentiation and development, TP53 and the cell cycle, RAS signaling, JAK/STAT, NOTCH, PI3K/AKT/mTOR, Wnt/β-catenin signaling, chromatin structure modifiers, and epigenetic regulators. The implementation of NGS strategies has enabled important mutated genes in each pathway, their associations with the genetic subtypes of ALL, and their outcomes, which will be described further. We also discuss classic and new cryptic DNA rearrangements in ALL identified by mRNA-seq strategies. Novel cooperative abnormalities in ALL could be key prognostic and/or predictive biomarkers for selecting the best frontline treatment and for developing therapies after the first relapse or refractory disease. PMID:29642462

  7. Relapsed or refractory pediatric acute lymphoblastic leukemia: current and emerging treatments.

    Science.gov (United States)

    Martin, Alissa; Morgan, Elaine; Hijiya, Nobuko

    2012-12-01

    Relapsed acute lymphoblastic leukemia (ALL) represents a major cause of morbidity and mortality in pediatrics. With contemporary chemotherapy, >85% of patients with newly diagnosed ALL survive. Unfortunately, 20% of these patients will relapse and for these children, outcomes remain poor despite our best known chemotherapy protocols. Most of these children will achieve a second complete remission, but maintaining this remission remains difficult. Because relapsed ALL is such a significant cause of morbidity and mortality, it is the focus of much research interest. Efforts have been made and continue to focus on understanding the underlying biology that drives relapse. The role of hematopoietic stem cell transplantation in relapsed ALL remains unclear, but many clinicians still favor this for high-risk patients given the poor prognosis with current chemotherapy alone. It is important to use new drugs with little cross-resistance in the treatment of relapsed ALL. New classes of agents are currently being studied. We also discuss prognostic factors and the biology of relapsed ALL.

  8. Identification of Differentially Expressed Genes Associated with Prognosis of B Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Idalia Garza-Veloz

    2015-01-01

    Full Text Available Background. Acute lymphoblastic leukemia type B (B-ALL is a neoplastic disorder with high mortality rates. The aim of this study was to validate the expression profile of 45 genes associated with signaling pathways involved in leukemia and to evaluate their association with the prognosis of B-ALL. Methods. 219 samples of peripheral blood mononuclear cells obtained from 73 B-ALL patients were studied at diagnosis, four, and eight weeks after starting treatment. Gene expression was analyzed by quantitative real-time polymerase chain reaction. Results. Normalized delta Cq values of 23 genes showed differences between B-ALL and controls at diagnosis time (P values < 0.05. There were significant associations between B-ALL patients relapse/death and the expression levels of IL2RA, SORT1, DEFA1, and FLT3 genes at least in one of the times evaluated (P values < 0.05 and odds ratio ranges: 3.73–27. The association between FLT3 deregulation and relapse/death was a constant in the times studied and their overexpression significantly increased the odds of relapse/death in a range of 3.73 and 6.05 among study population (P values < 0.05. Conclusions. Overexpression of FLT3 and DEFA1 genes retained independent prognostic significance for B-ALL outcome, reflected as increased risks of relapse/death among the study population.

  9. Using adaptive model predictive control to customize maintenance therapy chemotherapeutic dosing for childhood acute lymphoblastic leukemia.

    Science.gov (United States)

    Noble, Sarah L; Sherer, Eric; Hannemann, Robert E; Ramkrishna, Doraiswami; Vik, Terry; Rundell, Ann E

    2010-06-07

    Acute lymphoblastic leukemia (ALL) is a common childhood cancer in which nearly one-quarter of patients experience a disease relapse. However, it has been shown that individualizing therapy for childhood ALL patients by adjusting doses based on the blood concentration of active drug metabolite could significantly improve treatment outcome. An adaptive model predictive control (MPC) strategy is presented in which maintenance therapy for childhood ALL is personalized using routine patient measurements of red blood cell mean corpuscular volume as a surrogate for the active drug metabolite concentration. A clinically relevant mathematical model is developed and used to describe the patient response to the chemotherapeutic drug 6-mercaptopurine, with some model parameters being patient-specific. During the course of treatment, the patient-specific parameters are adaptively identified using recurrent complete blood count measurements, which sufficiently constrain the patient parameter uncertainty to support customized adjustments of the drug dose. While this work represents only a first step toward a quantitative tool for clinical use, the simulated treatment results indicate that the proposed mathematical model and adaptive MPC approach could serve as valuable resources to the oncologist toward creating a personalized treatment strategy that is both safe and effective. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  10. Altered brain function in new onset childhood acute lymphoblastic leukemia before chemotherapy: A resting-state fMRI study.

    Science.gov (United States)

    Hu, Zhanqi; Zou, Dongfang; Mai, Huirong; Yuan, Xiuli; Wang, Lihong; Li, Yue; Liao, Jianxiang; Liu, Liwei; Liu, Guosheng; Zeng, Hongwu; Wen, Feiqiu

    2017-10-01

    Cognitive impairments had been reported in childhood acute lymphoblastic leukemia, what caused the impairments needed to be demonstrated, chemotherapy-related or the disease itself. The primary aim of this exploratory investigation was to determine if there were changes in brain function of children with acute lymphoblastic leukemia before chemotherapy. In this study, we advanced a measure named regional homogeneity to evaluate the resting-state brain activities, intelligence quotient test was performed at same time. Using regional homogeneity, we first investigated the resting state brain function in patients with new onset childhood acute lymphoblastic leukemia before chemotherapy, healthy children as control. The decreased ReHo values were mainly founded in the default mode network and left frontal lobe, bilateral inferior parietal lobule, bilateral temporal lobe, bilateral occipital lobe, precentral gyrus, bilateral cerebellum in the newly diagnosed acute lymphoblastic leukemia patients compared with the healthy control. While in contrast, increased ReHo values were mainly shown in the right frontal lobe (language area), superior frontal gyrus-R, middle frontal gyrus-R and inferior parietal lobule-R for acute lymphoblastic leukemia patients group. There were no significant differences for intelligence quotient measurements between the acute lymphoblastic leukemia patient group and the healthy control in performance intelligence quotient, verbal intelligence quotient, total intelligence quotient. The altered brain functions are associated with cognitive change and language, it is suggested that there may be cognition impairment before the chemotherapy. Regional homogeneity by functional magnetic resonance image is a sensitive way for early detection on brain damage in childhood acute lymphoblastic leukemia. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  11. Recent advances in the management of pediatric acute lymphoblastic leukemia [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Jan Starý

    2016-11-01

    Full Text Available Acute lymphoblastic leukemia (ALL is the most common malignancy in childhood. Despite enormous improvement of prognosis during the last half century, ALL remains a major cause of childhood cancer-related mortality. During the past decade, whole genomic methods have enhanced our knowledge of disease biology. Stratification of therapy according to early treatment response measured by minimal residual disease allows risk group assignment into different treatment arms, ranging from reduction to intensification of treatment. Progress has been achieved in academic clinical trials by optimization of combined chemotherapy, which continues to be the mainstay of contemporary treatment. The availability of suitable volunteer main histocompatibility antigen-matched unrelated donors has increased the rates of hematopoietic stem cell transplantation (HSCT over the past two decades. Allogeneic HSCT has become an alternative treatment for selected, very-high-risk patients. However, intensive treatment burdens children with severe acute toxic effects that can cause permanent organ damage and even toxic death. Immunotherapeutic approaches have recently come to the forefront in ALL therapy. Monoclonal antibodies blinatumomab and inotuzumab ozogamicin as well as gene-modified T cells directed to specific target antigens have shown efficacy against resistant/relapsed leukemia in phase I/II studies. Integration of these newer modalities into combined regimens with chemotherapy may rescue a subset of children not curable by contemporary therapy. Another major challenge will be to incorporate less toxic regimens into the therapy of patients with low-risk disease who have a nearly 100% chance of being cured, and the ultimate goal is to improve their quality of life while maintaining a high cure rate.

  12. Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Francis Richard W

    2010-04-01

    Full Text Available Abstract Background Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic/severe combined immunodeficient (NOD/SCID mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL. However, for this model to be effective for studying engraftment and therapy responses at the whole genome level, careful molecular characterisation is essential. Results Here, we sought to validate species-specific gene expression profiling in the high engraftment continuous ALL NOD/SCID xenograft. Using the human Affymetrix whole transcript platform we analysed transcriptional profiles from engrafted tissues without prior cell separation of mouse cells and found it to return highly reproducible profiles in xenografts from individual mice. The model was further tested with experimental mixtures of human and mouse cells, demonstrating that the presence of mouse cells does not significantly skew expression profiles when xenografts contain 90% or more human cells. In addition, we present a novel in silico and experimental masking approach to identify probes and transcript clusters susceptible to cross-species hybridisation. Conclusions We demonstrate species-specific transcriptional profiles can be obtained from xenografts when high levels of engraftment are achieved or with the application of transcript cluster masks. Importantly, this masking approach can be applied and adapted to other xenograft models where human tissue infiltration is lower. This model provides a powerful platform for identifying genes and pathways associated with ALL disease progression and response to therapy in vivo.

  13. Functional expression of P2X family receptors in macrophages is affected by microenvironment in mouse T cell acute lymphoblastic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Shayan; Feng, Wenli; Yang, Xiao; Yang, Wanzhu; Ru, Yongxin; Liao, Jinfeng; Wang, Lina; Lin, Yongmin; Ren, Qian [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China); Zheng, Guoguang, E-mail: zhengggtjchn@aliyun.com [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China); Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing 100730 (China)

    2014-04-18

    Highlights: • We study the impact of leukemic microenvironment on P2X family receptors in Mφs. • Bone marrow and spleen Mφs are studied in Notch1-induced mouse leukemia model. • Increased expression of P2X7R is found in Mφs during the development of leukemia. • Elevated P2X7R-mediated calcium response is found in Mφs at late stage of leukemia. • More apoptotic Mφs are found in bone marrow and spleen at late stage of leukemia. - Abstract: Nucleotides are important players in intercellular signaling communication network. P2X family receptors (P2XRs) are ATP-gated plasma membrane ion channels with diverse biological functions. Macrophages are important components in the microenvironment of hematopoiesis participating in both physiological and pathological processes. However, the role of P2XRs in macrophages in leukemia has not been established. Here we investigated expression pattern and functions of P2XRs in macrophages from bone marrow (BM) and spleen of Notch1-induced T-ALL mice. Real-time PCR showed that P2XRs except P2X5R were expressed in BM and spleen macrophages. Furthermore, with the development of leukemia, the expression of P2X7R increased in both BM and spleen macrophages whereas expression of P2X1R increased in spleen macrophages. Live cell imaging recoding the Ca{sup 2+} response demonstrated that P2X7R expressed in macrophages was functional. TUNEL and electron microscopy analysis found that apoptotic macrophages were frequently observed in BM and spleen at late stage of leukemia, which was partly contributed by the activation of overexpressed P2X7R. Our results suggested that the intercellular communication mediated by nucleotides might orchestrate in the pathological process of leukemia and could be a potential target for the treatment of leukemia.

  14. Functional expression of P2X family receptors in macrophages is affected by microenvironment in mouse T cell acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Chen, Shayan; Feng, Wenli; Yang, Xiao; Yang, Wanzhu; Ru, Yongxin; Liao, Jinfeng; Wang, Lina; Lin, Yongmin; Ren, Qian; Zheng, Guoguang

    2014-01-01

    Highlights: • We study the impact of leukemic microenvironment on P2X family receptors in Mφs. • Bone marrow and spleen Mφs are studied in Notch1-induced mouse leukemia model. • Increased expression of P2X7R is found in Mφs during the development of leukemia. • Elevated P2X7R-mediated calcium response is found in Mφs at late stage of leukemia. • More apoptotic Mφs are found in bone marrow and spleen at late stage of leukemia. - Abstract: Nucleotides are important players in intercellular signaling communication network. P2X family receptors (P2XRs) are ATP-gated plasma membrane ion channels with diverse biological functions. Macrophages are important components in the microenvironment of hematopoiesis participating in both physiological and pathological processes. However, the role of P2XRs in macrophages in leukemia has not been established. Here we investigated expression pattern and functions of P2XRs in macrophages from bone marrow (BM) and spleen of Notch1-induced T-ALL mice. Real-time PCR showed that P2XRs except P2X5R were expressed in BM and spleen macrophages. Furthermore, with the development of leukemia, the expression of P2X7R increased in both BM and spleen macrophages whereas expression of P2X1R increased in spleen macrophages. Live cell imaging recoding the Ca 2+ response demonstrated that P2X7R expressed in macrophages was functional. TUNEL and electron microscopy analysis found that apoptotic macrophages were frequently observed in BM and spleen at late stage of leukemia, which was partly contributed by the activation of overexpressed P2X7R. Our results suggested that the intercellular communication mediated by nucleotides might orchestrate in the pathological process of leukemia and could be a potential target for the treatment of leukemia

  15. Alteration in Bone Mineral Metabolism in Children with Acute Lymphoblastic Leukemia (ALL: A Review

    Directory of Open Access Journals (Sweden)

    Chowdhury Yakub Jamal

    2009-11-01

    Full Text Available In recent years there has been a significant increase in event free survival (EFS and overall survival in children with cancer. As survival rates for childhood cancer have radically improved, late effects associated with the successful but highly intensive chemotherapy and/or radiotherapy have dramatically increased. Many possible late effects of cancer treatment are recognized in pediatric cancer patients as infertility, endocrine deficiency, renal failure, pulmonary and cardiac toxicity, obesity and osteopenia/osteoporosis. Decreased bone mineral density (BMD and bone metabolism disturbances have been recognized and reported in literature. Osteopenia/osteoporosis skeletal abnormalities, osteonecrosis and pathological fractures are known to occur frequently in childhood acute lymphoblastic leukemia (ALL at diagnosis, during and after treatment with chemotherapy. Various studies have revealed different metabolic alterations related to ALL. Some suggestions have been made about their relationship with the disease process. Various metabolic abnormalities may be encountered in the newly diagnosed ALL patients. It includes decreased and increased serum levels of calcium and phosphate. Hypercalcemia may result from leukemic infiltrations of bone and release of parathormone like substance from lymphoblast. Elevated serum phosphate can occur as a result of leukemic cell lysis and may induce hypocalcemia. It has been postulated by other authors that leukemic cells may directly infiltrate bone and produce parathroid hormone related peptides, prostaglandin E and osteoblast inhibiting factors. Hypomagnesemia, hypocalcaemia and hypothyroidisum have been demonstrated in patients with ALL. Some patients may have poor nutrition and decreased physical activities during treatment. However postulations have also been made that chemotherapy may play a role in creating metabolic alterations in children with ALL. Corticosteroid, methotraxate and cranial irradiations

  16. Isocitrate dehydrogenase mutation hot spots in acute lymphoblastic leukemia and oral cancer

    Directory of Open Access Journals (Sweden)

    Jen-Yang Tang

    2012-03-01

    Full Text Available Isocitrate dehydrogenase (IDH encodes a nicotinamide adenine dinucleotide phosphate+-dependent enzyme for oxidative decarboxylation of isocitrate and has an essential role in the tricarboxylic acid cycle. Mutations of IDH1 and IDH2 have been identified in patients with glioma, leukemia, and other cancers. However, the incidence of IDH mutations in acute myeloid leukemia in Taiwan is much lower than that reported in Western countries. The reason for the difference is unknown and its clinical implications remain unclear. Acute lymphoblastic leukemia (ALL is a heterogenous hematopoietic malignancy. Oral squamous cell carcinoma (OSCC results from chronic carcinogen exposures and is highly prevalent in trucking workers, especially in southern Taiwan. Subtypes of both diseases require specific treatments, and molecular markers for developing tailored treatments are limited. High-resolution melting (HRM analysis is now a widely used methodology for rapid, accurate, and low-cost mutation scanning. In this study, 90 adults with OSC and 31 children with ALL were scanned by HRM analysis for IDH1 and IDH2 mutation hot spots. In ALL, the allele frequency was 3.23% in both IDH1 and IDH2. In OSCC, the allele frequency was 2.22% in IDH2. A synonymous mutation over pG313 (c.939A > G of IDH2 was found in both pediatric ALL and adult OSCC. Therefore, we concluded that mutations of IDH are uncommon in ALL and OSCC and are apparently not a major consideration when selecting treatment modalities.

  17. Acute respiratory infections in children and adolescents with acute lymphoblastic leukemia.

    Science.gov (United States)

    Hakim, Hana; Dallas, Ronald; Zhou, Yinmei; Pei, Dequing; Cheng, Cheng; Flynn, Patricia M; Pui, Ching-Hon; Jeha, Sima

    2016-03-01

    Knowledge regarding the incidence, clinical course, and impact of respiratory viral infections in children with acute lymphoblastic leukemia (ALL) is limited. A retrospective cohort of patients with newly diagnosed ALL who were treated on the Total Therapy XVI protocol at St Jude Children's Research Hospital between 2007 and 2011 was evaluated. Of 223 children, 95 (43%) developed 133 episodes of viral acute respiratory illness (ARI) (incidence, 1.1 per 1000 patient-days). ARI without viral etiology was identified in 65 patients (29%) and no ARI was detected in 63 patients (28%). There were no significant associations noted between race, sex, age, or ALL risk group and the development of ARI. Children receiving induction chemotherapy were found to be at the highest risk of viral ARI (incidence, 2.3 per 1000 patient-days). Influenza virus was the most common virus (38%) followed by respiratory syncytial virus (33%). Of 133 episodes of viral ARI, 61% of patients were hospitalized, 26% experienced a complicated course, 80% had their chemotherapy delayed, and 0.7% of patients died. Twenty-four patients (18%) developed viral lower respiratory tract infections (LRTI), 5 of whom (21%) had complications. Patients with viral LRTI had a significantly lower nadir absolute lymphocyte count; were sicker at the time of presentation; and were more likely to have respiratory syncytial virus, to be hospitalized, and to have their chemotherapy delayed for longer compared with those with viral upper respiratory tract infections. Despite the low incidence of viral ARI in children with ALL, the associated morbidity, mortality, and delay in chemotherapy remain clinically significant. Viral LRTI was especially associated with high morbidity requiring intensive care-level support. Cancer 2016;122:798-805. © 2015 American Cancer Society. © 2015 American Cancer Society.

  18. Incidence and risk factors for central nervous system relapse in children and adolescents with acute lymphoblastic leukemia

    Science.gov (United States)

    Cancela, Camila Silva Peres; Murao, Mitiko; Viana, Marcos Borato; de Oliveira, Benigna Maria

    2012-01-01

    Background Despite all the advances in the treatment of childhood acute lymphoblastic leukemia, central nervous system relapse remains an important obstacle to curing these patients. This study analyzed the incidence of central nervous system relapse and the risk factors for its occurrence in children and adolescents with acute lymphoblastic leukemia. Methods This study has a retrospective cohort design. The studied population comprised 199 children and adolescents with a diagnosis of acute lymphoblastic leukemia followed up at Hospital das Clinicas, Universidade Federal de Minas Gerais (HC-UFMG) between March 2001 and August 2009 and submitted to the Grupo Brasileiro de Tratamento de Leucemia da Infância - acute lymphoblastic leukemia (GBTLI-LLA-99) treatment protocol. Results The estimated probabilities of overall survival and event free survival at 5 years were 69.5% (± 3.6%) and 58.8% (± 4.0%), respectively. The cumulative incidence of central nervous system (isolated or combined) relapse was 11.0% at 8 years. The estimated rate of isolated central nervous system relapse at 8 years was 6.8%. In patients with a blood leukocyte count at diagnosis ≥ 50 x 109/L, the estimated rate of isolated or combined central nervous system relapse was higher than in the group with a count 50 x 109/L at diagnosis seems to be a significant prognostic factor for a higher incidence of central nervous system relapse in childhood acute lymphoblastic leukemia. PMID:23323068

  19. Immune Thrombocytopenia in a Child with T Cell Lymphoblastic Lymphoma

    Directory of Open Access Journals (Sweden)

    Kayo Tokeji

    2016-01-01

    Full Text Available We describe the case of a 13-year-old boy who presented with persistent thrombocytopenia during maintenance chemotherapy with mercaptopurine and methotrexate for T cell lymphoblastic lymphoma. He was diagnosed with immune thrombocytopenia (ITP after thorough investigations for the relapse of lymphoma and was successfully treated with immunoglobulin and steroids. ITP is known to be associated with chronic lymphocytic leukemia, Hodgkin lymphoma, and various types of non-Hodgkin lymphoma but rarely with T cell non-Hodgkin lymphoma or in children. Diagnosis of ITP with lymphoma is challenging due to the many factors affecting platelet counts, and ITP often complicates the diagnosis or treatment course of lymphoma. The underlying mechanism of ITP with NHL is still unclear. Drug-induced immunomodulation with a reduction of regulatory T cells might have contributed to the development of ITP in our case.

  20. Current Concepts in Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Bernt, Kathrin M.; Hunger, Stephen P.

    2014-01-01

    The t(9;22)(q34;q11) or Philadelphia chromosome creates a BCR–ABL1 fusion gene encoding for a chimeric BCR–ABL1 protein. It is present in 3–4% of pediatric acute lymphoblastic leukemia (Ph+ ALL), and about 25% of adult ALL cases. Prior to the advent of tyrosine kinase inhibitors (TKI), Ph+ ALL was associated with a very poor prognosis despite the use of intensive chemotherapy and frequently hematopoietic stem-cell transplantation (HSCT) in first remission. The development of TKIs revolutionized the therapy of Ph+ ALL. Addition of the first generation ABL1 class TKI imatinib to intensive chemotherapy dramatically increased the survival for children with Ph+ ALL and established that many patients can be cured without HSCT. In parallel, the mechanistic understanding of Ph+ ALL expanded exponentially through careful mapping of pathways downstream of BCR–ABL1, the discovery of mutations in master regulators of B-cell development such as IKZF1 (Ikaros), PAX5, and early B-cell factor (EBF), the recognition of the complex clonal architecture of Ph+ ALL, and the delineation of genomic, epigenetic, and signaling abnormalities contributing to relapse and resistance. Still, many important basic and clinical questions remain unanswered. Current clinical trials are testing second generation TKIs in patients with newly diagnosed Ph+ ALL. Neither the optimal duration of therapy nor the optimal chemotherapy backbone are currently defined. The role of HSCT in first remission and post-transplant TKI therapy also require further study. In addition, it will be crucial to continue to dig deeper into understanding Ph+ ALL at a mechanistic level, and translate findings into complementary targeted approaches. Expanding targeted therapies hold great promise to decrease toxicity and improve survival in this high-risk disease, which provides a paradigm for how targeted therapies can be incorporated into treatment of other high-risk leukemias. PMID:24724051

  1. Decreased PARP and procaspase-2 protein levels are associated with cellular drug resistance in childhood acute lymphoblastic leukemia

    NARCIS (Netherlands)

    A. Holleman (Amy); M.L. den Boer (Monique); K.M. Kazemier (Karin); H.B. Beverloo (Berna); A.R.M. von Bergh (Anne); G.E. Janka-Schaub (Gritta); R. Pieters (Rob)

    2005-01-01

    textabstractDrug resistance in childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) is associated with impaired ability to induce apoptosis. To elucidate causes of apoptotic defects, we studied the protein expression of Apaf-1, procaspases-2, -3, -6, -7,

  2. DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Milani, Lili; Lundmark, Anders; Kiialainen, Anna

    2010-01-01

    CpG sites in regulatory regions of 416 genes in cells from 401 children diagnosed with ALL. Hierarchical clustering of 300 CpG sites distinguished between T-lineage ALL and B-cell precursor (BCP) ALL and between the main cytogenetic subtypes of BCP ALL. It also stratified patients with high......Despite improvements in the prognosis of childhood acute lymphoblastic leukemia (ALL), subgroups of patients would benefit from alternative treatment approaches. Our aim was to identify genes with DNA methylation profiles that could identify such groups. We determined the methylation levels of 1320...... hyperdiploidy and t(12;21) ALL into 2 subgroups with different probability of relapse. By using supervised learning, we constructed multivariate classifiers by external cross-validation procedures. We identified 40 genes that consistently contributed to accurate discrimination between the main subtypes of BCP...

  3. DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Milani, Lili; Lundmark, Anders; Kiialainen, Anna

    2010-01-01

    Despite improvements in the prognosis of childhood acute lymphoblastic leukemia (ALL), subgroups of patients would benefit from alternative treatment approaches. Our aim was to identify genes with DNA methylation profiles that could identify such groups. We determined the methylation levels of 1320...... CpG sites in regulatory regions of 416 genes in cells from 401 children diagnosed with ALL. Hierarchical clustering of 300 CpG sites distinguished between T-lineage ALL and B-cell precursor (BCP) ALL and between the main cytogenetic subtypes of BCP ALL. It also stratified patients with high...... ALL and gene sets that discriminated between subtypes of ALL and between ALL and controls in pairwise classification analyses. We also identified 20 individual genes with DNA methylation levels that predicted relapse of leukemia. Thus, methylation analysis should be explored as a method to improve...

  4. Risk group assignment differs for children and adults 1-45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol

    DEFF Research Database (Denmark)

    Toft, Nina; Birgens, Henrik; Abrahamsson, Jonas

    2013-01-01

    The prognosis of acute lymphoblastic leukemia is poorer in adults than in children. Studies have indicated that young adults benefit from pediatric treatment, although no upper age limit has been defined.......The prognosis of acute lymphoblastic leukemia is poorer in adults than in children. Studies have indicated that young adults benefit from pediatric treatment, although no upper age limit has been defined....

  5. Karyotype in Pediatric Acute Lymphoblastic Leukemia: Impact On Clinical Presentation and Duration of First Remission

    International Nuclear Information System (INIS)

    Khairy, A.M.D.; EL-SISSY, M.D.

    2003-01-01

    In this study we are aiming at investigating the correlation between karyotype and the clinico pathologic features of pediatric acute lymphoblastic leukemia, duration of first remission and outcome of patients. Material and Methods: A total of 40 pediatric patients with the diagnosis of acute ]lymphoblastic leukemia (ALL) were included in this study. The patients were treated according to ALL P.NCI III/98 protocol used at the Pediatric Oncology Unit, National Cancer Institute, Cairo University. Analyzing the patients with respect to their chromosomal pattern; the majority of patients (17/40, 42.5%) showed a pseudo diploid karyotype. Their mean age was 10.2±4.8 years, M/F ratio 2.4: I. Massive hepatosplenomegaly (HSM) was encountered in 64.7%. The mean total leucocyte count (TLC) was 66.53±5.2 cells per μl. Their mean first complete remission (CR]) was 11.05±2.3 months, EFS was 40% at 12 months and 17.78% at 24 months. Patients with normal karyotype came next, representing ]3/40 (32.5%). Their mean age was 8.4±1.8 years, M/F 0.8: I. Massive HSM was found in 62.5%. The mean TLC was 78.74±3.8 cells per μl. Their mean CR 1 was I I.62±1.2 months, EFS was 41.67% at 12 months and 33.33% at 24 months. The third group represented patients with hyper diploidy (8/40; 20%). Their mean age was 8. 8±3. I years, M/F 7: I. Massive HSM was found in 50%. The mean TLC was 45.16±3.1 cells per μl], their mean CR I was 18.] 0±3.4 months, EFS was 75% at 12 months and 62.5% at 24 months. The least group showed a hypo diploid pattern (5/40; 12.5%). Their mean age was] 3±2.6 years, all were males. Massive HSM was encountered in 100%. The mean TLC was 20.00±2.9 cells per Ill. Their mean CRI was 10±2.8 months. Egyptian patients with childhood ALL who have hyper diploid karyotype, specially those having >50 chromosomes carry a better prognosis than patients with other chromosomal abnormalities. Pseudo diploid karyotype is the most frequent among Egyptian ALL cases and this could

  6. Acute Lymphoblastic Leukemia with Hypereosinophilia in a Child: Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Valentina Ferruzzi

    2018-06-01

    Full Text Available Background: Hypereosinophilia in children can be primary or secondary. Numerous malignant diseases can cause hypereosinophilia, but it is seldom caused by acute lymphoblastic leukemia (ALL. In the event of protracted hypereosinophilia, it is extremely important to make a correct differential diagnosis. Case presentation: We present the case of an 11-year-old boy of Moroccan origin with ALL with hypereosinophilic onset (eosinophils in peripheral blood, 10,000/µL in the absence of other signs of neoplastic disease, and compare this case with 61 similar cases in the literature. Following hospital admission, the patient initially presented with headache-caused nocturnal awakenings, evening fever, and cough, and he also lost approximately 7 kg in weight in a month not associated with sweating or itching. We first performed bone marrow aspiration, which showed an increase in eosinophils without cellular morphological abnormalities, and bone marrow immunophenotyping showed that 4.5% of cells had a phenotype compatible with lymphoid blasts. A lumbar puncture was negative. Given the poor marrow involvement, it was necessary to repeat a new bone marrow aspiration two days later, which showed an increase in blasts to 14%. A concomitant bone marrow biopsy showed an infiltration of blasts typical of B-cell ALL equal to 20–30% with associated hypereosinophilia. Cytogenetic analysis showed an hyperdiploid karyotype: 53–55, XY, +X, add(1(q21q25, +4, +9, +10, +14, +2, +1, +21/46, XY. Conclusions: ALL is one of the possible causes of persistent hypereosinophilia. In patients with ALL and hypereosinophilia, peripheral hypereosinophilia can precede the appearance of blasts. Due to the negative prognosis and the increased risk of complications in these patients, bone marrow aspiration and biopsy are recommended if common causes of secondary hypereosinophilia are excluded.

  7. Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia: Clinical Facts and Fiction

    Science.gov (United States)

    Nielsen, Stine N.; Frandsen, Thomas L.; Nersting, Jacob

    2014-01-01

    The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug dosing. Because of significant interindividual and intraindividual variations in drug disposition and pharmacodynamics, vigorous dose adjustments are needed to obtain a target degree of myelosuppression. As the normal white blood cell counts vary by patients’ ages and ethnicity, and also within age groups, identical white blood cell levels for 2 patients may not reflect the same treatment intensity. Measurements of intracellular levels of cytotoxic metabolites of 6MP and MTX can identify nonadherent patients, but therapeutic target levels remains to be established. A rise in serum aminotransferase levels during maintenance therapy is common and often related to high levels of methylated 6MP metabolites. However, except for episodes of hypoglycemia, serious liver dysfunction is rare, the risk of permanent liver damage is low, and aminotransferase levels usually normalize within a few weeks after discontinuation of therapy. 6MP and MTX dose increments should lead to either leukopenia or a rise in aminotransferases, and if neither is experienced, poor treatment adherence should be considered. The many genetic polymorphisms that determine 6MP and MTX disposition, efficacy, and toxicity have precluded implementation of pharmacogenomics into treatment, the sole exception being dramatic 6MP dose reductions in patients who are homozygous deficient for thiopurine methyltransferase, the enzyme that methylates 6MP and several of its metabolites. In conclusion, maintenance therapy is as important as the more intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments

  8. Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia

    Science.gov (United States)

    Boer, Judith M.; Steeghs, Elisabeth M.P.; Marchante, João R.M.; Boeree, Aurélie; Beaudoin, James J.; Berna Beverloo, H.; Kuiper, Roland P.; Escherich, Gabriele; van der Velden, Vincent H.J.; van der Schoot, C. Ellen; de Groot-Kruseman, Hester A.; Pieters, Rob; den Boer, Monique L.

    2017-01-01

    Approximately 15% of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by gene expression similar to that of BCR-ABL1-positive disease and unfavorable prognosis. This BCR-ABL1-like subtype shows a high frequency of B-cell development gene aberrations and tyrosine kinase-activating lesions. To evaluate the clinical significance of tyrosine kinase gene fusions in children with BCP-ALL, we studied the frequency of recently identified tyrosine kinase fusions, associated genetic features, and prognosis in a representative Dutch/German cohort. We identified 14 tyrosine kinase fusions among 77 BCR-ABL1-like cases (18%) and none among 76 non-BCR-ABL1-like B-other cases. Novel exon fusions were identified for RCSD1-ABL2 and TERF2-JAK2. JAK2 mutation was mutually exclusive with tyrosine kinase fusions and only occurred in cases with high CRLF2 expression. The non/late response rate and levels of minimal residual disease in the fusion-positive BCR-ABL1-like group were higher than in the non-BCR-ABL1-like B-others (p<0.01), and also higher, albeit not statistically significant, compared with the fusion-negative BCR-ABL1-like group. The 8-year cumulative incidence of relapse in the fusion-positive BCR-ABL1-like group (35%) was comparable with that in the fusion-negative BCR-ABL1-like group (35%), and worse than in the non-BCR-ABL1-like B-other group (17%, p=0.07). IKZF1 deletions, predominantly other than the dominant-negative isoform and full deletion, co-occurred with tyrosine kinase fusions. This study shows that tyrosine kinase fusion-positive cases are a high-risk subtype of BCP-ALL, which warrants further studies with specific kinase inhibitors to improve outcome. PMID:27894077

  9. Disseminated fusariosis and endogenous fungal endophthalmitis in acute lymphoblastic leukemia following platelet transfusion possibly due to transfusion-related immunomodulation

    Directory of Open Access Journals (Sweden)

    Yong Ku

    2011-11-01

    Full Text Available Abstract Background To report a case of disseminated fusariosis with endogenous endophthalmitis in a patient with acute lymphoblastic leukemia. Transfusion-associated immune modulation secondary to platelet transfusion could play an important role in the pathophysiology of this case. Case Presentation A 9 year-old male with acute lymphoblastic leukemia complicated by pancytopenia and disseminated Intravascular coagulation was given platelet transfusion. He developed disseminated fusariosis and was referred to the ophthalmology team for right endogenous endophthalmitis. The infection was controlled with aggressive systemic and intravitreal antifungals. Conclusion Patients with acute lymphoblastic leukemia are predisposed to endogenous fungal endophthalmitis. Transfusion-associated immune modulation may further increase host susceptibility to such opportunistic infections.

  10. [THE COMPARISON OF RESULTS OF DETECTION OF MINIMAL RESIDUAL DISEASE IN PERIPHERAL BLOOD AND MARROW IN CHILDREN OF THE FIRST YEAR OF LIFE WITH ACUTE LYMPHOBLASTIC LEUCOSIS].

    Science.gov (United States)

    Tsaur, G A; Riger, T O; Popov, A M; Nasedkina, T V; Kustanovich, A M; Solodovnikov, A G; Streneva, O V; Shorikov, E V; Tsvirenko, S V; Saveliev, L I; Fechina, L G

    2015-04-01

    The occurrence of minimal residual disease is an important prognostic factor under acute lymphoblastic leucosis in children and adults. In overwhelming majority of research studies bone marrow is used to detect minimal residual disease. The comparative characteristic of detection of minimal residual disease in peripheral blood and bone marrow was carried out. The prognostic role of occurrence of minimal residual disease in peripheral blood and bone marrow under therapy according protocol MLL-Baby was evaluated. The analysis embraced 142 pair samples from 53 patients with acute lymphoblastic leucosis and various displacements of gene MLL younger than 365 days. The minimal residual disease was detected by force of identification of chimeric transcripts using polymerase chain reaction in real-time mode in 7 sequential points of observation established by protocol of therapy. The comparability of results of qualitative detection of minimal residual disease in bone marrow and peripheral blood amounted to 84.5%. At that, in all 22 (15.5%) discordant samples minimal residual disease was detected only in bone marrow. Despite of high level of comparability of results of detection of minimal residual disease in peripheral blood and bone marrow the occurrence of minimal residual disease in peripheral blood at various stages of therapy demonstrated no independent prognostic significance. The established differences had no relationship with sensitivity of method determined by value of absolute expression of gene ABL. Most likely, these differences reflected real distribution of tumor cells. The results of study demonstrated that application of peripheral blood instead of bone marrow for monitoring of minimal residual disease under acute lymphoblastic leucosis in children of first year of life is inappropriate. At the same time, retention of minimal residual disease in TH4 in bone marrow was an independent and prognostic unfavorable factor under therapy of acute lymphoblastic

  11. [Local involvement of the optic nerve by acute lymphoblastic leukemia].

    Science.gov (United States)

    Bernardczyk-Meller, Jadwiga; Stefańska, Katarzyna

    2005-01-01

    The leucemias quite commonly involve the eyes and adnexa. In some cases it causes visual complants. Both, the anterior chamber of the eye and the posterior portion of the globe may sites of acute or chronic leukemia and leucemic relapse. We report an unique case of a 14 years old leucemic patient who suffered visual loss and papilloedema, due to a unilateral local involvement within optic nerve, during second relapse of acute lymphocytic leuemia. In spite of typical treatment of main disease, the boy had died. The authors present typical ophthalmic features of the leucemia, too.

  12. Influence of socioeconomic status on childhood acute lymphoblastic leukemia treatment in Indonesia.

    Science.gov (United States)

    Mostert, Saskia; Sitaresmi, Mei N; Gundy, Chad M; Sutaryo; Veerman, Anjo J P

    2006-12-01

    A major reason for poor survival of childhood acute lymphoblastic leukemia in developing countries is treatment refusal or abandonment. This can be associated with parental socioeconomic status and attitudes of health care providers. Our study examined the influence of 2 socioeconomic status determinants, parental income and education, on treatment in an Indonesian academic hospital. Medical charts of 164 patients who received a diagnosis of acute lymphoblastic leukemia between 1997 and 2002 were abstracted retrospectively. Data on treatment results and parental financial and educational background were collected. Open interviews were conducted with parents and health care providers. Of all patients, 35% refused or abandoned treatment, 23% experienced treatment-related death, 22% had progressive or relapsed leukemia, and 20% had an overall event-free survival. Treatment results differed significantly between patients with different socioeconomic status; 47% of poor and 2% of prosperous patients refused or abandoned treatment. Although poor and prosperous patients used the same protocol, the provided treatment differed. Poor patients received less individualized attention from oncologists and less structured parental education. Strong social hierarchical structures hindered communication with doctors, resulting in a lack of parental understanding of the necessity to continue treatment. Most poor patients could not afford treatment. Access to donated chemotherapy also was inadequate. Treatment refusal or abandonment frequently resulted. There was no follow-up system to detect and contact dropouts. Health care providers were not fully aware that their own attitude and communication skills were important for ensuring compliance of patients and parents. Children's survival of acute lymphoblastic leukemia in developing countries could improve if problems that are associated with parental financial and educational background and medical teams' attitudes to treatment and

  13. Chemotherapeutic treatment reduces circulating levels of surfactant protein-D in children with acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Rathe, Mathias; Sorensen, Grith L; Skov Wehner, Peder

    2017-01-01

    with acute lymphoblastic leukemia (ALL). PROCEDURE: In a prospective study, 43 children receiving treatment for ALL were monitored for mucosal toxicity from diagnosis through the induction phase of treatment. Serial blood draws were taken to determine the levels of SP-D, interleukin-6 (IL-6), C......BACKGROUND: Surfactant protein D (SP-D) is a host defense molecule of the innate immune system that enhances pathogen clearance and modulates inflammatory responses. We hypothesized that circulating SP-D levels are associated with chemotherapy-induced mucositis and infectious morbidity in children...

  14. Extremely low-frequency magnetic fields and survival from childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Schüz, J; Grell, K; Kinsey, S

    2012-01-01

    A previous US study reported poorer survival in children with acute lymphoblastic leukemia (ALL) exposed to extremely low-frequency magnetic fields (ELF-MF) above 0.3 μT, but based on small numbers. Data from 3073 cases of childhood ALL were pooled from prospective studies conducted in Canada......, Denmark, Germany, Japan, UK and US to determine death or relapse up to 10 years from diagnosis. Adjusting for known prognostic factors, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival and event-free survival for ELF-MF exposure categories and by 0.1 μT increases...

  15. X-ray examination of the thoracic organs in children with acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Fil'shtinskij, A.Ya.; Efimenko, S.I.

    1987-01-01

    The authors presented a combined clinicoroentgenological study of the thoracic organs in 12 children with acute lymphoblastic leukemia. It revealed specific involvement of the thoracic organs supported by clinicomorphological findings and assessment of therapeutic results in 66 patients (55.0 ± 3.2 %). It also played an important role in the recognition of disease starting with changes in the bone marrow, in the differential diagnosis of specific and nonspecific changes in the thoracic organs, and in the assessment of a degree of remission

  16. Central Venous Catheters and Bloodstream Infection During Induction Therapy in Children With Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Bergmann, Kristin; Hasle, Henrik; Asdahl, Peter

    2016-01-01

    The purpose of the study was to assess the r