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Sample records for cell leukemia infiltration

  1. Inverse relationship of tumors and mononuclear cell leukemia infiltration in the lungs of F344 rats

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    Lundgren, D.L.; Griffith, W.C.; Hahn, F.F.

    1995-12-01

    In 1970 and F344 rat, along with the B6C3F{sub 1} mouse, were selected as the standard rodents for the National Cancer Institute Carcinogenic Bioassay program for studies of potentially carcinogenic chemicals. The F344 rat has also been used in a variety of other carcinogenesis studies, including numerous studies at ITRI. A major concern to be considered in evaluating carcinogenic bioassay studies using the F344 rat is the relatively high background incidence of mononuclear cell leukemia (MCL) (also referred to as large granular lymphocytic leukemia, Fischer rat leukemia, or monocytic leukemia). Incidences of MCL ranging from 10 to 72% in male F344 rats to 6 to 31% in female F344 rats have been reported. Gaining the understanding of the mechanisms involved in the negative correlations noted should enhance our understanding of the mechanisms involved in the development of lung cancer.

  2. Bone marrow infiltration of CD20-negative follicular lymphoma after rituximab therapy: a histological mimicker of hematogones and B-cell acute lymphoblastic leukemia/lymphoma

    Science.gov (United States)

    Matsuda, Ikuo; Hirota, Seiichi

    2015-01-01

    Rituximab is a monoclonal antibody against CD20. Rituximab combined with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, termed R-CHOP, have improved the overall survival of patients with B-cell lymphoma in comparison with that of CHOP therapy. However, as with other molecularly-targeted therapies, resistance to rituximab could emerge sooner or later after rituximab administration. A number of mechanisms for rituximab resistance have been proposed, including downregulation of CD20 protein expression. Differential diagnosis of B-cell proliferation with reduced or lost CD20 expression includes not only B-cell lymphomas with CD20 downregulation, but also other tumorous and non-tumorous lesions. These include precursor B-cell neoplasms such as B acute lymphoblastic leukemia/lymphoblastic lymphoma (B-ALL/LBL) and hematogones, a normal precursor B-cell proliferation during regeneration of hematopoiesis, typically observed following bone marrow suppression by chemotherapy. It is important to distinguish these possibilities because distinct therapies are required for each. In this paper, we report a case where bone marrow infiltration of follicular lymphoma histopathologically mimicked hematogones or B-ALL/LBL when CD20 expression was downregulated in follicular lymphoma after R-CHOP therapy. PMID:26464748

  3. Phosphoinositide 3-kinase/Akt Pathway Mediates Fip1-like1-platelet-derived Growth Factor Receptor α-induced Cell Infiltration and Activation: Possible Molecular Mechanism for the Malignant Phenotype of Chronic Eosinophilic Leukemia

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    Bin Li

    2015-01-01

    Full Text Available The fip1-like1/platelet-derived growth factor receptor-α fusion gene (F/P is responsible for 14-60% cases of hypereosinophilia syndrome (HES, also known as F/P-positive chronic eosinophilic leukemia (F/P(+ CEL. The major pathogenesis of F/P(+ CEL is known to involve migration and activation of mast cells and eosinophils, leading to severe multi-organ dysfunction, but the mechanism was still unclear. Phosphoinositide 3-kinase (PI3K and serine-threonine protein kinase Akt have been reported to be targets of F/P in the F/P-promoted cell proliferation. They are extensively involved in the migration and adhesion of hematopoietic stem/progenitor cells, and also control cell invasion in some leukemias. The PI3K/Akt pathway is involved in eosinophil/neutrophil activation and infiltration; its possible role in regulating F/P induced cytotoxicity and upregulation of A4-integrin in eosinophils, and inducing eosinophil activation through controlling F/P-induced Nuclear factor-kB activity. Akt was recently shown to be stimulated by F/P, synergistically with stem cell factor, resulting in the induction of MCs migration and excessive activation. PI3K/Akt pathway is also a principal mediator of interleukin-5 (IL-5-induced signal transduction promoting eosinophil trafficking and degranulation, whereas IL-5 is a necessary cytokine for F/P-mediated CEL development. We, therefore, propose the hypothesis that the PI3K/Akt pathway might be vital downstream of F/P to induce target cell activation and tissue infiltration, resulting in the malignant phenotype seen in F/P(+ CEL.

  4. Plasma cell leukemia

    OpenAIRE

    Gertz, Moria A.; Buadi, Francis K.

    2010-01-01

    Plasma cell leukemia (PCL) is a rare, yet aggressive plasma cell (PC) neoplasm, variant of multiple myeloma (MM), characterized by high levels of PCs circulating in the peripheral blood. PCL can either originate de novo (primary PCL) or as a secondary leukemic transformation of MM (secondary PCL). Presenting signs and symptoms are similar to those seen in MM such as renal insufficiency, hypercalcemia, lytic bone lesions, anemia, and thrombocytopenia, but can also include hepatomegaly and sple...

  5. Plasma cell leukemia

    DEFF Research Database (Denmark)

    Fernández de Larrea, C; Kyle, R A; Durie, B G M;

    2013-01-01

    -pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for......Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic...

  6. Regulating the leukemia stem cell

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    Cleary, Michael L.

    2009-01-01

    Leukemia stem cells (LSCs) are responsible for sustaining and propagating malignant disease, and, as such, are promising targets for therapy. Studies of human LSCs have served an important role in defining the major tenets of the cancer stem cell model, which center on the frequencies of cancer stem cells, their potential hierarchical organization, and their degree of maturation. LSCs in acute myeloid leukemia (AML) have recently been studied using mouse syngeneic models of leukemia induced b...

  7. Distinguishing the Causes of Pulmonary Infiltrates in Patients With Acute Leukemia.

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    Nucci, Marcio; Nouér, Simone A; Anaissie, Elias

    2015-06-01

    Pulmonary infiltrates are commonly observed in patients with acute leukemia (AL), particularly acute myeloid leukemia, who undergo remission induction therapy. The mortality rate is unacceptably high and depends on 3 factors: the host (performance status, comorbidities, and frailty), the etiology of the infiltrates and the type of response to antileukemic therapy. The approach to the diagnosis of pulmonary infiltrates in patients with AL includes a medical history, thorough physical examination, radiologic pattern of the infiltrates (focal vs. diffuse), and timing of their appearance in relation to the start of antileukemic therapy (early, ie, within the first 2 weeks or late). Localized infiltrates are most commonly caused by bacterial (early) and fungal infections (late). Diffuse early infiltrates might be caused by leukemic infiltration of the lungs, pulmonary hemorrhage and/or edema, diffuse alveolar damage, viral pneumonia, and rarely transfusion-related acute lung injury (TRALI) or the differentiation syndrome. Similar to the early phase, pulmonary edema, viral pneumonia, and rarely TRALI might cause diffuse infiltrates during the late phase, in addition to immune reconstitution and pneumocystosis, particularly among patients with acute lymphoblastic leukemia. Diagnostic tests, invasive and noninvasive, can be particularly useful to establish the diagnosis. Early intervention is critical and is based on the most likely diagnosis with modification when the etiology is confirmed. PMID:26297289

  8. Leukemia Stem Cells and Human Acute Lymphoblastic Leukemia

    OpenAIRE

    Bernt, Kathrin M.; Armstrong, Scott A.

    2009-01-01

    Leukemias and other cancers have been proposed to contain a subpopulation of cells that display characteristics of stem cells, and which maintain tumor growth. That most anti-cancer therapy is directed against the bulk of the tumor, and possibly spares the cancer stem cells, may lie at the heart of treatment failures with conventional modalities. Leukemia stem cells are fairly well described for acute myeloid leukemia (AML), but their existence and relevance for acute lymphoblastic leukemia (...

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

    Science.gov (United States)

    2016-07-18

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

  10. ADULT T CELL LEUKEMIA LYMPHOMA

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    Neely, S. M.

    2004-01-01

    Adult T cell leukemia lymphoma (ATLL) is a CD4+ lymphoproliferative malignancy resulting from human T-cell leukemia virus type 1 (HTLV1) infection. It includes differing clinical forms classified as smoldering, chronic, lymphomatous, and acute ATLL. The Tax protein of HTLV-1 has been implicated as a viral oncoprotein which enhances virus replication and alters cellular gene expression, including activation of nuclear factor kappa B (NF kB), to result in lymphoid transformation. Chemotherapy f...

  11. Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. ...

  12. Notch1-induced T cell leukemia can be potentiated by microenvironmental cues in the spleen

    OpenAIRE

    Ma, Shihui; Shi, Yingxu; Pang, Yakun; Dong, Fang; Cheng, Hui; Hao, Sha; Xu, Jing; Zhu, Xiaofan; Yuan, Weiping; Cheng, Tao; Zheng, Guoguang

    2014-01-01

    Background Leukemia is a systemic malignancy originated from hematopoietic cells. The extracellular environment has great impacts on the survival, proliferation and dissemination of leukemia cells. The spleen is an important organ for extramedullary hematopoiesis and a common infiltration site in lymphoid malignancies. Splenomegaly, frequently observed in T cell acute lymphoblastic leukemia (T-ALL), is associated with poor prognosis. However, how the spleen microenvironment distinctly affects...

  13. A Case Report of Hairy Cell Leukemia Presenting Concomitantly with Sweet Syndrome

    OpenAIRE

    Mohammad Alkayem; Waina Cheng

    2014-01-01

    Hairy cell leukemia and Sweet syndrome are both uncommon hematological diagnoses. We present a patient who was admitted with fevers, pancytopenia, pneumonia, and rash. Diagnostic bone marrow biopsy demonstrates Hairy cell Leukemia and skin biopsy demonstrates neutrophils infiltration consistent with Sweet syndrome. The patient was treated with purine analogs with resolution of the cytopenias, infection, and rash.

  14. A Case Report of Hairy Cell Leukemia Presenting Concomitantly with Sweet Syndrome

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    Mohammad Alkayem

    2014-01-01

    Full Text Available Hairy cell leukemia and Sweet syndrome are both uncommon hematological diagnoses. We present a patient who was admitted with fevers, pancytopenia, pneumonia, and rash. Diagnostic bone marrow biopsy demonstrates Hairy cell Leukemia and skin biopsy demonstrates neutrophils infiltration consistent with Sweet syndrome. The patient was treated with purine analogs with resolution of the cytopenias, infection, and rash.

  15. Leukemia cutis

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    Varuna Mallya

    2015-01-01

    Full Text Available Patients with leukemia may show involvement of the skin. This skin involvement can be due to infiltration of skin by leukemic cells or it may be a part of nonspecific cutaneous manifestations. Leukemia cutis is the infiltration of neoplastic leucocytes or their precursors into the skin resulting in extensive clinical manifestations. Described mostly in acute myeloid leukemia and acute myelocytic monocytic leukemia, it is rare in chronic myeloid leukemia and is seen mostly during the blast crises. Its presence signals poor prognosis.

  16. Hairy Cell Leukemia Treatment Option Overview

    Science.gov (United States)

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

  17. General Information About Hairy Cell Leukemia

    Science.gov (United States)

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

  18. Leukemia cutis with lymphoglandular bodies: a clue to acute lymphoblastic leukemia cutis

    OpenAIRE

    Obiozor, Cynthia; Ganguly, Siddhartha; Fraga, Garth R.

    2015-01-01

    Leukemia cutis describes cutaneous lesions produced by infiltrates of leukemic cells. It usually manifests contemporaneously with the initial diagnosis of systemic leukemia, but may also precede or follow systemic leukemia. Most cases are associated with acute myeloid leukemia. Adult B-cell lymphoblastic leukemia cutis is very rare. We report a 59-year-old woman with a history of B-cell acute lymphoblastic leukemia who relapsed with aleukemic lymphoblastic leukemia cutis. Lymphoglandular bodi...

  19. Treatment of Aggressive NK-Cell Leukemia

    DEFF Research Database (Denmark)

    Boysen, Anders Kindberg; Jensen, Paw; Johansen, Preben;

    2011-01-01

    Aggressive NK-cell leukemia is a rare malignancy with neoplastic proliferation of natural killer cells. It often presents with constitutional symptoms, a rapid declining clinical course, and a poor prognosis with a median survival of a few months. The disease is usually resistant to cytotoxic...... literature concerning treatment of aggressive NK-cell leukemia....

  20. Hypertension, high-dose corticosteroids, and renal infiltration in children with acute lymphoblastic leukemia

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    Andry Juliansen

    2014-11-01

    Full Text Available Background Hypertension is a rarely recognized complication of acute lymphoblastic leukemia (ALL. The incidence of hypertension in ALL patients in Indonesia remains unknown, but the most common risk factors are corticosteroid use during induction-phase chemotherapy and renal leukemic infiltration. Objective To determine the incidence of hypertension in children with ALL, and to assess for associations of high-dose corticosteroids, renal infiltration, and hyperleukocytosis to hypertension. Methods This was a cross-sectional study involving 100 children aged 2-18 years. Subjects were newly diagnosed ALL patients and those underwent induction-phase chemotherapy in the Pediatric Ward or Outpatient Clinic at Cipto Mangunkusumo or Dharmais Hospitals. Results Hypertension occurred in 6 (10% of 60 newly diagnosed ALL patients and 8 (20% of 40 patients who had received high-dose corticosteroids, but the difference was not statistically significant (OR=2.25; 95%CI 0.72 to 7.07; P=0.239. Hypertension was reported in 8 of 29 subjects who received dexamethasone, but in none of the subjects who received prednisone. However, the difference in these subgroups was also not statistically significant. Renal enlargement was found in 1 of 14 hypertensive patients, but it was not associated with hypertension (OR=0.80; 95%CI 0.52 to 1.24; P=0.417. Hyperleukocytosis was also not associated with hypertension (OR= 0.79; 95% CI 0.20 to 3.11; P=1.000. Conclusion The incidence of hypertension in ALL patients was 14%. Hypertension is not associated with renal infiltration or hyperleukocytosis. Furthermore, hypertension is not associated with corticosteroid dose, though is found only in subjects who receive dexamethasone. [Paediatr Indones. 2014;54:372-6.].

  1. RNAi Screening of Leukemia Cells Using Electroporation.

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    Agarwal, Anupriya; Tyner, Jeffrey W

    2016-01-01

    RNAi-mediated screening has been an integral tool for biological discovery for the past 15 years. A variety of approaches have been employed for implementation of this technique, including pooled, depletion/enrichment screening with lentiviral shRNAs, and segregated screening of panels of individual siRNAs. The latter approach of siRNA panel screening requires efficient methods for transfection of siRNAs into the target cells. In the case of suspension leukemia cell lines and primary cells, many of the conventional transfection techniques using liposomal or calcium phosphate-mediated transfection provide very low efficiency. In this case, electroporation is the only transfection technique offering high efficiency transfection of siRNAs into the target leukemia cells. Here, we describe methods for optimization and implementation of siRNA electroporation into leukemia cell lines and primary patient specimens, and we further offer suggested electroporation settings for some commonly used leukemia cell lines. PMID:27581286

  2. Vertebral bone marrow infiltration of acute leukemia: diffusion-weighted imaging study

    International Nuclear Information System (INIS)

    Objective: Using single direction dispersion breathless DWI, to analyze the value of DWI for vertebral bone marrow infiltration in patients with acute leukemia (AL). Methods: Forty-two patients with AL and 15 healthy volunteers received vertebral sagittal DWI with single shot spin-echo echo- plan imaging (SS-SE-EPI) sequence (b value =0, 650 s/mm2) at a GE Signa Excite 1.5 T scanner with 8 channels body coil. DWI for all patients were performed from three directions, including from superior to inferior (S/I), from anterior to posterior (A/P) and from right to left (R/L). The apparent diffusion coefficient (ADC) value was measured on ADC map from each direction using GE-Function tool DWI software. Forty two patients consisted of 13 onset with untreated patients and 29 treated patients (7 non- remission, 8 complete remission and 14 consolidation therapy). The ADC values among the three diffusion directions were compared. Analysis of variance and t test were used to compare the ADC values in different AL stages, Pearson correlation analysis was used to analyze the correlation between ADC values and the percentage of bone marrow progenitor cells. Results: The ADC values from S/I, A/P and R/L of 362 vertebras in the 57 subjects are (0.758±0.009) × 10-3 mm2/s, (0.732±0.009) × 10-3 mm2/s and (0.758±0.009) × 10-3 mm2/s, respectively. There is no statistical significance (F=2.958, P>0.05). The ADC values from S/I of 94 vertebras in 15 healthy volunteers is (0.697±0.122) × 10-3 mm2/s, of 85 vertebras in 13 untreated AL patients is (0.592±0.071) × 10-3 mm2/s. There is statistical significance between them (t=2.568, P-3 mm2/s] is higher than that in untreated patients with statistical significance (t=-1.332, P-3 mm2/s], and 43 vertebras in patients with non-remission (NR) [(0.804± 0.327) × 10-3 mm2/s], there was not statistical significance between them (t=-0.160, P>0.05). The ADC values from S/I direction of untreated patients showed significant negative

  3. Eliminating Hairy Cell Leukemia Minimal Residual Disease

    Science.gov (United States)

    In this trial, patients with hairy cell leukemia who have disease-related symptoms that require treatment will be randomly assigned to receive cladribine with either concurrent rituximab or rituximab at least 6 months after completing cladribine therapy.

  4. PDT and tumour infiltrating immune cells

    International Nuclear Information System (INIS)

    Mechanisms involved in tumor destruction following PhotoDynamic Therapy are still under investigation. Direct killing of tumor cells by phototoxic action is not the only mechanism responsible for tumor destruction. When Photofrin is used as a photosensitizer a majority of tumor cells is killed by secondary mechanisms, expressed only if tumor is left in situ for at least 6-12 hours after light treatment. The indirect mechanism of tumor destruction by PDT has been described as a massive necrosis of tumor tissue resulting from hypoxia induced by destruction of tumor vasculature. Earliest changes in tumor vasculature already occur during the course of light illumination. They include accumulation of polymorphonuclear leukocytes (neutrophils), platelet aggregation, vasoconstriction followed by vascular stasis and hemorrhage. Release of mediators of inflammation (e.g. prostaglandin E2, thromboxane), cytokines, proteolytic enzymes and other substances was also demonstrated. These events are typical for inflammatory response. Nature and significance of this response has, however, not been studied in detail. Initial results on host immune cell infiltration into PDT treated murine tumor are reported here. (author). 16 refs., 1 fig., 1 tab

  5. Plumbagin Modulates Leukemia Cell Redox Status

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    François Gaascht

    2014-07-01

    Full Text Available Plumbagin is a plant naphtoquinone exerting anti-cancer properties including apoptotic cell death induction and generation of reactive oxygen species (ROS. The aim of this study was to elucidate parameters explaining the differential leukemia cell sensitivity towards this compound. Among several leukemia cell lines, U937 monocytic leukemia cells appeared more sensitive to plumbagin treatment in terms of cytotoxicity and level of apoptotic cell death compared to more resistant Raji Burkitt lymphoma cells. Moreover, U937 cells exhibited a ten-fold higher ROS production compared to Raji. Neither differential incorporation, nor efflux of plumbagin was detected. Pre-treatment with thiol-containing antioxidants prevented ROS production and subsequent induction of cell death by apoptosis whereas non-thiol-containing antioxidants remained ineffective in both cellular models. We conclude that the anticancer potential of plumbagin is driven by pro-oxidant activities related to the cellular thiolstat.

  6. Leukemia cutis

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    Angoori G Rao

    2012-01-01

    Full Text Available Leukemia cutis is the infiltration of neoplastic leukocytes or their precursors into the epidermis, the dermis, or the subcutis, resulting in clinically identifiable cutaneous lesions. Leukemia cutis may follow, precede or occur concomitantly with the diagnosis of systemic leukemia. A 50-year-old woman presented with asymptomatic multiple cutaneous nodules all over the body of 4 months duration. Cutaneous examination showed multiple hyperpigmented nodules and plaques involving face, trunk, and extremities. Peripheral smear showed abnormally elevated leucocyte count (TLC-70,000 with abnormal cells: myeloblasts 40%, promyelocytes 8% and myelocytes 39%. Auer rods were present in few myeloblasts. Bone marrow aspiration showed increased cellularity, erythroid hyperplasia with megaloblastic change, increased myeloblasts with maturation arrest. Immunohistochemistry showed strongly positive myeloperoxidase infiltrating cells and negative for CD20 and CD3 consistent with the diagnosis of AML-M 2 with leukemia cutis. This case is reported for its rarity.

  7. Hemorrhagic Skin Nodules and Plaques: A Diagnostic Clue to Underlying Primary Plasma Cell Leukemia.

    Science.gov (United States)

    Gupta, Ranjan; Nath, Amiya Kumar; Subbian, Murugavel; Basu, Debdatta; Hamide, Abdoul; D'Souza, Mariette

    2016-01-01

    Plasma cell leukemia (PCL) is a rare lymphoproliferative disorder characterized by a malignant proliferation of plasma cells (PC) in blood and marrow. Cutaneous involvement is very rare in PCL. We present the case of a 45-year-old lady who presented with multiple hemorrhagic nodules and plaques in the skin. Her total leucocyte count was 2,00,200/cmm with 85% abnormal plasmacytoid cells in peripheral smear. Biopsy of the skin lesions revealed diffuse infiltration by plasma cells with 'choked' blood vessels. A diagnosis of plasma cell leukemia with cutaneous involvement was made. On the second day of admission, the patient expired probably because of intracranial bleed due to thrombocytopenia. Post-mortem bone marrow and liver biopsy also showed diffuse infiltration by plasma cells. Monoclonality of the cells was proven by demonstrating the production of only kappa light chains. PMID:27057024

  8. Tumor infiltrating immune cells in gliomas and meningiomas.

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    Domingues, Patrícia; González-Tablas, María; Otero, Álvaro; Pascual, Daniel; Miranda, David; Ruiz, Laura; Sousa, Pablo; Ciudad, Juana; Gonçalves, Jesús María; Lopes, María Celeste; Orfao, Alberto; Tabernero, María Dolores

    2016-03-01

    Tumor-infiltrating immune cells are part of a complex microenvironment that promotes and/or regulates tumor development and growth. Depending on the type of cells and their functional interactions, immune cells may play a key role in suppressing the tumor or in providing support for tumor growth, with relevant effects on patient behavior. In recent years, important advances have been achieved in the characterization of immune cell infiltrates in central nervous system (CNS) tumors, but their role in tumorigenesis and patient behavior still remain poorly understood. Overall, these studies have shown significant but variable levels of infiltration of CNS tumors by macrophage/microglial cells (TAM) and to a less extent also lymphocytes (particularly T-cells and NK cells, and less frequently also B-cells). Of note, TAM infiltrate gliomas at moderate numbers where they frequently show an immune suppressive phenotype and functional behavior; in contrast, infiltration by TAM may be very pronounced in meningiomas, particularly in cases that carry isolated monosomy 22, where the immune infiltrates also contain greater numbers of cytotoxic T and NK-cells associated with an enhanced anti-tumoral immune response. In line with this, the presence of regulatory T cells, is usually limited to a small fraction of all meningiomas, while frequently found in gliomas. Despite these differences between gliomas and meningiomas, both tumors show heterogeneous levels of infiltration by immune cells with variable functionality. In this review we summarize current knowledge about tumor-infiltrating immune cells in the two most common types of CNS tumors-gliomas and meningiomas-, as well as the role that such immune cells may play in the tumor microenvironment in controlling and/or promoting tumor development, growth and control. PMID:26216710

  9. Leukemias

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    Riccardo Masetti

    2011-01-01

    Full Text Available Acute leukemia is the most common type of childhood and adolescence cancer, characterized by clonal proliferation of variably differentiated myeloid or lymphoid precursors. Recent insights into the molecular pathogenesis of leukemia have shown that epigenetic modifications, such as deacetylation of histones and DNA methylation, play crucial roles in leukemogenesis, by transcriptional silencing of critical genes. Histone deacetylases (HDACs are potential targets in the treatment of leukaemia, and, as a consequence, inhibitors of HDACs (HDIs are being studied for therapeutic purposes. HDIs promote or enhance several different anticancer mechanisms, such as apoptosis, cell cycle arrest, and cellular differentiation and, therefore, are in evidence as promising treatment for children and adolescents with acute leukemia, in monotherapy or in association with other anticancer drugs. Here we review the main preclinical and clinical studies regarding the use of HDIs in treating childhood and adolescence leukemia.

  10. Treatment of hairy-cell leukemia with chemoradiotherapy and identical-twin bone-marrow transplantation

    International Nuclear Information System (INIS)

    A patient with progressive hairy-cell leukemia and a normal genetically identical twin presented an opportunity to determine the sensitivity of this disease to high-dose alkylating-agent chemotherapy and total-body irradiation, since the marrow aplasia induced could potentially be overcome by reconstitution with normal marrow stem cells from the twin. After such therapy the patient rapidly recovered normal marrow function with no evidence of infiltrating hairy cells; he is still in complete remission four years after transplantation. In contrast to other patients with this disorder, he has had no predisposition to infections since transplantation. These results demonstrate that hairy-cell leukemia is sensitive to high-dose cytotoxic therapy and is not associated with any microenvironmental abnormalities that prevent repopulation with normal stem cells. Thus, high-dose chemoradiotherapy followed by bone-marrow transplantation is an effective and potentially curative therapy for hairy-cell leukemia

  11. Clonal expansion of renal cell carcinoma-infiltrating T lymphocytes

    DEFF Research Database (Denmark)

    Sittig, Simone; Køllgaard, Tania; Grønbæk, Kirsten;

    2013-01-01

    T lymphocytes can mediate the destruction of cancer cells by virtue of their ability to recognize tumor-derived antigenic peptides that are presented on the cell surface in complex with HLA molecules and expand. Thus, the presence of clonally expanded T cells within neoplastic lesions is an...... indication of ongoing HLA-restricted T cell-mediated immune responses. Multiple tumors, including renal cell carcinomas (RCCs), are often infiltrated by significant amounts of T cells, the so-called tumor-infiltrating lymphocytes (TILs). In the present study, we analyzed RCC lesions (n = 13) for the presence...... of expanded T-cell clonotypes using T-cell receptor clonotype mapping. Surprisingly, we found that RCCs comprise relatively low numbers of distinct expanded T-cell clonotypes as compared with melanoma lesions. The numbers of different T-cell clonotypes detected among RCC-infiltrating lymphocytes were...

  12. Immunotoxin Therapy for Relapsed Hairy Cell Leukemia

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    In this trial, patients with hairy cell leukemia who have relapsed multiple times or not responded to prior chemotherapy will be treated with an experimental immunotoxin called moxetumomab pasudotox given intravenously on days 1, 3, and 5 of 28-day cycles

  13. Induction of T-cell immunity against leukemia by dendritic cells pulsed with total RNA isolated from leukemia cells

    Institute of Scientific and Technical Information of China (English)

    李牧; 尤胜国; 葛薇; 马双; 马楠; 赵春华

    2003-01-01

    Objectives To assess the feasibility and efficacy of eliciting leukemia-specific T-cell responses in syngeneic mice in vitro and in vivo using dendritic cells (DCs) pulsed with total RNA from leukemia cells.Methods DCs generated from bone marrow culture in vitro in the presence of combined cytokines were pulsed with cellular total RNA isolated from cultured L615 cells by cationic lipid 1,2-dioleoyloxy-3-(trimethylammonium) propane (DOTAP). T-cell responses were evaluated by in vitro proliferation, and cytotoxicity assay. And in vivo immune protection and proghosis of mice with leukemia were studied.Conclusions These data support the use of DCs/RNA vaccine as a feasible and effective route to elicit leukemia immunity against unidentified leukemia-associated antigens for treatment of leukemia-bearing animals.

  14. Central Nervous System Involvement of T-cell Prolymphocytic Leukemia Diagnosed with Stereotactic Brain Biopsy: Case Report

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    Selçuk Göçmen

    2014-03-01

    Full Text Available Prolymphocytic leukemia (PLL is a generalized malignancy of the lymphoid tissue characterized by the accumulation of monoclonal lymphocytes, usually of B cell type. Involvement of the central nervous system (CNS is an extremely rare complication of T-cell prolymphocytic leukemia (T-PLL. We describe a case of T-PLL presenting with symptomatic infiltration of the brain that was histopathologically proven by stereotactic brain biopsy. We emphasize the importance of rapid diagnosis and immediate treatment for patients presenting with CNS involvement and a history of leukemia or lymphoma.

  15. Prolonged treatment response in aggressive natural killer cell leukemia.

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    Osuji, N; Matutes, E; Morilla, A; Del Giudice, I; Wotherspoon, A; Catovsky, D

    2005-05-01

    We describe a case of natural killer (NK) cell leukemia with acute presentation, systemic symptoms and hepatosplenomegaly. The uniform and aberrant phenotype of NK cells with infiltration of bone marrow and spleen was in keeping with a malignant diagnosis. Aggressive presentation was demonstrated by marked constitutional symptoms and significant tumor burden (liver, spleen, blood, bone marrow). The subsequent clinical course has been indolent, but this may have been influenced by treatment. Treatment consisted sequentially of splenectomy, intravenous pentostatin and the combination of cyclosporine A and recombinant human erythropoietin and has resulted in survival of over 48 months. We discuss the difficulties in the diagnosis of this condition, explore possible causes of cytopenia(s), and highlight the role of immunosuppression in controlling disease manifestations in large granular lymphocyte proliferative disorders. PMID:16019515

  16. [Bone marrow biopsy in non-Hodgkin's lymphomas, chronic lymphoid leukemia and mycosis fungoides. 1. Incidence and infiltration patterns].

    Science.gov (United States)

    Silva, M R; Mieza, M A; Saad, F A; Kerbauy, J; Burnier Júnior, M N

    1990-01-01

    Seventy bone marrow biopsies belonging to 53 patients with non-Hodgkin lymphomas, chronic lymphocytic leukemia, and micosis fungoides were studied. Bone marrow involvement was analyzed in correlation to staging before and after treatment. Bone marrow involvement was most frequently seen in CLL and IL followed by WDLL and PDLL/N and PDLL/D. Highest incidences after treatment were in CLL, WDLL, and PDLL/N and PDLL/D. With respect to staging, WDLL disseminated to bone marrow only in the late stages (III or IV), whereas the nodular and diffuse forms of PDLL presented similar infiltration in all stages. HLL and IL presented a slight trend to infiltrate only in the later stages. The pattern of bone marrow infiltration was also analyzed considering staging before and after treatment. No clear correlation was observed between staging and a specific pattern of bone marrow involvement in most cases, and disease evolution and treatment do not seem to change infiltration pattern. PMID:2287861

  17. Overexpression of Rac1 in leukemia patients and its role in leukemia cell migration and growth

    International Nuclear Information System (INIS)

    Rac1 belongs to the Rho family that act as critical mediators of signaling pathways controlling cell migration and proliferation and contributes to the interactions of hematopoietic stem cells with their microenvironment. Alteration of Rac1 might result in unbalanced interactions and ultimately lead to leukemogenesis. In this study, we analyze the expression of Rac1 protein in leukemia patients and determine its role in the abnormal behaviours of leukemic cells. Rac1 protein is overexpressed in primary acute myeloid leukemia cells as compared to normal bone marrow mononuclear cells. siRNA-mediated silencing of Rac1 in leukemia cell lines induced inhibition of cell migration, proliferation, and colony formation. Additionally, blocking Rac1 activity by an inhibitor of Rac1-GTPase, NSC23766, suppressed cell migration and growth. We conclude that overexpression of Rac1 contributes to the accelerated migration and high proliferation potential of leukemia cells, which could be implicated in leukemia development and progression.

  18. Improved infiltration of stem cells on electrospun nanofibers

    Energy Technology Data Exchange (ETDEWEB)

    Shabani, Iman [Polymer Engineering Department, Amirkabir University of Technology, P.O. Box 15875-4413, Tehran (Iran, Islamic Republic of); Department of Stem Cells and Tissue Engineering, Stem Cell Technology Co. Ltd., Tehran (Iran, Islamic Republic of); Haddadi-Asl, Vahid [Polymer Engineering Department, Amirkabir University of Technology, P.O. Box 15875-4413, Tehran (Iran, Islamic Republic of); Seyedjafari, Ehsan [Department of Biotechnology, College of Science, University of Tehran, Tehran (Iran, Islamic Republic of); Department of Stem Cells and Tissue Engineering, Stem Cell Technology Co. Ltd., Tehran (Iran, Islamic Republic of); Babaeijandaghi, Farshad [Department of Stem Cells and Tissue Engineering, Stem Cell Technology Co. Ltd., Tehran (Iran, Islamic Republic of); Faculty of Medicine, Tehran University of Medical Science, Tehran (Iran, Islamic Republic of); Soleimani, Masoud, E-mail: soleim_m@modares.ac.ir [Hematology Department, Faculty of Medical Science, Tarbiat Modares University, P.O. Box 14115-111, Tehran (Iran, Islamic Republic of)

    2009-04-24

    Nanofibrous scaffolds have been recently used in the field of tissue engineering because of their nano-size structure which promotes cell attachment, function, proliferation and infiltration. In this study, nanofibrous polyethersulfone (PES) scaffolds was prepared via electrospinning. The scaffolds were surface modified by plasma treatment and collagen grafting. The surface changes then investigated by contact angle measurements and FTIR-ATR. The results proved grafting of the collagen on nanofibers surface and increased hydrophilicity after plasma treatment and collagen grafting. The cell interaction study was done using stem cells because of their ability to differentiate to different kinds of cell lines. The cells had normal morphology on nanofibers and showed very high infiltration through collagen grafted PES nanofibers. This infiltration capability is very useful and needed to make 3D scaffolds in tissue engineering.

  19. Improved infiltration of stem cells on electrospun nanofibers

    International Nuclear Information System (INIS)

    Nanofibrous scaffolds have been recently used in the field of tissue engineering because of their nano-size structure which promotes cell attachment, function, proliferation and infiltration. In this study, nanofibrous polyethersulfone (PES) scaffolds was prepared via electrospinning. The scaffolds were surface modified by plasma treatment and collagen grafting. The surface changes then investigated by contact angle measurements and FTIR-ATR. The results proved grafting of the collagen on nanofibers surface and increased hydrophilicity after plasma treatment and collagen grafting. The cell interaction study was done using stem cells because of their ability to differentiate to different kinds of cell lines. The cells had normal morphology on nanofibers and showed very high infiltration through collagen grafted PES nanofibers. This infiltration capability is very useful and needed to make 3D scaffolds in tissue engineering.

  20. 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)

    2013-07-03

    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

  1. Hematopoietic stem cells and progenitors of chronic myeloid leukemia express leukemia-associated antigens: implications for the graft-versus-leukemia effect and peptide vaccine-based immunotherapy

    OpenAIRE

    Yong, Agnes S.M.; Keyvanfar, Keyvan; Eniafe, Rhoda; Savani, Bipin N.; Rezvani, Katayoun; Sloand, Elaine M.; Goldman, John M.; Barrett, A. John

    2008-01-01

    The cure of chronic myeloid leukemia (CML) patients following allogeneic stem cell transplantation (SCT) is attributed to graft-versus-leukemia (GVL) effects targeting alloantigens and/or leukemia-associated antigens (LAA) on leukemia cells. To assess the potential of LAA-peptide vaccines in eliminating leukemia in CML patients, we measured WT1, PR3, ELA2 and PRAME expression in CD34+ progenitor subpopulations in CML patients and compared them with minor histocompatibility antigens (mHAgs) HA...

  2. Cell death sensitization of leukemia cells by opioid receptor activation

    Science.gov (United States)

    Friesen, Claudia; Roscher, Mareike; Hormann, Inis; Fichtner, Iduna; Alt, Andreas; Hilger, Ralf A.; Debatin, Klaus-Michael; Miltner, Erich

    2013-01-01

    Cyclic AMP (cAMP) regulates a number of cellular processes and modulates cell death induction. cAMP levels are altered upon stimulation of specific G-protein-coupled receptors inhibiting or activating adenylyl cyclases. Opioid receptor stimulation can activate inhibitory Gi-proteins which in turn block adenylyl cyclase activity reducing cAMP. Opioids such as D,L-methadone induce cell death in leukemia cells. However, the mechanism how opioids trigger apoptosis and activate caspases in leukemia cells is not understood. In this study, we demonstrate that downregulation of cAMP induced by opioid receptor activation using the opioid D,L-methadone kills and sensitizes leukemia cells for doxorubicin treatment. Enhancing cAMP levels by blocking opioid-receptor signaling strongly reduced D,L-methadone-induced apoptosis, caspase activation and doxorubicin-sensitivity. Induction of cell death in leukemia cells by activation of opioid receptors using the opioid D,L-methadone depends on critical levels of opioid receptor expression on the cell surface. Doxorubicin increased opioid receptor expression in leukemia cells. In addition, the opioid D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux in leukemia cells, suggesting that the opioid D,L-methadone as well as doxorubicin mutually increase their cytotoxic potential. Furthermore, we found that opioid receptor activation using D,L-methadone alone or in addition to doxorubicin inhibits tumor growth significantly in vivo. These results demonstrate that opioid receptor activation via triggering the downregulation of cAMP induces apoptosis, activates caspases and sensitizes leukemia cells for doxorubicin treatment. Hence, opioid receptor activation seems to be a promising strategy to improve anticancer therapies. PMID:23633472

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

    Science.gov (United States)

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

    2015-09-01

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

  4. Molecular Hallmarks of Adult T Cell Leukemia

    Directory of Open Access Journals (Sweden)

    MakotoYamagishi

    2012-09-01

    Full Text Available The molecular hallmarks of adult T cell leukemia (ATL comprise outstanding deregulations of signaling pathways that control the cell cycle, resistance to apoptosis, and proliferation of leukemic cells, all of which have been identified by early excellent studies. Nevertheless, we are now confronted the therapeutic difficulties of ATL that is a most aggressive T cell leukemia/lymphoma. Using next-generation strategies, emerging molecular characteristics such as specific surface markers and an additional catalog of signals affecting the fate of leukemic cells have been added to the molecular hallmarks that constitute an organizing principle for rationalizing the complexities of ATL. Although human T cell leukemia virus type 1 (HTLV-1 is undoubtedly involved in ATL leukemogenesis, most leukemic cells do not express the viral protein Tax. Instead, cellular gene expression changes dominate homeostasis disorders of infected cells and characteristics of ATL. In this review, we summarize the state of the art of ATL molecular pathology, which supports the biological properties of leukemic cells. In addition, we discuss the recent discovery of two molecular hallmarks of potential generality; an abnormal microRNA (miRNA pattern and epigenetic reprogramming, which strongly involve the imbalance of the molecular network of lymphocytes. Global analyses of ATL have revealed the functional impact of crosstalk between multifunctional pathways. Clinical and biological studies on signaling inhibitory agents have also revealed novel oncogenic drivers that can be targeted in future. ATL cells, by deregulation of such pathways and their interconnections, may become masters of their own destinies. Recognizing and understanding of the widespread molecular applicability of these concepts will increasingly affect the development of novel strategies for treating ATL.

  5. Pulmonary leukemia in a child presenting with infiltrative and nodular lesions

    International Nuclear Information System (INIS)

    A leukemic child developed a pulmonary leukemic infiltration, confirmed by open lung biopsy. His radiograph showed a mixed interstitial and nodular pattern. Nodular lung lesions are rare in pediatric patients and exceptionally may represent leukemic invasion. (orig.)

  6. Quantitative Proteomics Analysis of Leukemia Cells.

    Science.gov (United States)

    Halbach, Sebastian; Dengjel, Jörn; Brummer, Tilman

    2016-01-01

    Chronic myeloid leukemia (CML) is driven by the oncogenic fusion kinase Bcr-Abl, which organizes its own signaling network with various proteins. These proteins, their interactions, and their role in relevant signaling pathways can be analyzed by quantitative mass spectrometry (MS) approaches in various models systems, e.g., in cell culture models. In this chapter, we describe in detail immunoprecipitations and quantitative proteomics analysis using stable isotope labeling by amino acids in cell culture (SILAC) of components of the Bcr-Abl signaling pathway in the human CML cell line K562. PMID:27581145

  7. Autonomous growth potential of leukemia blast cells is associated with poor prognosis in human acute leukemias

    Directory of Open Access Journals (Sweden)

    Jakubowski Ann A

    2009-12-01

    Full Text Available Abstract We have described a severe combined immunodeficiency (SCID mouse model that permits the subcutaneous growth of primary human acute leukemia blast cells into a measurable subcutaneous nodule which may be followed by the development of disseminated disease. Utilizing the SCID mouse model, we examined the growth potential of leukemic blasts from 133 patients with acute leukemia, (67 acute lymphoblastic leukemia (ALL and 66 acute myeloid leukemia (AML in the animals after subcutaneous inoculation without conditioning treatment. The blasts displayed three distinct growth patterns: "aggressive", "indolent", or "no tumor growth". Out of 133 leukemias, 45 (33.8% displayed an aggressive growth pattern, 14 (10.5% displayed an indolent growth pattern and 74 (55.6% did not grow in SCID mice. The growth probability of leukemias from relapsed and/or refractory disease was nearly 3 fold higher than that from patients with newly diagnosed disease. Serial observations found that leukemic blasts from the same individual, which did not initiate tumor growth at initial presentation and/or at early relapse, may engraft and grow in the later stages of disease, suggesting that the ability of leukemia cells for engraftment and proliferation was gradually acquired following the process of leukemia progression. Nine autonomous growing leukemia cell lines were established in vitro. These displayed an aggressive proliferation pattern, suggesting a possible correlation between the capacity of human leukemia cells for autonomous proliferation in vitro and an aggressive growth potential in SCID mice. In addition, we demonstrated that patients whose leukemic blasts displayed an aggressive growth and dissemination pattern in SClD mice had a poor clinical outcome in patients with ALL as well as AML. Patients whose leukemic blasts grew indolently or whose leukemia cells failed to induce growth had a significantly longer DFS and more favorable clinical course.

  8. CAR-pNK Cell Immunotherapy in CD7 Positive Leukemia and Lymphoma

    Science.gov (United States)

    2016-07-11

    Acute Myeloid Leukemia; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-cell Prolymphocytic Leukemia; T-cell Large Granular Lymphocytic Leukemia; Peripheral T-cell Lymphoma, NOS; Angioimmunoblastic T-cell Lymphoma; Extranodal NK/T-cell Lymphoma, Nasal Type; Enteropathy-type Intestinal T-cell Lymphoma; Hepatosplenic T-cell Lymphoma

  9. Stromal control of chronic lymphocytic leukemia cells

    Directory of Open Access Journals (Sweden)

    Seke Etet PF

    2013-09-01

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

  10. Immunological Analyses of Leukemia Stem Cells.

    Science.gov (United States)

    Naka, Kazuhito; Takihara, Yoshihiro

    2016-01-01

    Traditionally, the intracellular localization and expression levels of specific proteins in CML Leukemia stem cells (LSCs) have been evaluated by fluorescence immunohistochemistry (FIHC). More recently, Duolink(®) in situ PLA technology has opened up a new and more quantitative way to evaluate signal transduction, posttranslational modification, and protein-protein interaction at the single-stem-cell level. This novel methodology, which employs two antibody-based probes, has already increased our understanding of the biology of the rare CML LSC population. In the future, the use of this approach may contribute to the development of novel therapeutics aimed at eradicating CML LSCs in CML patients. PMID:27581137

  11. Leukemia Mediated Endothelial Cell Activation Modulates Leukemia Cell Susceptibility to Chemotherapy through a Positive Feedback Loop Mechanism.

    Directory of Open Access Journals (Sweden)

    Bahareh Pezeshkian

    Full Text Available In acute myeloid leukemia (AML, the chances of achieving disease-free survival are low. Studies have demonstrated a supportive role of endothelial cells (ECs in normal hematopoiesis. Here we show that similar intercellular relationships exist in leukemia. We demonstrate that leukemia cells themselves initiate these interactions by directly modulating the behavior of resting ECs through the induction of EC activation. In this inflammatory state, activated ECs induce the adhesion of a sub-set of leukemia cells through the cell adhesion molecule E-selectin. These adherent leukemia cells are sequestered in a quiescent state and are unaffected by chemotherapy. The ability of adherent cells to later detach and again become proliferative following exposure to chemotherapy suggests a role of this process in relapse. Interestingly, differing leukemia subtypes modulate this process to varying degrees, which may explain the varied response of AML patients to chemotherapy and relapse rates. Finally, because leukemia cells themselves induce EC activation, we postulate a positive-feedback loop in leukemia that exists to support the growth and relapse of the disease. Together, the data defines a new mechanism describing how ECs and leukemia cells interact during leukemogenesis, which could be used to develop novel treatments for those with AML.

  12. Adult T-cell leukemia/lymphoma presenting multiple lymphomatous polyposis

    Institute of Scientific and Technical Information of China (English)

    Akira Hokama; Nobuyuki Takasu; Jiro Fujita; Takeaki Tomoyose; Yu-ichi Yamamoto; Takako Watanabe; Tetsuo Hirata; Fukunori Kinjo; Seiya Kato; Koichi Ohshima; Hiroshi Uezato

    2008-01-01

    Multiple lymphomatous polyposis (HLP) is an unusual form of non-Hodgkin's lymphoma characterized by polyps throughout the gastrointestinal tract. It has been reported that most MLP are observed in cases with mantle cell lymphoma of B-cell type. We herein present a case of a 66-year-old man with adult T-cell leukemia/lymphoma (ATLL). Colonoscopy revealed MLP throughout the colon and histopathological findings of ATLL cell infiltration. The patient died despite combination of chemotherapy. The literature of manifestations of colonic involvement of ATLL is reviewed and the importance of endoscopic evaluation to differentiate ATLL intestinal lesions from opportunistic infectious enterocolitis is discussed.

  13. Rosacea-Like Leukemia Cutis: A Case Report.

    Science.gov (United States)

    Cruz Manzano, Mariana; Ramírez García, Lilliana; Sánchez Pont, Julio E; Velázquez Mañana, Ana I; Sánchez, Jorge L

    2016-08-01

    Leukemia cutis describes the infiltration and dissemination of neoplastic leukemic cells into the epidermis, dermis, or subcutis, resulting in clinically identifiable cutaneous lesions. Depending on the type of leukemia, a wide range of clinical and histopathological findings may be encountered. This report describes a patient with a rosacea-like eruption as a unique clinical presentation of T-cell prolymphocytic leukemia. PMID:27043335

  14. Methylation of Gene CHFR Promoter in Acute Leukemia Cells

    Institute of Scientific and Technical Information of China (English)

    GONG Hui; LIU Wengli; ZHOU Jianfeng; XU Huizhen

    2005-01-01

    Summary: In order to explore whether gene CHFR was inactivated by methylation in leukemia cells, the expression of CHFR was examined before and after treatment with demethylation agent in Molt-4, Jurkat and U937 leukemia cell lines by means of RT-PCR. The methylation of promoter in Molt-4, Jurkat and U937 cells as well as 41 acute leukemia patients was analyzed by MS-PCR. The results showed that methylation of CHFR promoter was inactivated and could be reversed by treatment with a demethylating agent in Molt-4, Jurkat and U937. CHFR promoter methylation was detected in 39 % of acute leukemia patients. There was no difference in incidence of CHFR promoter methylation between acute myelocytic leukemia and acute lymphocytic leukemia. In conclusion, CHFR is frequently inactivated in acute leukemia and is a good candidate for the leukemia supper gene. By affecting mitotic checkpoint function, CHFR inactivation likely plays a key role in tumorigenesis in acute leukemia. Moreover, the methylation of gene CHFR appears to be a good index with which to predict the sensitivity of acute leukemia to microtubule inhibitors.

  15. Selective host range restriction of goat cells for recombinant murine leukemia virus and feline leukemia virus type A.

    OpenAIRE

    Fischinger, P J; Thiel, H J; Blevins, C S; Dunlop, N M

    1981-01-01

    We isolated a strain of normal goat fibroblasts which was uniquely selective in that it allowed the replication of xenotropic murine leukemia virus but not polytropic recombinant murine leukemia virus. In addition, feline leukemia virus type A replication was severely diminished in these goat cells, whereas feline leukemia virus type B and feline endogenous RD114-CCC viruses replicated efficiently. No other known cells exhibit this pattern of virus growth restriction. These goat cells allow t...

  16. Tax fingerprint in adult T-cell leukemia.

    Science.gov (United States)

    Bazarbachi, Ali

    2016-04-01

    In this issue of Blood, Fujikawa et al demonstrate that the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax induces an epigenetic-dependent global modification of host gene expression in adult T-cell leukemia-lymphoma (ATL). Hence, the fingerprint of Tax is all over ATL and this may be used for finally capturing ATL. PMID:27056993

  17. Individualized leukemia cell-population profiles in common B-cell acute lymphoblastic leukemia patients

    Institute of Scientific and Technical Information of China (English)

    Jian-Hua Yu; Jing-Tao Dong; Yong-Qian Jia; Neng-Gang Jiang; Ting-Ting Zeng; Hong Xu; Xian-Ming Mo

    2013-01-01

    Immunophenotype is critical for diagnosing common B-cell acute lymphoblastic leukemia (common ALL) and detecting minimal residual disease.We developed a protocol to explore the immunophenotypic profiles of common ALL based on the expression levels of the antigens associated with B lymphoid development,including IL-7Rα (CD127),cytoplasmic CD79a (cCD79a),CD19,VpreB (CD179a),and slgM,which are successive and essential for progression of B cells along their developmental pathway.Analysis of the immunophenotypes of 48 common ALL cases showed that the immunophenotypic patterns were highly heterogeneous,with the leukemic cell population differing from case to case.Through the comprehensive analysis of immunophenotypic patterns,the profiles of patient-specific composite leukemia cell populations could provide detailed information helpful for the diagnosis,therapeutic monitoring,and individualized therapies for common ALL.

  18. Hepatic failure caused by plasma cell infiltration in multiple Myeloma

    Institute of Scientific and Technical Information of China (English)

    Fadi E Rahhal; Robert R Schade; Asha Nayak; Teresa A Coleman

    2009-01-01

    Although plasma cell infiltration is not rare in autopsy of patients with multiple myeloma (MM), it is very rarely detected in living patients. This is because MM rarely causes significant liver dysfunction that requires further evaluation. A 49-year-old man presented with acute renal failure and was diagnosed with kappa light chain MM stage ?B. Thalidomide and dexamethasone were initiated. The patient developed a continuous increase in bilirubin that led to severe cholestasis. A liver biopsy revealed plasma cell infiltration. He then rapidly progressed to liver failure and died. Treatment options are limited in MM with significant liver dysfunction.Despite new drug therapies in MM, those patients with rapidly progressive liver failure appear to have a dismal outcome.

  19. Role of Ikaros in T-cell acute lymphoblastic leukemia

    Institute of Scientific and Technical Information of China (English)

    Philippe; Kastner; Susan; Chan

    2011-01-01

    Ikaros is a zinc finger transcriptional regulator encoded by the Ikzf1 gene.Ikaros displays crucial functions in the hematopoietic system and its loss of function has been linked to the development of lymphoid leukemia.In particular,Ikaros has been found in recent years to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia.Its role in T-cell leukemia,however,has been more controversial.While Ikaros deficiency appears to be very frequent in murine T-cell leukemias,loss of Ikaros appears to be rare in human T-cell acute lymphoblastic leukemia (T-ALL).We review here the evidence linking Ikaros to T-ALL in mouse and human systems.

  20. Leukemia.

    Science.gov (United States)

    Juliusson, Gunnar; Hough, Rachael

    2016-01-01

    Leukemias are a group of life threatening malignant disorders of the blood and bone marrow. In the adolescent and young adult (AYA) population, the acute leukemias are most prevalent, with chronic myeloid leukemia being infrequently seen. Factors associated with more aggressive disease biology tend to increase in frequency with increasing age, whilst tolerability of treatment strategies decreases. There are also challenges regarding the effective delivery of therapy specific to the AYA group, consequences on the unique psychosocial needs of this age group, including compliance. This chapter reviews the current status of epidemiology, pathophysiology, treatment strategies and outcomes of AYA leukemia, with a focus on acute lymphoblastic leukemia and acute myeloid leukemia. PMID:27595359

  1. The target cell of transformation is distinct from the leukemia stem cell in murine CALM/AF10 leukemia models.

    Science.gov (United States)

    Dutta, S; Krause, A; Vosberg, S; Herold, T; Ksienzyk, B; Quintanilla-Martinez, L; Tizazu, B; Chopra, M; Graf, A; Krebs, S; Blum, H; Greif, P A; Vetter, A; Metzeler, K; Rothenberg-Thurley, M; Schneider, M R; Dahlhoff, M; Spiekermann, K; Zimber-Strobl, U; Wolf, E; Bohlander, S K

    2016-05-01

    The CALM/AF10 fusion gene is found in various hematological malignancies including acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia and malignant lymphoma. We have previously identified the leukemia stem cell (LSC) in a CALM/AF10-driven murine bone marrow transplant AML model as B220+ lymphoid cells with B-cell characteristics. To identify the target cell for leukemic transformation or 'cell of origin of leukemia' (COL) in non-disturbed steady-state hematopoiesis, we inserted the CALM/AF10 fusion gene preceded by a loxP-flanked transcriptional stop cassette into the Rosa26 locus. Vav-Cre-induced panhematopoietic expression of the CALM/AF10 fusion gene led to acute leukemia with a median latency of 12 months. Mice expressing CALM/AF10 in the B-lymphoid compartment using Mb1-Cre or CD19-Cre inducer lines did not develop leukemia. Leukemias had a predominantly myeloid phenotype but showed coexpression of the B-cell marker B220, and had clonal B-cell receptor rearrangements. Using whole-exome sequencing, we identified an average of two to three additional mutations per leukemia, including activating mutations in known oncogenes such as FLT3 and PTPN11. Our results show that the COL for CALM/AF10 leukemia is a stem or early progenitor cell and not a cell of B-cell lineage with a phenotype similar to that of the LSC in CALM/AF10+ leukemia. PMID:26686248

  2. Hematopoietic Stem Cell Transplantation in Children with Acute Lymphoblastic Leukemia

    OpenAIRE

    Ibrahim Bayram

    2014-01-01

    In children patients with acute lymphoblastic leukemia, according to the European bone marrow transplant handbook, the indications for stem cell transplantation, conditioning regimen, donor selection and information about sources of stem cells will be evaluated.

  3. Allogeneic cellular immunotherapy for chronic B-cell leukemia

    OpenAIRE

    Hoogendoorn, Mels

    2007-01-01

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

  4. Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma

    Science.gov (United States)

    Giannakis, Marios; Mu, Xinmeng Jasmine; Shukla, Sachet A.; Qian, Zhi Rong; Cohen, Ofir; Nishihara, Reiko; Bahl, Samira; Cao, Yin; Amin-Mansour, Ali; Yamauchi, Mai; Sukawa, Yasutaka; Stewart, Chip; Rosenberg, Mara; Mima, Kosuke; Inamura, Kentaro; Nosho, Katsuhiko; Nowak, Jonathan A.; Lawrence, Michael S.; Giovannucci, Edward L.; Chan, Andrew T.; Ng, Kimmie; Meyerhardt, Jeffrey A.; Van Allen, Eliezer M.; Getz, Gad; Gabriel, Stacey B.; Lander, Eric S.; Wu, Catherine J.; Fuchs, Charles S.; Ogino, Shuji; Garraway, Levi A.

    2016-01-01

    Summary Large-scale genomic characterization of tumors from prospective cohort studies may yield new insights into cancer pathogenesis. We performed whole-exome sequencing of 619 incident colorectal cancers (CRCs) and integrated the results with tumor immunity, pathology, and survival data. We identified recurrently mutated genes in CRC, such as BCL9L, RBM10, CTCF, and KLF5, that were not previously appreciated in this disease. Furthermore, we investigated the genomic correlates of immune-cell infiltration and found that higher neoantigen load was positively associated with overall lymphocytic infiltration, tumor-infiltrating lymphocytes (TILs), memory T cells, and CRC-specific survival. The association with TILs was evident even within microsatellite-stable tumors. We also found positive selection of mutations in HLA genes and other components of the antigen-processing machinery in TIL-rich tumors. These results may inform immunotherapeutic approaches in CRC. More generally, this study demonstrates a framework for future integrative molecular epidemiology research in colorectal and other malignancies. PMID:27149842

  5. Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma

    Directory of Open Access Journals (Sweden)

    Marios Giannakis

    2016-04-01

    Full Text Available Large-scale genomic characterization of tumors from prospective cohort studies may yield new insights into cancer pathogenesis. We performed whole-exome sequencing of 619 incident colorectal cancers (CRCs and integrated the results with tumor immunity, pathology, and survival data. We identified recurrently mutated genes in CRC, such as BCL9L, RBM10, CTCF, and KLF5, that were not previously appreciated in this disease. Furthermore, we investigated the genomic correlates of immune-cell infiltration and found that higher neoantigen load was positively associated with overall lymphocytic infiltration, tumor-infiltrating lymphocytes (TILs, memory T cells, and CRC-specific survival. The association with TILs was evident even within microsatellite-stable tumors. We also found positive selection of mutations in HLA genes and other components of the antigen-processing machinery in TIL-rich tumors. These results may inform immunotherapeutic approaches in CRC. More generally, this study demonstrates a framework for future integrative molecular epidemiology research in colorectal and other malignancies.

  6. Uncontrolled hypertension secondary to leukemic cell infiltration of kidneys in a hemodialysis patient

    Directory of Open Access Journals (Sweden)

    Kultigin Turkmen

    2010-06-01

    Full Text Available Kultigin Turkmen1, Lutfullah Altintepe2, Ibrahim Guney2, Ismet Aydogdu3, Osman Koc4, Mehmet Ali Erkut5, Halil Zeki Tonbul11Department of Nephrology, Meram School of Medicine, Selcuk University, 2Meram Training and Research Hospital, Selcuk University, 3Department of Hematology, Meram School of Medicine, Selcuk University, 4Department of Radiology, Meram School of Medicine, Selcuk University, 5Department of Hematology, Meram Training and Research Hospital, Selcuk UniversityAbstract: Leukemic infiltration of the kidney is usually silent, and the admission of the patients with renal dysfunction or acute kidney injury is uncommon. We present a 34-year old hemodialysis patient with new onset of uncontrolled hypertension, erythropoietin-resistant anemia, thrombocytopenia, and Bell’s palsy. On admission, his blood pressure (BP was 210/110 mmHg and he had petechiae and purpura at upper and lower extremities. Renal ultrasonography (USG showed bilaterally enlarged kidneys without hydronephrosis, unlike his previous USG, which determined bilaterally atrophic kidneys. Acute lymphoblastic leukemia, hypertensive crisis due to bilateral leukemic cell infiltration of kidneys, tumor lysis syndrome, and leukemic involvement of the facial nerve were diagnosed. Despite intense antihypertensive management, his BP was not controlled. After prednisolone, daunorubicine, and vincristine therapy, the size of kidneys diminished and his BP dropped under normal range. In conclusion, pathological findings such as uncontrolled hypertension, flank pain, skin rashes, and abnormal blood count should be considered carefully, even in patients with end-stage renal disease receiving renal replacement therapy.Keywords: leukemic cell infiltration, uncontrolled hypertension, hemodialysis

  7. Bone marrow infiltration in patients with acute leukemia: dynamic contrast-enhanced MRI and its clinical significance

    International Nuclear Information System (INIS)

    Objective: Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to evaluate the hemodynamic perfusion characteristics of bone marrow infiltration in patients with acute leukemia (AL). Methods: Forty-seven patients with AL received coronal pelvic T1WI DCE-MRI with fast low angle shot (FLASH) sequence. Among them, 25 were initial onset untreated (IOU) patients, 22 were treated AL patients, including 14 with complete remission (CR) and 8 with non-remission (NR). The hemodynamic perfusion parameters including maximum percentage of enhancement (Emax) and slope were determined based on enhancement-time curves (ETCs) of iliac and lumbar vertebra. The proportion of marrow myeloblasts was recorded. For all patients, quantitative perfusion parameters of bone marrow infiltration in ilium were compared with those in lumbar. The values of Emax and ES were compared among IOU, CR and NR patients. Correlations between perfusion parameters and histopathological results were assessed. Results: In all the 47 patients, the Emax values of bilateral iliac bone marrow (15.70±7.06) were slightly higher than that of lumbar bone marrow (11.28±5.52), and the difference was statistically significant (P0.05). In the 25 untreated patients, the Emax and slop values were 17.15±5.75 and 0.98±0.13, respectively; in the 14 CR patients, they were 8.76±3.93 and 0.26±0.04, respectively, and in the 8 NR patients, they were 21.62±6.50 and 1.38±0.02, respectively. There was significant difference in the Emax and slop values among the three groups (P0.05). A significant positive correlation was found between Emax value of iliac bone marrow and the proportion of marrow myeloblasts (r=0.501, P 0.05). Conclusions: DCE-MRI can be used for evaluating the hemodynamic characteristics of microcirculation of bone marrow infiltration in patients with AL, which can provide useful information in evaluating prognosis and monitoring therapeutic effect. (authors)

  8. Role of Ikaros in T-cell acute lymphoblastic leukemia

    OpenAIRE

    Kastner, Philippe; Chan, Susan

    2011-01-01

    Ikaros is a zinc finger transcriptional regulator encoded by the Ikzf1 gene. Ikaros displays crucial functions in the hematopoietic system and its loss of function has been linked to the development of lymphoid leukemia. In particular, Ikaros has been found in recent years to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia. Its role in T-cell leukemia, however, has been more controversial. While Ikaros deficiency appears to be very frequent in murine T-cell l...

  9. Uncontrolled hypertension secondary to leukemic cell infiltration of kidneys in a hemodialysis patient.

    Science.gov (United States)

    Turkmen, Kultigin; Altintepe, Lutfullah; Guney, Ibrahim; Aydogdu, Ismet; Koc, Osman; Erkut, Mehmet Ali; Tonbul, Halil Zeki

    2010-01-01

    Leukemic infiltration of the kidney is usually silent, and the admission of the patients with renal dysfunction or acute kidney injury is uncommon. We present a 34-year old hemodialysis patient with new onset of uncontrolled hypertension, erythropoietin-resistant anemia, thrombocytopenia, and Bell's palsy. On admission, his blood pressure (BP) was 210/110 mmHg and he had petechiae and purpura at upper and lower extremities. Renal ultrasonography (USG) showed bilaterally enlarged kidneys without hydronephrosis, unlike his previous USG, which determined bilaterally atrophic kidneys. Acute lymphoblastic leukemia, hypertensive crisis due to bilateral leukemic cell infiltration of kidneys, tumor lysis syndrome, and leukemic involvement of the facial nerve were diagnosed. Despite intense antihypertensive management, his BP was not controlled. After prednisolone, daunorubicine, and vincristine therapy, the size of kidneys diminished and his BP dropped under normal range. In conclusion, pathological findings such as uncontrolled hypertension, flank pain, skin rashes, and abnormal blood count should be considered carefully, even in patients with end-stage renal disease receiving renal replacement therapy. PMID:21694931

  10. Vitamin D Protects Acute Lymphoblastic Leukemia Cells from Dexamethasone

    OpenAIRE

    Antony, Reuben; Sheng, Xia; Ehsanipour, Ehsan A.; Ng, Emily; Pramanik, Rocky; Klemm, Lars; Ichihara, Brian; Mittelman, Steven D.

    2012-01-01

    Vitamin D deficiency has been linked with increased cancer risk, and vitamin D has been shown to be cytotoxic to some cancer cells in vitro. In the present study we evaluated whether vitamin D would have antiproliferative or cytotoxic effects on human pre-B acute lymphoblastic leukemia cells. Contrary to our hypotheses, calcitriol, the active form of vitamin D, had no effect on leukemia cell proliferation. Calcitriol actually had a modest effect to impair dexamethasone cytotoxicity and induct...

  11. Phenotypic characterisation of immune cell infiltrates in testicular germ cell neoplasia

    DEFF Research Database (Denmark)

    Hvarness, Tine; Nielsen, John E; Almstrup, Kristian; Skakkebaek, Niels E; Rajpert-De Meyts, Ewa; Claesson, Mogens H

    2013-01-01

    Immune cells often infiltrate testicular germ cell neoplasms, including pre-invasive carcinoma in situ (CIS), but the significance of this phenomenon remains unknown. The composition and distribution of infiltrating immune cells were examined by immunohistochemistry in testis samples with CIS and...... overt seminoma, in comparison to biopsies from infertile men without neoplasia. The composition of immune cells was similar across all the groups studied. Macrophages, CD8(+) and CD45R0(+) T lymphocytes constituted the majority of infiltrates, B lymphocytes were present in an intermediate proportion and...... very few CD4(+) and FoxP3(+) T cells were detected. HLA-I antigen was more abundant in Sertoli cells in tubules containing CIS than in those with normal spermatogenesis. This study showed a phenotypically comparable composition of infiltrating immune cells independently of the presence of neoplasia...

  12. Therapeutic Effects of Myeloid Cell Leukemia-1 siRNA on Human Acute Myeloid Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Hadi Karami

    2014-05-01

    Full Text Available Purpose: Up-regulation of Mcl-1, a known anti-apoptotic protein, is associated with the survival and progression of various malignancies including leukemia. The aim of this study was to explore the effect of Mcl-1 small interference RNA (siRNA on the proliferation and apoptosis of HL-60 acute myeloid leukemia (AML cells. Methods: siRNA transfection was performed using Lipofectamine™2000 reagent. Relative mRNA and protein expressions were quantified by quantitative real-time PCR and Western blotting, respectively. Trypan blue assay was performed to assess tumor cell proliferation after siRNA transfection. The cytotoxic effect of Mcl-1 siRNA on leukemic cells was measured using MTT assay. Apoptosis was detected using ELISA cell death assay. Results: Mcl-1 siRNA clearly lowered both Mcl-1 mRNA and protein levels in a time-dependent manner, leading to marked inhibition of cell survival and proliferation. Furthermore, Mcl-1 down-regulation significantly enhanced the extent of HL-60 apoptotic cells. Conclusion: Our results suggest that the down-regulation of Mcl-1 by siRNA can effectively trigger apoptosis and inhibit the proliferation of leukemic cells. Therefore, Mcl-1 siRNA may be a potent adjuvant in AML therapy.

  13. BRAF mutation in hairy cell leukemia

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    Ahmad Ahmadzadeh

    2014-09-01

    Full Text Available BRAF is a serine/threonine kinase with a regulatory role in the mitogen-activated protein kinase (MAPK signaling pathway. A mutation in the RAF gene, especially in BRAF protein, leads to an increased stimulation of this cascade, causing uncontrolled cell division and development of malignancy. Several mutations have been observed in the gene coding for this protein in a variety of human malignancies, including hairy cell leukemia (HCL. BRAF V600E is the most common mutation reported in exon15 of BRAF, which is observed in almost all cases of classic HCL, but it is negative in other B-cell malignancies, including the HCL variant. Therefore it can be used as a marker to differentiate between these B-cell disorders. We also discuss the interaction between miRNAs and signaling pathways, including MAPK, in HCL. When this mutation is present, the use of BRAF protein inhibitors may represent an effective treatment. In this review we have evaluated the role of the mutation of the BRAF gene in the pathogenesis and progression of HCL.

  14. In vitro radiosensitivity of human leukemia cell lines

    International Nuclear Information System (INIS)

    The in vitro radiobiologic survival values (n, D0) of four tumor lines derived from human hematopoietic tumors were studied. These cell lines were HL50 (n . 1.3, D0 . 117 rad[1.17 Gy]), promyelocytic leukemia; K562 (n . 1.4, D0 . 165 rad[1.65 Gy]), erythroleukemia; 45 (n . 1.1, D0 . 147 rad[1.47 Gy]), acute lymphocyte leukemia; and 176 (n . 4.0, D0 . 76 rad[0.76 Gy]), acute monomyelogenous leukemia. More cell lines must be examined before the exact relationship between in vitro radiosensitivity and clinical radiocurability is firmly established

  15. Treating Multiply Relapsed or Refractory Hairy Cell Leukemia

    Science.gov (United States)

    In this trial, patients with hairy cell leukemia who have not responded or relapsed after initial chemotherapy will be randomly assigned to receive rituximab combined with either pentostatin or bendamustine.

  16. Individualized leukemia cell-population profiles in common B-cell acute lymphoblastic leukemia patients

    OpenAIRE

    Xian-Ming Mo; Hong Xu; Ting-Ting Zeng; Neng-Gang Jiang; Yong-Qian Jia; Jing-Tao Dong; Jian-Hua Yu; Wen-Tong Meng

    2013-01-01

    Immunophenotype is critical for diagnosing common B-cell acute lymphoblastic leukemia (common ALL) and detecting minimal residual disease. We developed a protocol to explore the immunophenotypic profiles of common ALL based on the expression levels of the antigens associated with B lymphoid development, including IL-7R alpha (CD127), cytoplasmic CD79a (cCD79a), CD19, VpreB (CD179a), and sIgM, which are successive and essential for progression of B cells along their developmental pathway. Anal...

  17. T- cell prolymphocytic leukemia - A rare case

    Directory of Open Access Journals (Sweden)

    Ghosh Sharmila

    2005-01-01

    Full Text Available T- cell Prolymhocytic leukemia (T-PLL is a rare mature post-thymic T-cell malignancy that is usually reported in the elderly and follows an aggressive course. A 68 year old male presented with a history of weakness and weight loss of two months duration. Clinical examination revealed pallor, enlarged cervical and axillary lymph nodes and splenomegaly. He also had a maculo- papular skin rash. There was marked leucocytosis, anemia and thrombocytopenia (WBC 445 x103sub/ml, Hb 8.5gm/dl, Platelet 25x103/µl with 60% prolymphocytes in the peripheral blood. Bone marrow was hypercellular with an excess of prolymphocytes. Flow cytometric analysis of the bone marrow showed positivity for CD2, CD3, CD4, CD5 and CD7. T- PLL is a rare T cell disorder with characteristic clinical and laboratory features.Currently, no optimal treatment exists although there has been some success with 2′- deoxycoformycin or Campath-1H

  18. A Unique Hairy Cell Leukemia Variant.

    Science.gov (United States)

    Jian, Charles; Hsia, Cyrus C

    2016-01-01

    A 65-year-old woman presented with easy bruising, left upper quadrant pain, decreased appetite, and weight loss. She had splenomegaly and lymphocytosis (lymphocyte count of 11.6 × 10(9)/l), with remarkably abnormal appearing morphology. Her hemoglobin and platelet counts were normal. Peripheral blood flow cytometry revealed a monoclonal B-cell population expressing CD11c, CD25, CD19, CD20, and CD103. An initial diagnosis of hairy cell leukemia (HCL) was made, and the patient was treated with a standard 5-day course of cladribine. However, her lymphocytosis improved transiently, with a relapse 4 months later. There was no improvement in her splenomegaly. An HCL variant (HCL-v) was considered based on her resistance to treatment with a purine nucleoside analog. A subsequent splenectomy improved symptoms. Two years after, the patient suffered a relapse and underwent 6 cycles of CHOP-R (cyclophosphamide, hydroxydaunomycin, oncovin, prednisone, and rituximab), achieving partial remission. While under observation, she progressed with lymphocytosis 6 months later and was treated with pentostatin. There was no significant improvement in her disease, and she died 8 weeks following treatment initiation. HCL-v is a clinically more aggressive mature B-cell lymphoma than HCL with worse splenomegaly, higher lymphocyte counts, and resistance to typical HCL therapy with purine nucleoside analogs. Early recognition of HCL-v in the history, physical examination, and investigations with morphology and flow cytometry is key to patient management. Further, as in our case of HCL-v, cell morphology can be distinctly atypical, with large nucleoli and extremely convoluted nuclei. The distinction between HCL and HCL-v is important as HCL-v patients require more aggressive therapy and closer follow-up. PMID:27462230

  19. CML Mouse Model Generated from Leukemia Stem Cells.

    Science.gov (United States)

    Hu, Yiguo

    2016-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder with a high number of well-differentiated neutrophils in peripheral blood and myeloid cells in bone marrow (BM). CML is derived from the hematopoietic stem cells (HSCs) with the Philadelphia chromosome (Ph(+), t(9;22)-(q34;q11)), resulting in generating a fusion oncogene, BCR/ABL1. HSCs with Ph(+) are defined as leukemia stem cells (LSCs), a subpopulation cell at the apex of hierarchies in leukemia cells and responsible for the disease continuous propagation. Several kinds of CML models have been developed to reveal the mechanism of CML pathogenesis and evaluate therapeutic drugs in the past three decades. Here, we describe the procedures to generate a CML mouse model by introducing BCR/ABL1 into Lin(-)Sca1(+) cKit(+) population cells purified from mouse bone marrow. In CML retroviral transduction/transplantation mouse models, this modified model can mimic CML pathogenesis on high fidelity. PMID:27581136

  20. Primary Plasma Cell Leukemia: Identity Card 2016.

    Science.gov (United States)

    Musto, Pellegrino; Simeon, Vittorio; Todoerti, Katia; Neri, Antonino

    2016-04-01

    Primary plasma cell leukemia (PPCL) is an aggressive and rare variant of multiple myeloma (MM), characterized by peculiar adverse clinical and biological features. Though the poor outcome of PPCL has been slightly improved by novel treatments during the last 10 years, due to the limited number of available studies in this uncommon disease, optimal therapy remains a classic unmet clinical need. Anyway, in the real-life practice, induction with a bortezomib-based three-drug combination, including dexamethasone and, possibly, lenalidomide, or, alternatively, thalidomide, cyclophosphamide, or doxorubicin, is a reasonable first-line option. This approach may be particularly advisable for patients with adverse cytogenetics, hyperleucocytosis, and rapidly progressive disease, in whom a fast response is required, or for those with suboptimal renal function, where, however, lenalidomide should be used with caution until renal activity is restored. In younger subjects, leukemia/lymphoma-like more intensive regimens, including hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone or continue-infusion cisplatin, doxorubicin, cyclophosphamide, and etoposide, may be also combined with bortezomib +/- thalidomide. Treatment must be started immediately after a diagnosis of PPCL is made to avoid the risk of irreversible disease complications and, in such a context, the prevention of tumor lysis syndrome is mandatory. In patients eligible for autologous stem cell transplantation (AuSCT), other alkylating agents, in particular melphalan, should be initially avoided in order to allow adequate collections of CD34+ peripheral blood stem cells (PBSC). A combination of lenalidomide and dexamethasone may be a valuable alternative option to manage older or unfit patients or those with slower disease evolution or with signs of neuropathy, contraindicating the use of bortezomib. Patients not suitable for transplant procedures should continue the treatment, if a

  1. Juvenile Myelomonocytic Leukemia (JMML Cells Spontaneously Differentiate into Dendritic-Cell Like Populations in vitro

    Directory of Open Access Journals (Sweden)

    Parviz Shayan

    2008-09-01

    Full Text Available Objective: Juvenile myelomonocytic leukemia (JMML is a rare myelodysplastic/ myeloproliferative malignancy of early childhood, characterized by monocytosis, hepatosplenomegaly and an aggressive clinical course. Methods: In semi-solid culture JMML progenitor cells proliferate spontaneously into colony forming units. In order to study the mechanisms of proliferation and differentiation of JMML cells we developed a suspension culture system without additional exogenous growth factor supplement. Mononuclear cells (MNC from peripheral blood, bone marrow or spleen of 14 patients with JMML and 24 controls were studied. Findings: JMML cells expressed higher levels of the proliferation marker Ki67 (median 24% [7-39%] vs a median of 3.5% in controls. 90% of JMML cells were CD68-positive (vs 35% in controls and by day 7 all JMML samples contained CD1a- positive cells. Electron microscopy demonstrated cytoplasmic vesicular structures resembling multilamellar MHC II compare­timents, which together with the expression of CD1a - support a dendritic cell (DC-phenotype. Conclusion: Differentiation into CD1a-positive DC seems to be a frequent phenomenon in cultured JMML MNC, which in vivo may contribute to clinical characteristics such as skin and organ infiltration.

  2. Bilateral breast involvement in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Hakeem A, Mandakini BT, Asif K, Firdaus, Shagufta RC

    2013-04-01

    Full Text Available Breast involvement by leukemic infiltration is usually bilateral, but may be unilateral. Clinically patients can present with either single or multiple masses, or with diffuse breast engorgement, with or without nodularity. The affected patients are predominantly young adults. We present a case of an adolescent girl with acute myeloid leukemia having bilateral breast infiltration by leukemic cells.

  3. [Hypercalcemia of T-cell leukemia in adults].

    Science.gov (United States)

    Jean-Baptiste, G; Arfi, S; Plumelle, Y; Panelatti, G; Mangin, J L; Pascaline, N

    1993-04-01

    A retrospective study of 26 adults with acute T-cell leukemia showed that 14 patients (54%) had hypercalcemia at some point of the disease. Hypercalcemia was found at presentation in nine patients and revealed the disease in one. Eight patients had hypercalcemia at the time of death. Serum phosphorus and parathyroid hormone levels were normal. All patients with hypercalcemia tested positive for the HTLV-1 by Elisa and Western blot. Six patients had focalized or diffuse lytic roentgenographic bone lesions. Hypercalcemia in acute T-cell leukemia may involve production of interleukin-1-alpha and parathyroid hormone-related protein by HTLV-1-infected cells. PMID:8167627

  4. MiR-146b negatively regulates migration and delays progression of T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Correia, Nádia C; Fragoso, Rita; Carvalho, Tânia; Enguita, Francisco J; Barata, João T

    2016-01-01

    Previous results indicated that miR-146b-5p is downregulated by TAL1, a transcription factor critical for early hematopoiesis that is frequently overexpressed in T-cell acute lymphoblastic leukemia (T-ALL) where it has an oncogenic role. Here, we confirmed that miR-146b-5p expression is lower in TAL1-positive patient samples than in other T-ALL cases. Furthermore, leukemia T-cells display decreased levels of miR-146b-5p as compared to normal T-cells, thymocytes and other hematopoietic progenitors. MiR-146b-5p silencing enhances the in vitro migration and invasion of T-ALL cells, associated with increased levels of filamentous actin and chemokinesis. In vivo, miR-146b overexpression in a TAL1-positive cell line extends mouse survival in a xenotransplant model of human T-ALL. In contrast, knockdown of miR-146b-5p results in leukemia acceleration and decreased mouse overall survival, paralleled by faster tumor infiltration of the central nervous system. Our results suggest that miR-146b-5p is a functionally relevant microRNA gene in the context of T-ALL, whose negative regulation by TAL1 and possibly other oncogenes contributes to disease progression by modulating leukemia cell motility and disease aggressiveness. PMID:27550837

  5. [Novelties in the diagnostics and therapy of hairy cell leukemia].

    Science.gov (United States)

    Sári, Eszter; Rajnai, Hajnalka; Dénes, Kitti; Bödör, Csaba; Csomor, Judit; Körösmezey, Gábor; Tárkányi, Ilona; Eid, Hanna; Nagy, Zsolt; Demeter, Judit

    2016-06-01

    Differential diagnosis of hairy cell leukemia (HCL) and related disorders (hairy cell leukemia variant and splenic marginal zone lymphoma) is of utmost importance since the treatment and prognosis of these lymphomas differ. Since 2011 diagnosis of hairy cell leukemia has been easier because of discovery of the disease defining somatic mutation BRAF V600E mutation, which has been also known as driver mutation in malignant melanoma. The presence of this mutation enabled targeted molecular therapy in HCL as well. As first line therapy purine nucleoside analogues are the gold standard, but refractory/relapsed patient are candidates for targeted BRAF-inhibitor therapy. This manuscript serves as guidance in making diagnosis and standard treatment of HCL, and summarizes newest data about molecular therapy, including our single center experience collected from 75 patients. PMID:27275640

  6. RAGE regulates immune cell infiltration and angiogenesis in choroidal neovascularization.

    Directory of Open Access Journals (Sweden)

    Mei Chen

    Full Text Available PURPOSE: RAGE regulates pro-inflammatory responses in diverse cells and tissues. This study has investigated if RAGE plays a role in immune cell mobilization and choroidal neovascular pathology that is associated with the neovascular form of age-related macular degeneration (nvAMD. METHODS: RAGE null (RAGE-/- mice and age-matched wild type (WT control mice underwent laser photocoagulation to generate choroidal neovascularization (CNV lesions which were then analyzed for morphology, S100B immunoreactivity and inflammatory cell infiltration. The chemotactic ability of bone marrow derived macrophages (BMDMs towards S100B was investigated. RESULTS: RAGE expression was significantly increased in the retina during CNV of WT mice (p<0.001. RAGE-/- mice exhibited significantly reduced CNV lesion size when compared to WT controls (p<0.05. S100B mRNA was upregulated in the lasered WT retina but not RAGE-/- retina and S100B immunoreactivity was present within CNV lesions although levels were less when RAGE-/- mice were compared to WT controls. Activated microglia in lesions were considerably less abundant in RAGE-/- mice when compared to WT counterparts (p<0.001. A dose dependent chemotactic migration was observed in BMDMs from WT mice (p<0.05-0.01 but this was not apparent in cells isolated from RAGE-/- mice. CONCLUSIONS: RAGE-S100B interactions appear to play an important role in CNV lesion formation by regulating pro-inflammatory and angiogenic responses. This study highlights the role of RAGE in inflammation-mediated outer retinal pathology.

  7. Acute respiratory failure in 3 children with juvenile myelomonocytic leukemia

    DEFF Research Database (Denmark)

    Gustafsson, Britt; Hellebostad, Marit; Ifversen, Marianne;

    2011-01-01

    Juvenile myelomonocytic leukemia is a rare hematopoietic stem cell disease in children with features of both myelodysplasia and myeloproliferation. Extramedullary involvement has been reported and pulmonary involvement secondary to leukemic infiltration is an initial manifestation, which may result...

  8. Acute Respiratory Failure in 3 Children With Juvenile Myelomonocytic Leukemia

    DEFF Research Database (Denmark)

    Gustafsson, Britt; Hellebostad, Marit; Ifversen, Marianne;

    2011-01-01

    Juvenile myelomonocytic leukemia is a rare hematopoietic stem cell disease in children with features of both myelodysplasia and myeloproliferation. Extramedullary involvement has been reported and pulmonary involvement secondary to leukemic infiltration is an initial manifestation, which may result...

  9. Benign mast cell hyperplasia and atypical mast cell infiltrates in penile lichen planus in adult men.

    Science.gov (United States)

    Regauer, Sigrid; Beham-Schmid, Christine

    2014-08-01

    Introduction. Lichen planus (LP) is a chronic cytokine-mediated disease of possible auto-immune etiology. 25% of men have anogenital manifestations. Erosive penile LP causes a scarring phimosis of the foreskin in uncircumcised men. Mast cells as potent immune modulators have been implicated in a number of autoimmune and chronic inflammatory diseases, but have not been investigated in LP. Material and Methods. Formalin-fixed tissues of 117 circumcision specimens of adult men affected by LP were evaluated for the extent of mast cell and lymphocyte infiltrates, characterized immunohistochemically with antibodies to CD 3, 4, 8, 20, 21, 25, 30, 117c and human mast cell tryptase. Specimens with dense mast cell infiltrates were analyzed for point mutations of the c-kit gene (D816V). Results. Unaffected skin and modified mucosa of foreskins contained ⟨5 mast cells/mm². The inflammatory infiltrate of LP-lesions displayed ⟨15 mast cells/mm² in 33/117 foreskins, 16-40 mast cells/mm² in 22/117 and ⟩40 mast cells/mm² (average 70, range 40-100) in 62/117 foreskins. Lesional mast cells of 29/117 (24%) foreskins showed aberrant CD25-expression and/or spindled morphology, with 11/29 men having erosive LP, 13/29 a lymphocytic vasculitis and 1/28 a systemic mastocytosis. Neither CD30-expression nor c-kit mutations were identified. Atypical mast cell infiltrates in LP correlated with high disease activity, erosive LP and presence of lymphocytic vasculitis Conclusions. Increased mast cells in penile LP, mostly representing a benign hyperplasia/activation syndrome, suggests them as targets for innovative therapy options for symptomatic LP-patients not responding to corticosteroid therapy. Presently, the biological implications of atypical mast cell infiltrates in penile LP are unknown. PMID:24402730

  10. CD8+ Tumor-Infiltrating T Cells Are Trapped in the Tumor-Dendritic Cell Network

    Directory of Open Access Journals (Sweden)

    Alexandre Boissonnas

    2013-01-01

    Full Text Available Chemotherapy enhances the antitumor adaptive immune T cell response, but the immunosuppressive tumor environment often dominates, resulting in cancer relapse. Antigen-presenting cells such as tumor-associated macrophages (TAMs and tumor dendritic cells (TuDCs are the main protagonists of tumor-infiltrating lymphocyte (TIL immuno-suppression. TAMs have been widely investigated and are associated with poor prognosis, but the immuno-suppressive activity of TuDCs is less well understood. We performed two-photon imaging of the tumor tissue to examine the spatiotemporal interactions between TILs and TuDCs after chemotherapy. In a strongly immuno-suppressive murine tumor model, cyclophosphamide-mediated chemotherapy transiently enhanced the antitumor activity of adoptively transferred ovalbumin-specific CD8+ T cell receptor transgenic T cells (OTI but barely affected TuDC compartment within the tumor. Time lapse imaging of living tumor tissue showed that TuDCs are organized as a mesh with dynamic interconnections. Once infiltrated into the tumor parenchyma, OTI T cells make antigen-specific and long-lasting contacts with TuDCs. Extensive analysis of TIL infiltration on histologic section revealed that after chemotherapy the majority of OTI T cells interact with TuDCs and that infiltration is restricted to TuDC-rich areas. We propose that the TuDC network exerts antigen-dependent unproductive retention that trap T cells and limit their antitumor effectiveness.

  11. Identification and targeting leukemia stem cells: The path to the cure for acute myeloid leukemia

    Institute of Scientific and Technical Information of China (English)

    Jianbiao; Zhou; Wee-Joo; Chng

    2014-01-01

    Accumulating evidence support the notion that acute myeloid leukemia(AML) is organized in a hierarchical system, originating from a special proportion of leukemia stem cells(LSC). Similar to their normal counterpart, hematopoietic stem cells(HSC), LSC possess selfrenewal capacity and are responsible for the continued growth and proliferation of the bulk of leukemia cells in the blood and bone marrow. It is believed that LSC are also the root cause for the treatment failure and relapse of AML because LSC are often resistant to chemotherapy. In the past decade, we have made significant advancement in identification and understanding the molecular biology of LSC, but it remains a daunting task to specifically targeting LSC, while sparing normalHSC. In this review, we will first provide a historical overview of the discovery of LSC, followed by a summary of identification and separation of LSC by either cell surface markers or functional assays. Next, the review will focus on the current, various strategies for eradicating LSC. Finally, we will highlight future directions and challenges ahead of our ultimate goal for the cure of AML by targeting LSC.

  12. Cordycepin Regulates GSK-3β/β-Catenin Signaling in Human Leukemia Cells

    OpenAIRE

    Ko, Bor-Sheng; Lu, Yi-Jhu; Yao, Wen-Ling; Liu, Tzu-An; Tzean, Shean-Shong; Shen, Tang-Long; Liou, Jun-Yang

    2013-01-01

    Background Leukemia stem cells (LSCs) are a limitless cell source for the initiation and maintenance of leukemia. Activation of the Wnt/β-catenin pathway is required for the survival and development of LSCs. Therefore, targeting β-catenin is considered a therapeutic strategy for the treatment of leukemia. The goal of this study was to explore whether cordycepin, an active component of the traditional medicine Cordyceps sinensis, regulates β-catenin expression in leukemia cells. Methodology an...

  13. Advanced Data Mining of Leukemia Cells Micro-Arrays

    Directory of Open Access Journals (Sweden)

    Ryan M. Pierce

    2009-12-01

    Full Text Available This paper provides continuation and extensions of previous research by Segall and Pierce (2009a that discussed data mining for micro-array databases of Leukemia cells for primarily self-organized maps (SOM. As Segall and Pierce (2009a and Segall and Pierce (2009b the results of applying data mining are shown and discussed for the data categories of microarray databases of HL60, Jurkat, NB4 and U937 Leukemia cells that are also described in this article. First, a background section is provided on the work of others pertaining to the applications of data mining to micro-array databases of Leukemia cells and micro-array databases in general. As noted in predecessor article by Segall and Pierce (2009a, micro-array databases are one of the most popular functional genomics tools in use today. This research in this paper is intended to use advanced data mining technologies for better interpretations and knowledge discovery as generated by the patterns of gene expressions of HL60, Jurkat, NB4 and U937 Leukemia cells. The advanced data mining performed entailed using other data mining tools such as cubic clustering criterion, variable importance rankings, decision trees, and more detailed examinations of data mining statistics and study of other self-organized maps (SOM clustering regions of workspace as generated by SAS Enterprise Miner version 4. Conclusions and future directions of the research are also presented.

  14. IFN-γ promotes graft-versus-leukemia effects without directly interacting with leukemia cells in mice after allogeneic hematopoietic cell transplantation

    OpenAIRE

    Yang, Yanping; Wang, Hui; Yu, Hui; Yeap, Beow Yong; Liang, Tingting; Wang, Guanjun; Cheng, Tao; Yang, Yong-Guang

    2011-01-01

    The ability of IFN-γ to enhance graft-versus-leukemia (GVL) activity without direct interaction with leukemia cells was examined by comparing GVL effects against IFN-γ receptor-deficient (GRKO) leukemia between wild-type (WT) and IFN-γ–deficient (GKO) allogeneic hematopoietic cell transplantation (allo-HCT). We established a primary IFN-γ–unresponsive T-cell leukemia model using virally-transduced GRKO B6 mouse bone marrow cells overexpressing Notch1. We first assessed GVL effects in lethally...

  15. NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells

    NARCIS (Netherlands)

    S.W. Paugh (Steven); E.J. Bonten (Erik J.); D. Savic (Daniel); L.B. Ramsey (Laura B.); W.E. Thierfelder (William E.); P. Gurung (Prajwal); R.K.S. Malireddi (R. K. Subbarao); M. Actis (Marcelo); A. Mayasundari (Anand); J. Min (Jaeki); D.R. Coss (David R.); L.T. Laudermilk (Lucas T.); J.C. Panetta (John); J.R. McCorkle (J. Robert); Y. Fan (Yiping); K.R. Crews (Kristine R.); G. Stocco (Gabriele); M.R. Wilkinson (Mark R.); A.M. Ferreira (Antonio M.); C. Cheng (Cheng); W. Yang (Wenjian); S.E. Karol (Seth E.); C.A. Fernandez (Christian A.); B. Diouf (Barthelemy); C. Smith (Colton); J.K. Hicks (J Kevin); A. Zanut (Alessandra); A. Giordanengo (Audrey); D.J. Crona; J.J. Bianchi (Joy J.); L. Holmfeldt (Linda); C.G. Mullighan (Charles); M.L. den Boer (Monique); R. Pieters (Rob); S. Jeha (Sima); T.L. Dunwell (Thomas L.); F. Latif (Farida); D. Bhojwani (Deepa); W.L. Carroll (William L.); C.-H. Pui (Ching-Hon); R.M. Myers (Richard M.); R.K. Guy (R Kiplin); T.-D. Kanneganti (Thirumala-Devi); M.V. Relling (Mary); W.E. Evans (William)

    2015-01-01

    textabstractGlucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and resistance to glucocorticoids in leukemia cells confers poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia ce

  16. Childhood Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. It is the most common type of childhood cancer. ... blood cells help your body fight infection. In leukemia, the bone marrow produces abnormal white blood cells. ...

  17. Serological analysis of cell surface antigens of null cell acute lymphocytic leukemia by mouse monoclonal antibodies.

    OpenAIRE

    Ueda, R; Tanimoto, M; Takahashi, T.; Ogata, S; Nishida, K; Namikawa, R.; Nishizuka, Y; Ota, K.

    1982-01-01

    Nine antigens systems were defined. Two were related to HLA-A,B,C and to Ia-like antigens; the others could be grouped into three categories. (i) NL-22, NL-1: NL-22 antibody reacted with leukemia cells from 12 to 16 cases of null cell acute lymphocytic leukemia (null-ALL) but not with any other type of leukemia tested or with lymphoid cells of various origins. Among cultured cell lines tested, one (NALM-6) of three null-ALL cell lines was positive, the others were negative. Absorption analysi...

  18. Cell surface antigens of radiation leukemia virus-induced BALB/c leukemias defined by syngeneic cytotoxic T lymphocytes

    International Nuclear Information System (INIS)

    Two cell surface antigens of mouse leukemias were defined by BALB/c cytotoxic T lymphocytes (CTL) generated against syngeneic radiation leukemia virus (RadLV)-induced leukemia, BALBRV1 or BALBRVD. Hyperimmunization of BALB/c mice with irradiated leukemias followed by in vitro sensitization of primed spleen cells resulted in the generation of CTL with high killing activity. The specificity of CTL was examined by direct cytotoxicity assays and competitive inhibition assays. A shared cell surface antigen, designated as BALBRV1 antigen, was detected by BALB/c anti-BALBRV1 CTL. BALBRV1 antigen was expressed not only on RadLV-induced BALB/c leukemias except for BALBRVD, but also on spontaneous or X-ray-induced BALB/c leukemias, chemically-induced leukemias with the H-2d haplotype and some chemically-induced BALB/c sarcomas. In contrast, a unique cell surface antigen, designated as BALBRVD antigen, was detected by BALB/c anti-BALBRVD CTL. BALBRVD antigen was expressed only on BALBRVD, but not on thirty-nine normal lymphoid or tumor cells. These two antigens could be distinguished from those previously defined on Friend, Moloney, Rauscher or Gross murine leukemia virus (MuLV) leukemias, or MuLV-related antigens. Both cytotoxic responses were blocked by antisera against H-2Kd, but not H-2Dd. The relationship of BALBRV1 antigen and BALBRVD antigen to endogenous MuLV is discussed with regard to the antigenic distribution on tumor cell lines. (author)

  19. Formation of infectious hybrid virions with gibbon ape leukemia virus and human T-cell leukemia virus retroviral envelope glycoproteins and the gag and pol proteins of Moloney murine leukemia virus.

    OpenAIRE

    C. Wilson; Reitz, M S; Okayama, H; Eiden, M V

    1989-01-01

    The gibbon ape leukemia virus, SEATO strain, and human T-cell leukemia virus type I envelope glycoproteins can be functionally assembled with a Moloney murine leukemia virus core into infectious particles. The envelope-host cell receptor interaction is the major determinant of the host cell specificity for these hybrid virions.

  20. Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer.

    Science.gov (United States)

    Berntsson, Jonna; Nodin, Björn; Eberhard, Jakob; Micke, Patrick; Jirström, Karin

    2016-09-01

    Multiple studies have described associations between infiltrating immune cells and prognosis in cancer; however, the clinical relevance has most often been attributed to the T-cell linage. This study aimed to further investigate the clinicopathological correlates and prognostic impact of B cell and plasma cell infiltration in CRC. Immunohistochemical expression of CD20, CD138 and immunoglobulin kappa C (IGKC) was analysed in tissue microarrays with tumours from 557 incident cases of CRC from a prospective population-based cohort. Kaplan-Meier analysis and Cox regression analysis were used to determine the impact of CD20, CD138 and IGKC expression on 5-year overall survival. Immune cell-specific CD20, CD138, and IGKC expression correlated significantly with lower T-stage (p stage, differentiation grade and vascular invasion (HR = 0.51; 95% CI 0.33-0.80). Immune cell-specific CD138 and IGKC expression correlated significantly with an improved OS in univariable Cox regression analysis; however, these associations did not remain significant in multivariable analysis. Finally, tumour cell-specific CD138 expression was found to be an independent factor of poor prognosis (HR 1.52; 95% CI 1.03-2.24). The results from the present study demonstrate that B cell infiltration in CRC has a significant impact on tumour progression and prognosis. These findings supplement and extend the current knowledge of the immune landscape in colorectal cancer, and merit further study. PMID:27074317

  1. HIGH EFFICIENCY RETROVIRUS-MEDIATED GENE TRANSFER TO LEUKEMIA CELLS

    Institute of Scientific and Technical Information of China (English)

    FU Jian-xin; CHEN Zi-xing; CEN Jian-nong; WANG Wei; RUAN Chang-geng

    1999-01-01

    Objective: To establish an efficient and safe gene transfer system mediated by retrovirus for gene marking and gene therapy of human leukemia. Method: The retroviral vector LXSN, containing the neomycin resistance (NeoR) gene, was transferred into amphotropic packaging cells GP+envAm12 by liposome transfection or by ecotropic retrovirus transduction. Amphotropic retrovirus in supernatants with higher titer was used to infect human leukemic cell lines NB4, U937, and THP-1.The efficiency of gene transfer was assayed on colonies formed by transduced K562 cells. Results: The titer of DOSPER directly transfected GP+envAm12 cells determined on NIH3T3 cells was 8.0×105 CFU/ml, while that of producer infected with retrovirus was 1.6×107CFU/ml. Integration of NeoR gene into all leukemia cells was confirmed by polymerase chain reaction (PCR).Absence of replication-competent virus was proved by both nested PCR for env gene and marker gene rescue assay. Gene transfer with the efficiency as high as 93.3 to 100% in K562 cells was verified by seminested PCR for integrated NeoR gene on colonies after 7 days' culture.Conclusion: The efficiency and safety of retrovirus mediated gene transfer system might provide an optimal system in gene therapy for leukemia or genetic diseases.

  2. Oncogenic Kras initiates leukemia in hematopoietic stem cells.

    OpenAIRE

    Amit J Sabnis; Cheung, Laurene S.; Monique Dail; Hio Chung Kang; Marianne Santaguida; Hermiston, Michelle L.; Emmanuelle Passegué; Kevin Shannon; Braun, Benjamin S.

    2009-01-01

    Author Summary Ras proteins act as molecular switches that relay growth signals from outside the cell. This mechanism is often subverted in cancer, and Ras proteins are activated directly by RAS gene mutations in approximately one-third of human malignancies. We have modeled this in mice engineered to have a Ras mutation. These mice develop a disease similar to chronic leukemias in humans called myeloproliferative disorders. It is marked by a fatal accumulation of mature and immature cells in...

  3. Oncogenic Kras Initiates Leukemia in Hematopoietic Stem Cells

    OpenAIRE

    Sabnis, Amit J; Cheung, Laurene S.; Dail, Monique; Kang, Hio Chung; Santaguida, Marianne; Hermiston, Michelle L.; Passegué, Emmanuelle; Shannon, Kevin; Braun, Benjamin S.

    2009-01-01

    Author Summary Ras proteins act as molecular switches that relay growth signals from outside the cell. This mechanism is often subverted in cancer, and Ras proteins are activated directly by RAS gene mutations in approximately one-third of human malignancies. We have modeled this in mice engineered to have a Ras mutation. These mice develop a disease similar to chronic leukemias in humans called myeloproliferative disorders. It is marked by a fatal accumulation of mature and immature cells in...

  4. Mantle cell leukemia as a cause of leukostasis

    Directory of Open Access Journals (Sweden)

    Rappaport E

    2011-04-01

    Full Text Available Daniel Smith1, Christian Cable2, Cary Chisholm1, Walter Linz1, William Koss1, Sheila Dobin1, Edward Rappaport11Department of Pathology, 2Internal Medicine, Scott and White Healthcare/Texas A & M Health Science Center College of Medicine, Temple, TX, USAAbstract: A 72-year-old man was admitted with hypoxemic respiratory distress. Given a white blood cell count of 600 × 109/L and symptoms of leukostasis, emergency leukapheresis was initiated. The white blood cell count immediately after the first leukapheresis was paradoxically increased to over 700 × 109/L. Peripheral blood smear findings showed morphologically immature mononuclear cells and numerous circulating mitotic figures. Initial flow cytometry results showed a lambda light chain-restricted B lymphoid population positive for CD20, CD19, CD5, and FMC-7, and negative for TdT, CD10, CD23, CD34, CD117, and myeloid markers, suggesting classification as a blastoid variant of mantle cell lymphoma in a leukemic phase. Subsequent testing using DNA fluorescence in situ hybridization was positive for t(11;14, confirming the diagnosis of mantle cell leukemia. Although mantle cell lymphoma occasionally transforms or can even present as leukemia (leukocytes >40 × 109/L, it is rare for it to present with such profound leukocytosis and an overwhelming number of pleomorphic/blastoid forms. Although morphology suggested acute lymphoblastic leukemia, a more specific diagnosis of blastoid variant mantle cell lymphoma was obtained in 12 hours by applying complementary techniques of flow cytometry and rapid cytogenetics.Keywords: mantle cell lymphoma, chemotherapy, leukapheresis, lymphocytic leukemia

  5. Cannabinoids induce incomplete maturation of cultured human leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Murison, G.; Chubb, C.B.H.; Maeda, S.; Gemmell, M.A.; Huberman, E.

    1987-08-01

    Monocyte maturation markers were induced in cultured human myeloblastic ML-2 leukemia cells after treatment for 1-6 days with 0.03-30 ..mu..M ..delta../sup 9/-tetrahydrocannabinol (THC), the major psychoactive component of marijuana. After a 2-day or longer treatment, 2- to 5-fold increases were found in the percentages of cells exhibiting reactivity with either the murine OKM1 monoclonal antibody of the Leu-M5 monoclonal antibody, staining positively for nonspecific esterase activity, and displaying a promonocyte morphology. The increases in these differentiation markers after treatment with 0.03-1 ..mu..M THC were dose dependent. At this dose range, THC did not cause an inhibition of cell growth. The THC-induced cell maturation was also characterized by specific changes in the patterns of newly synthesized proteins. The THC-induced differentiation did not, however, result in cells with a highly developed mature monocyte phenotype. However, treatment of these incompletely matured cells with either phorbol 12-myristate 13-acetate of 1..cap alpha..,25-dihydroxycholecalciferol, which are inducers of differentiation in myeloid leukemia cells (including ML-2 cells), produced cells with a mature monocyte morphology. The ML-2 cell system described here may be a useful tool for deciphering critical biochemical events that lead to the cannabinoid-induced incomplete cell differentiation of ML-2 cells and other related cell types. Findings obtained from this system may have important implications for studies of cannabinoid effects on normal human bone-marrow progenitor cells.

  6. Graft-infiltrating host dendritic cells play a key role in organ transplant rejection.

    Science.gov (United States)

    Zhuang, Quan; Liu, Quan; Divito, Sherrie J; Zeng, Qiang; Yatim, Karim M; Hughes, Andrew D; Rojas-Canales, Darling M; Nakao, A; Shufesky, William J; Williams, Amanda L; Humar, Rishab; Hoffman, Rosemary A; Shlomchik, Warren D; Oberbarnscheidt, Martin H; Lakkis, Fadi G; Morelli, Adrian E

    2016-01-01

    Successful engraftment of organ transplants has traditionally relied on preventing the activation of recipient (host) T cells. Once T-cell activation has occurred, however, stalling the rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, recipient (host) dendritic cells (DCs) play a key role in driving the rejection of transplanted organs by activated (effector) T cells. We show that donor DCs that accompany heart or kidney grafts are rapidly replaced by recipient DCs. The DCs originate from non-classical monocytes and form stable, cognate interactions with effector T cells in the graft. Eliminating recipient DCs reduces the proliferation and survival of graft-infiltrating T cells and abrogates ongoing rejection or rejection mediated by transferred effector T cells. Therefore, host DCs that infiltrate transplanted organs sustain the alloimmune response after T-cell activation has already occurred. Targeting these cells provides a means for preventing or treating rejection. PMID:27554168

  7. Heterogeneity of leukemia-initiating capacity of chronic myelogenous leukemia stem cells.

    Science.gov (United States)

    Zhang, Bin; Li, Ling; Ho, Yinwei; Li, Min; Marcucci, Guido; Tong, Wei; Bhatia, Ravi

    2016-03-01

    Chronic myelogenous leukemia (CML) results from transformation of a long-term hematopoietic stem cell (LTHSC) by expression of the BCR-ABL fusion gene. However, BCR-ABL-expressing LTHSCs are heterogeneous in their capacity as leukemic stem cells (LSCs). Although discrepancies in proliferative, self-renewal, and differentiation properties of normal LTHSCs are being increasingly recognized, the mechanisms underlying heterogeneity of leukemic LTHSCs are poorly understood. Using a CML mouse model, we identified gene expression differences between leukemic and nonleukemic LTHSCs. Expression of the thrombopoietin (THPO) receptor MPL was elevated in leukemic LTHSC populations. Compared with LTHSCs with low MPL expression, LTHSCs with high MPL expression showed enhanced JAK/STAT signaling and proliferation in response to THPO in vitro and increased leukemogenic capacity in vivo. Although both G0 and S phase subpopulations were increased in LTHSCs with high MPL expression, LSC capacity was restricted to quiescent cells. Inhibition of MPL expression in CML LTHSCs reduced THPO-induced JAK/STAT signaling and leukemogenic potential. These same phenotypes were also present in LTHSCs from patients with CML, and patient LTHSCs with high MPL expression had reduced sensitivity to BCR-ABL tyrosine kinase inhibitor treatment but increased sensitivity to JAK inhibitors. Together, our studies identify MPL expression levels as a key determinant of heterogeneous leukemia-initiating capacity and drug sensitivity of CML LTHSCs and suggest that high MPL-expressing CML stem cells are potential targets for therapy. PMID:26878174

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

    International Nuclear Information System (INIS)

    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

  9. High myeloperoxidase positive cell infiltration in colorectal cancer is an independent favorable prognostic factor.

    Directory of Open Access Journals (Sweden)

    Raoul A Droeser

    Full Text Available BACKGROUND: Colorectal cancer (CRC infiltration by adaptive immune system cells correlates with favorable prognosis. The role of the innate immune system is still debated. Here we addressed the prognostic impact of CRC infiltration by neutrophil granulocytes (NG. METHODS: A TMA including healthy mucosa and clinically annotated CRC specimens (n = 1491 was stained with MPO and CD15 specific antibodies. MPO+ and CD15+ positive immune cells were counted by three independent observers. Phenotypic profiles of CRC infiltrating MPO+ and CD15+ cells were validated by flow cytometry on cell suspensions derived from enzymatically digested surgical specimens. Survival analysis was performed by splitting randomized data in training and validation subsets. RESULTS: MPO+ and CD15+ cell infiltration were significantly correlated (p<0.0001; r = 0.76. However, only high density of MPO+ cell infiltration was associated with significantly improved survival in training (P = 0.038 and validation (P = 0.002 sets. In multivariate analysis including T and N stage, vascular invasion, tumor border configuration and microsatellite instability status, MPO+ cell infiltration proved an independent prognostic marker overall (P = 0.004; HR = 0.65; CI:±0.15 and in both training (P = 0.048 and validation (P = 0.036 sets. Flow-cytometry analysis of CRC cell suspensions derived from clinical specimens showed that while MPO+ cells were largely CD15+/CD66b+, sizeable percentages of CD15+ and CD66b+ cells were MPO-. CONCLUSIONS: High density MPO+ cell infiltration is a novel independent favorable prognostic factor in CRC.

  10. Targeting Leukemia Stem Cells in vivo with AntagomiR-126 Nanoparticles in Acute Myeloid Leukemia

    Science.gov (United States)

    Dorrance, Adrienne M.; Neviani, Paolo; Ferenchak, Greg J.; Huang, Xiaomeng; Nicolet, Deedra; Maharry, Kati S.; Ozer, Hatice G; Hoellarbauer, Pia; Khalife, Jihane; Hill, Emily B.; Yadav, Marshleen; Bolon, Brad N.; Lee, Robert J.; Lee, L.James; Croce, Carlo M.; Garzon, Ramiro; Caligiuri, Michael A.; Bloomfield, Clara D.; Marcucci., Guido

    2015-01-01

    Current treatments for acute myeloid leukemia (AML) are designed to target rapidly dividing blast populations with limited success in eradicating the functionally distinct leukemia stem cell (LSC) population, which is postulated to be responsible for disease resistance and relapse. We have previously reported high miR-126 expression levels to be associated with a LSC-gene expression profile. Therefore, we hypothesized that miR-126 contributes to “stemness” and is a viable target for eliminating the LSC in AML. Here we first validate the clinical relevance of miR-126 expression in AML by showing that higher expression of this microRNA (miR) is associated with worse outcome in a large cohort of older (≥60 years) cytogenetically normal AML patients treated with conventional chemotherapy. We then show that miR-126 overexpression characterizes AML LSC-enriched cell subpopulations and contributes to LSC long-term maintenance and self-renewal. Finally, we demonstrate the feasibility of therapeutic targeting of miR-126 in LSCs with novel targeting nanoparticles (NP) containing antagomiR-126 resulting in in vivo reduction of LSCs likely by depletion of the quiescent cell subpopulation. Our findings suggest that by targeting a single miR, i.e., miR-126, it is possible to interfere with LSC activity, thereby opening potentially novel therapeutic approaches to treat AML patients. PMID:26055302

  11. TRAIL-mediated killing of acute lymphoblastic leukemia by plasmacytoid dendritic cell-activated natural killer cells

    OpenAIRE

    Lelaidier, Martin; Dìaz-Rodriguez, Yildian; Cordeau, Martine; Cordeiro, Paulo; Haddad, Elie; Herblot, Sabine; Duval, Michel

    2015-01-01

    Acute lymphoblastic leukemia (ALL) still frequently recurs after hematopoietic stem cell transplantation (HSCT), underscoring the need to improve the graft-versus-leukemia (GvL) effect. Natural killer (NK) cells reconstitute in the first months following HSCT when leukemia burden is at its lowest, but ALL cells have been shown to be resistant to NK cell-mediated killing. We show here that this resistance is overcome by NK cell stimulation with TLR-9-activated plasmacytoid dendritic cells (pDC...

  12. Comparison of microglia and infiltrating CD11c+ cells as antigen presenting cells for T cell proliferation and cytokine response

    DEFF Research Database (Denmark)

    Wlodarczyk, Agnieszka; Løbner, Morten; Cédile, Oriane;

    2014-01-01

    BACKGROUND: Tissue-resident antigen-presenting cells (APC) exert a major influence on the local immune environment. Microglia are resident myeloid cells in the central nervous system (CNS), deriving from early post-embryonic precursors, distinct from adult hematopoietic lineages. Dendritic cells...... (DC) and macrophages infiltrate the CNS during experimental autoimmune encephalomyelitis (EAE). Microglia are not considered to be as effective APC as DC or macrophages. METHODS: In this work we compared the antigen presenting capacity of CD11c+ and CD11c- microglia subsets with infiltrating CD11c......+ APC, which include DC. The microglial subpopulations (CD11c- CD45dim CD11b+ and CD11c+ CD45dim CD11b+) as well as infiltrating CD11c+ CD45high cells were sorted from CNS of C57BL/6 mice with EAE. Sorted cells were characterised by flow cytometry for surface phenotype and by quantitative real-time PCR...

  13. Allogeneic stem cell transplantation in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Natasha Ali

    2012-11-01

    Full Text Available We report a case series of 12 patients with acute myeloid leukemia who underwent allogeneic stem cell transplant with a matched related donor. Male to female ratio was 1:1. The main complication post-transplant was graft-versus-host disease (n=7 patients. Transplant-related mortality involved one patient; cause of death was multi-organ failure. After a median follow up of 36.0±11.3 months, overall survival was 16%.

  14. RESULTS OF HEMATOPOIETIC CELL TRANSPLANTATION IN PEDIATRIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    A. Mousavi

    2008-05-01

    Full Text Available Hematopoietic cell transplantation (HCT is an accepted treatment for acute myeloid leukemia (AML in first remission, the treatment of choice for chronic myeloid leukemia (CML and high risk groups of ALL who relapse with conventional chemotherapy. We assessed results of HCT for pediatric leukemia in our center. A total of 92 children, 63 with diagnose of AML, 23 with ALL and 6 with CML received allogeneic transplantation from HLA full matched siblings (57.6% and autologous transplantation (42.4%. Source of hematopoietic cells were peripheral blood 83.7%, bone marrow 15.2% and cord blood 1.6%. The median transplanted nucleated cells were 6.4 ± 4.7 ×108 /Kg (body weight of patients and mononuclear cells were 5.5 ± 2.9×108/Kg. The most common conditioning regimens were cyclophosphamide + busulfan. Prophylaxis regimen for GVHD was cyclosporin ± methotrexate. GVHD occurred in 50 (54.3% patients. Eighty five of children had engraftment, 26 (28.6% relapsed and 57 (62% are alive. The most common cause of death was relapse (68.6%. Five years overall survival of patients with AML and ALL were 49% and 44% respectively and disease free survival of them were 52% and 49%. One year overall survival and disease free survival of CML was 57%. Overall survival increased with increasing age of patients at transplantation time (P = 0.06. Longer survival significantly related to earlier WBC and platelet recovery (P < 0.0001 and P = 0.006 respectively. Considering acceptable overall and disease free survival of patients after HCT, we concluded that is a good modality in treatment of leukemia of children.

  15. Adult T-cell lymphoma/leukemia presenting as isolated central nervous system T-cell lymphoma.

    Science.gov (United States)

    Ma, Wei-Li; Li, Chi-Cheng; Yu, Shan-Chi; Tien, Hwei-Fang

    2014-01-01

    Adult T-cell leukemia/lymphoma (ATLL) is a T-cell neoplasm, associated with infection by the retrovirus human T-lymphotropic virus type 1 (HTLV-1). Central nervous system (CNS) involved by ATLL is often occurred in advanced disease, such as acute and lymphomatous variants. On the other hand, isolated CNS lymphoma is rare. We repot a 50-year-old woman who presented with multiple infiltrative brain lesions on the magnetic resonance (MR) imaging. Results of initial biopsy of brain tumor indicated CNS vasculitis. The patient received one course of high-dose methotrexate and MR imaging of brain revealed remission of infiltrative lesions. Two years later, new brain lesions were detected. Histopathologic examination of specimens via craniotomy revealed T-cell lymphoma. The patient responded poorly to subsequent chemotherapy, and salvage whole-brain irradiation was performed. Six months later, the patient had hepatosplenomegaly, hypercalcemia, and multiple lymphocytes with a cloverleaf appearance in circulation. Results of flow cytometry analysis of peripheral blood indicated ATLL and antibodies to human T-lymphotropic virus type 1 (HTLV-1) were detected. Clinicians should screen HTLV-1 infection when patients are diagnosed with peripheral T-cell lymphoma. Combined antiviral therapy and intensive chemotherapy may improve the outcomes of ATLL. PMID:25587470

  16. Adult T-Cell Lymphoma/Leukemia Presenting as Isolated Central Nervous System T-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Wei-Li Ma

    2014-01-01

    Full Text Available Adult T-cell leukemia/lymphoma (ATLL is a T-cell neoplasm, associated with infection by the retrovirus human T-lymphotropic virus type 1 (HTLV-1. Central nervous system (CNS involved by ATLL is often occurred in advanced disease, such as acute and lymphomatous variants. On the other hand, isolated CNS lymphoma is rare. We repot a 50-year-old woman who presented with multiple infiltrative brain lesions on the magnetic resonance (MR imaging. Results of initial biopsy of brain tumor indicated CNS vasculitis. The patient received one course of high-dose methotrexate and MR imaging of brain revealed remission of infiltrative lesions. Two years later, new brain lesions were detected. Histopathologic examination of specimens via craniotomy revealed T-cell lymphoma. The patient responded poorly to subsequent chemotherapy, and salvage whole-brain irradiation was performed. Six months later, the patient had hepatosplenomegaly, hypercalcemia, and multiple lymphocytes with a cloverleaf appearance in circulation. Results of flow cytometry analysis of peripheral blood indicated ATLL and antibodies to human T-lymphotropic virus type 1 (HTLV-1 were detected. Clinicians should screen HTLV-1 infection when patients are diagnosed with peripheral T-cell lymphoma. Combined antiviral therapy and intensive chemotherapy may improve the outcomes of ATLL.

  17. B-cell leukemia/lymphoma panel

    Science.gov (United States)

    B lymphocyte cell surface markers ... sample is needed. In some cases, white blood cells are removed during a bone marrow biopsy . The ... to a laboratory, where a specialist checks the cell type and characteristics. This procedure is called immunophenotyping. ...

  18. Acute myeloid leukemia arising from a donor derived premalignant hematopoietic clone: A possible mechanism for the origin of leukemia in donor cells

    OpenAIRE

    Dickson, Mark A.; Papadopoulos, Esperanza B.; Hedvat, Cyrus V.; Jhanwar, Suresh C.; Brentjens, Renier J.

    2014-01-01

    During recent years, it has become increasingly evident that donor leukemia following allogeneic transplant may be more common then realized in the past. We identified five cases of potential donor leukemia cases during past five years. The precise mechanism of the origin of such leukemias, however, remains poorly defined. In this short communication, we report a well documented case of donor-derived de novo acute myeloid leukemia (AML) that developed fourteen years after allogeneic stem cell...

  19. Human T cell leukemia virus type 1 infection drives spontaneous proliferation of natural killer cells

    OpenAIRE

    Norris, Philip J; Hirschkorn, Dale F.; DeVita, Deborah A.; Lee, Tzong-Hae; Murphy, Eedward L

    2010-01-01

    Most human T cell leukemia virus type 1 (HTLV-1) infected subjects remain asymptomatic throughout their lives, with a few individuals developing HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T cell leukemia. Lymphocytes from about half of HTLV-1 infected subjects spontaneously proliferate in vitro, and how this phenomenon relates to symptomatic disease outcome and viral burden is poorly understood. Spontaneous proliferation was measured in lymphocyte subsets, an...

  20. Mitochondrial DNA sequence variation in single cells from leukemia patients

    OpenAIRE

    Yao, Yong-Gang; Ogasawara, Yoji; Kajigaya, Sachiko; Molldrem, Jeffrey J.; Falcão, Roberto P; Pintão, Maria-Carolina; McCoy, J. Philip; Rizzatti, Edgar Gil; Young, Neal S

    2007-01-01

    A high frequency of mtDNA somatic mutation has been observed in many tumors as well as in aging tissues. In this study, we analyzed the mtDNA control region sequence variation in 3534 single normal cells and individual blasts from 18 patients with leukemia and 10 healthy donors, to address the mutation process in leukemic cells. We found significant differences in mtDNA sequence, as represented by the number of haplotypes and the mean number of cells with each nonaggregate haplotype in a popu...

  1. 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

  2. Target cells involved in radiation and radiation leukemia virus leukemogenesis

    International Nuclear Information System (INIS)

    Comparative studies concerned with the induction and early proliferation phases of preleukemic cells in relation to host environments using radiation or radiation leukemia virus as the leukemogenic agents, indicated different developmental pathways. The lack of thymus in mice exposed to fractionated irradiation did not prevent preleukemic cell induction but did interfere with the incidence of RadLV induced preleukemic cells. Thymus removal within several days following RadLV inoculation prevented the establishment of preleukemic cells in the bone marrow. The radiation induced preleukemic cells in the bone marrow. The radiation induced preleukemic cells were not lysed by anti-Thy-1.2 serum treatment and guinea pig complement whereas the RadLV induced ones were lysed to different degrees. Elimination of Thy-1.2 bearing cells from the virus induced preleukemic population reduced the development of overt T leukemias of donor origin. The thymus seemed of essential importance for establishing the proliferation of RadLV induced preleukemic cells but not for those induced by fractionated irradiation

  3. ECM hydrogel for the treatment of stroke: Characterization of the host cell infiltrate.

    Science.gov (United States)

    Ghuman, Harmanvir; Massensini, Andre R; Donnelly, Julia; Kim, Sung-Min; Medberry, Christopher J; Badylak, Stephen F; Modo, Michel

    2016-06-01

    Brain tissue loss following stroke is irreversible with current treatment modalities. The use of an acellular extracellular matrix (ECM), formulated to produce a hydrogel in situ within the cavity formed by a stroke, was investigated as a method to replace necrotic debris and promote the infiltration of host brain cells. Based on magnetic resonance imaging measurements of lesion location and volume, different concentrations of ECM (0, 1, 2, 3, 4, 8 mg/mL) were injected at a volume equal to that of the cavity (14 days post-stroke). Retention of ECM within the cavity occurred at concentrations >3 mg/mL. A significant cell infiltration into the ECM material in the lesion cavity occurred with an average of ∼36,000 cells in the 8 mg/mL concentration within 24 h. An infiltration of cells with distances of >1500 μm into the ECM hydrogel was observed, but the majority of cells were at the tissue/hydrogel boundary. Cells were typically of a microglia, macrophage, or neural and oligodendrocyte progenitor phenotype. At the 8 mg/mL concentration, ∼60% of infiltrating cells were brain-derived phenotypes and 30% being infiltrating peripheral macrophages, polarizing toward an M2-like anti-inflammatory phenotype. These results suggest that an 8 mg/mL ECM concentration promotes a significant acute endogenous repair response that could potentially be exploited to treat stroke. PMID:27031811

  4. IGFBP7 induces apoptosis of acute myeloid leukemia cells and synergizes with chemotherapy in suppression of leukemia cell survival

    OpenAIRE

    Verhagen, H JMP; de Leeuw, D C; Roemer, M GM; Denkers, F; Pouwels, W; Rutten, A; Celie, P H; Ossenkoppele, G. J.; Schuurhuis, G. J.; Smit, L.

    2014-01-01

    Despite high remission rates after chemotherapy, only 30–40% of acute myeloid leukemia (AML) patients survive 5 years after diagnosis. This extremely poor prognosis of AML is mainly caused by treatment failure due to chemotherapy resistance. Chemotherapy resistance can be caused by various features including activation of alternative signaling pathways, evasion of cell death or activation of receptor tyrosine kinases such as the insulin growth factor-1 receptor (IGF-1R). Here we have studied ...

  5. 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.)

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

    Science.gov (United States)

    2016-04-26

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

  7. Myeloid Cell Nuclear Differentiation Antigen (MNDA) Expression Distinguishes Extramedullary Presentations of Myeloid Leukemia From Blastic Plasmacytoid Dendritic Cell Neoplasm.

    Science.gov (United States)

    Johnson, Ryan C; Kim, Jinah; Natkunam, Yasodha; Sundram, Uma; Freud, Aharon G; Gammon, Bryan; Cascio, Michael J

    2016-04-01

    Myeloid neoplasms constitute one of the most common malignancies in adults. In most cases these proliferations initially manifest in the blood and marrow; however, extramedullary involvement may precede blood or marrow involvement in a subset of cases, making a definitive diagnosis challenging by morphologic and immunohistochemical assessment alone. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive entity that frequently presents in extramedullary sites and can show morphologic and immunophenotypic overlap with myeloid neoplasms. Given that BPDCN and myeloid neoplasms may both initially present in extramedullary sites and that novel targeted therapies may be developed that exploit the unique molecular signature of BPDCN, new immunophenotypic markers that can reliably separate myeloid neoplasms from BPDCN are desirable. We evaluated the utility of myeloid cell nuclear differentiation antigen (MNDA) expression in a series of extramedullary myeloid leukemias (EMLs) and BPDCN. Forty biopsies containing EML and 19 biopsies containing BPDCN were studied by MNDA immunohistochemistry. The majority of myeloid neoplasms showed nuclear expression of MNDA (65%). In contrast, all cases of BPDCN lacked MNDA expression. These findings show that MNDA is expressed in the majority of EMLs and support the inclusion of MNDA immunohistochemistry in the diagnostic evaluation of blastic hematopoietic infiltrates, particularly when the differential diagnosis is between myeloid leukemia and BPDCN. PMID:26796502

  8. Ultraporous nanofeatured PCL-PEO microfibrous scaffolds enhance cell infiltration, colonization and myofibroblastic differentiation

    Science.gov (United States)

    Li, Yan-Fang; Gregersen, Hans; Nygaard, Jens Vinge; Cheng, Weilu; Yu, Ying; Huang, Yudong; Dong, Mingdong; Besenbacher, Flemming; Chen, Menglin

    2015-09-01

    In the field of tissue engineering, integration of micro-porosity, nano-topogaphical features and weattability into one three-dimensional (3D) scaffold remains a challenge. The extracellular matrix (ECM) mimicking feature of electrospun fibers endows them wide applications in tissue engineering. However, the tight-packing of electrospun submicron fibers hinder cell infiltration and further colonization. In this study, we fabricated hydrophilic, micro-porous scaffolds with nano-topographical cues by one-step electrospinning, and investigated NIH3T3 fibroblasts cell infiltration, colonization and myofibroblastic differentiation. The hierarchical porosity enhanced cell infiltration and proliferation significantly. Besides, the nano-topography influenced the cell actin distribution and cell morphology that stimulated myofibroblastic differentiation in a drastically different manner from that of traditional solid, smooth electrospun fibers, which may hold great potential in reconstructing tissues that require strong contractile forces.In the field of tissue engineering, integration of micro-porosity, nano-topogaphical features and weattability into one three-dimensional (3D) scaffold remains a challenge. The extracellular matrix (ECM) mimicking feature of electrospun fibers endows them wide applications in tissue engineering. However, the tight-packing of electrospun submicron fibers hinder cell infiltration and further colonization. In this study, we fabricated hydrophilic, micro-porous scaffolds with nano-topographical cues by one-step electrospinning, and investigated NIH3T3 fibroblasts cell infiltration, colonization and myofibroblastic differentiation. The hierarchical porosity enhanced cell infiltration and proliferation significantly. Besides, the nano-topography influenced the cell actin distribution and cell morphology that stimulated myofibroblastic differentiation in a drastically different manner from that of traditional solid, smooth electrospun fibers

  9. Lethal cutaneous disease in transgenic mice conditionally expressing type I human T cell leukemia virus Tax.

    Science.gov (United States)

    Kwon, Hakju; Ogle, Louise; Benitez, Bobby; Bohuslav, Jan; Montano, Mauricio; Felsher, Dean W; Greene, Warner C

    2005-10-21

    Type I human T cell leukemia virus (HTLV-I) is etiologically linked with adult T cell leukemia, an aggressive and usually fatal expansion of activated CD4+ T lymphocytes that frequently traffic to skin. T cell transformation induced by HTLV-I involves the action of the 40-kDa viral Tax transactivator protein. Tax both stimulates the HTLV-I long terminal repeat and deregulates the expression of select cellular genes by altering the activity of specific host transcription factors, including cyclic AMP-responsive element-binding protein (CREB)/activating transcription factor, NF-kappaB/Rel, and serum response factor. To study initiating events involved in HTLV-I Tax-induced T cell transformation, we generated "Tet-off" transgenic mice conditionally expressing in a lymphocyte-restricted manner (EmuSR alpha promoter-enhancer) either wild-type Tax or mutant forms of Tax that selectively compromise the NF-kappaB (M22) or CREB/activating transcription factor (M47) activation pathways. Wild-type Tax and M47 Tax-expressing mice, but not M22-Tax expressing mice, developed progressive alopecia, hyperkeratosis, and skin lesions containing profuse activated CD4 T cell infiltrates with evidence of deregulated inflammatory cytokine production. In addition, these animals displayed systemic lymphadenopathy and splenomegaly. These findings suggest that Tax-mediated activation of NF-kappaB plays a key role in the development of this aggressive skin disease that shares several features in common with the skin disease occurring during the preleukemic stage in HTLV-I-infected patients. Of note, this skin disease completely resolved when Tax transgene expression was suppressed by administration of doxycycline, emphasizing the key role played by this viral oncoprotein in the observed pathology. PMID:16105841

  10. Ethyl Pyruvate Combats Human Leukemia Cells but Spares Normal Blood Cells.

    Science.gov (United States)

    Birkenmeier, Gerd; Hemdan, Nasr Y A; Kurz, Susanne; Bigl, Marina; Pieroh, Philipp; Debebe, Tewodros; Buchold, Martin; Thieme, Rene; Wichmann, Gunnar; Dehghani, Faramarz

    2016-01-01

    Ethyl pyruvate, a known ROS scavenger and anti-inflammatory drug was found to combat leukemia cells. Tumor cell killing was achieved by concerted action of necrosis/apoptosis induction, ATP depletion, and inhibition of glycolytic and para-glycolytic enzymes. Ethyl lactate was less harmful to leukemia cells but was found to arrest cell cycle in the G0/G1 phase. Both, ethyl pyruvate and ethyl lactate were identified as new inhibitors of GSK-3β. Despite the strong effect of ethyl pyruvate on leukemia cells, human cognate blood cells were only marginally affected. The data were compiled by immune blotting, flow cytometry, enzyme activity assay and gene array analysis. Our results inform new mechanisms of ethyl pyruvate-induced cell death, offering thereby a new treatment regime with a high therapeutic window for leukemic tumors. PMID:27579985

  11. Microenvironmental cues for T-cell acute lymphoblastic leukemia development.

    Science.gov (United States)

    Passaro, Diana; Quang, Christine Tran; Ghysdael, Jacques

    2016-05-01

    Intensive chemotherapy regimens have led to a substantial improvement in the cure rate of patients suffering from T-cell acute lymphoblastic leukemia (T-ALL). Despite this progress, about 15% and 50% of pediatric and adult cases, respectively, show resistance to treatment or relapse with dismal prognosis, calling for further therapeutic investigations. T-ALL is an heterogeneous disease, which presents intrinsic alterations leading to aberrant expression of transcription factors normally involved in hematopoietic stem/progenitor cell development and mutations in genes implicated in the regulation of cell cycle progression, apoptosis, and T-cell development. Gene expression profiling allowed the classification of T-ALL into defined molecular subgroups that mostly reflects the stage of their differentiation arrest. So far this knowledge has not translated into novel, targeted therapy. Recent evidence points to the importance of extrinsic signaling cues in controlling the ability of T-ALL to home, survive, and proliferate, thus offering the perspective of new therapeutic options. This review summarizes the present understanding of the interactions between hematopoietic cells and bone marrow/thymic niches during normal hematopoiesis, describes the main signaling pathways implicated in this dialog, and finally highlights how malignant T cells rely on specific niches to maintain their ability to sustain and propagate leukemia. PMID:27088913

  12. In situ quantitation of inflammatory mononuclear cells in ductal infiltrating breast carcinoma. Relation to prognostic parameters.

    OpenAIRE

    An, T.; Sood, U.; Pietruk, T.; Cummings, G.; Hashimoto, K; Crissman, J. D.

    1987-01-01

    The authors examined inflammatory mononuclear cells in 10 fibroadenomas and 56 ductal infiltrating type carcinomas of the breast to see whether the distribution of various subpopulations of the mononuclear cells were correlated with known histologic, biochemical, and clinical parameters of the cancers. T cells, B cells, natural killer cells, and macrophages were quantitated on frozen tissue sections, which were stained with monoclonal antibodies, as demonstrated by the immunoperoxidase techni...

  13. IgG4-positive plasma cell infiltration in explanted livers for primary sclerosing cholangitis

    OpenAIRE

    Zen, Yoh; Quaglia, Alberto; Portmann, Bernard

    2011-01-01

    Abstract Aims: To explore whether IgG4-related sclerosing cholangitis (IgG4-SC) contributes to end-stage primary sclerosing cholangitis (PSC) in UK. Methods and Results: This study consisted of 41 patients who underwent liver transplantation for advanced PSC. Explanted livers were histologically examined with an emphasis on IgG4-positive plasma cell infiltration. Thirty-nine cases (95%) had minimal or mild infiltration of IgG4-positive plasma cells (? 30 cells/high power field)...

  14. Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissue

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Hansen, Ulla; Christensen, Ib Jarle;

    1999-01-01

    .0001), high age ( p=0.0003), and tumour location in the rectum predicted poor survival, while high counts of eosinophils ( p=0.006) and mast cells ( p=0.02) predicted good survival. Tumour-associated eosinophilia and mastocytosis appear to be independent prognostic variables in colorectal cancer. Future......Overall peritumoural inflammatory cell infiltration is a prognostic variable in solid tumours, but the survival-related impact of the individual cell types within the infiltrate has still not been fully evaluated and compared with the conventional disease classification. In the present study, the...

  15. Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia

    OpenAIRE

    Guenther, Matthew G.; Lawton, Lee N.; Rozovskaia, Tatiana; Frampton, Garrett M.; Levine, Stuart S.; Thomas L Volkert; Croce, Carlo M.; Nakamura, Tatsuya; Canaani, Eli; Young, Richard A.

    2008-01-01

    Mixed-lineage leukemia (MLL) fusion proteins are potent inducers of leukemia, but how these proteins generate aberrant gene expression programs is poorly understood. Here we show that the MLL-AF4 fusion protein occupies developmental regulatory genes important for hematopoietic stem cell identity and self-renewal in human leukemia cells. These MLL-AF4-bound regions have grossly altered chromatin structure, with histone modifications catalyzed by trithorax group proteins and DOT1 extending acr...

  16. Unrelated Hematopoietic Stem Cell Transplantation for Children with Acute Leukemia: Experience at a Single Institution

    OpenAIRE

    Lee, Jae Hee; Yoon, Hoi Soo; Song, Joon Sup; Choi, Eun Seok; Moon, Hyung Nam; Seo, Jong Jin; Im, Ho Joon

    2009-01-01

    We evaluate the outcomes in children with acute leukemia who received allogeneic hematopoietic stem cell transplantation (HCT) using unrelated donor. Fifty-six children in complete remission (CR) received HCT from unrelated donors between 2000 and 2007. Thirty-five had acute myeloid leukemia, and 21 had acute lymphoid leukemia. Stem cell sources included bone marrow in 38, peripheral blood in 4, and cord blood (CB) in 14. Four patients died before engraftment and 52 engrafted. Twenty patients...

  17. Characterization of xenoantiserum produced against B cell acute lymphoblastic leukemia cell line

    Directory of Open Access Journals (Sweden)

    Akagi,Tadaatsu

    1982-10-01

    Full Text Available Antiserum was produced in white rabbit by intravenously injecting living cells of a B cell acute lymphoblastic leukemia (ALL line (BALL-1. The reactivity of the antiserum against various lymphoid cell lines was examined by membrane immunofluorescence after appropriate absorption. Serum absorbed with non-T, non-B (NALL-1 and T-ALL (TALL-1 cells recognized B cell antigens distinct from Ia-like antigens on both normal and neoplastic B cells. After further absorption with tonsillar cells or normal B cell line (KO-HL-3, it reacted only with BALL-1 cells and did not react with other leukemia/lymphoma and normal B cell lines. The serum absorbed with tonsillar cells reacted only with BALL-1 and some B cell lines. Thus we were able to obtain antisera with specificity to B cell antigen, B-ALL antigen, and B cell line antigen.

  18. B-cell leukemia/lymphoma panel

    Science.gov (United States)

    ... is broken) Alternative Names B lymphocyte cell surface markers Images Blood test References Czuchlewski DR, Viswanatha DS, Larson RS. Molecular diagnosis of hematopoietic neoplasms. In: McPherson RA, Pincus ...

  19. Synthesis and Stability of a Nanoparticle-Infiltrated Solid OxideFuel Cell Electrode

    Energy Technology Data Exchange (ETDEWEB)

    Sholklapper, Tal Z.; Radmilovic, Velimir; Jacobson, Craig P.; Visco, Steven J.; De Jonghe, Lutgard C.

    2006-11-20

    Nanoparticulate catalysts infiltrated into SOFC (Solid OxideFUel Cell) electrodes can significantly enhance the cell performance, butthe stability of these electrodes has been an open issue. An infiltrationprocedure is reported that leads to a stable scandia-stablized zirconia(SSZ) cathode electrode performance.

  20. Effect of CeO2 Infiltration on Hybrid Direct Carbon Fuel Cell Performance

    DEFF Research Database (Denmark)

    Ippolito, Davide; Deleebeeck, Lisa; Kammer Hansen, Kent

    2014-01-01

    The effect of CeO2 infiltration into the anode or CeO2 mixed with the carbon-fuel on the performance of a Hybrid Direct Carbon Fuel Cell (HDCFC) was studied through the use of polarization curves and electrochemical impedance spectroscopy. The use CeO2 in both ways helped to increase the cell...

  1. Characterization of xenoantiserum produced against B cell acute lymphoblastic leukemia cell line

    OpenAIRE

    Akagi,Tadaatsu; Sonobe, Hiroshi; Miyoshi, Isao; Yoshimoto,Shizuo

    1982-01-01

    Antiserum was produced in white rabbit by intravenously injecting living cells of a B cell acute lymphoblastic leukemia (ALL) line (BALL-1). The reactivity of the antiserum against various lymphoid cell lines was examined by membrane immunofluorescence after appropriate absorption. Serum absorbed with non-T, non-B (NALL-1) and T-ALL (TALL-1) cells recognized B cell antigens distinct from Ia-like antigens on both normal and neoplastic B cells. After further absorption with tonsillar cells or n...

  2. Analysis of Vδ1 T cells in clinical grade melanoma-infiltrating lymphocytes

    DEFF Research Database (Denmark)

    Donia, Marco; Ellebaek, Eva; Andersen, Mads Hald;

    2012-01-01

    . In this study, we have detected low frequencies of Vδ1 T cells among tumor-infiltrating lymphocyte (TIL) products for adoptive cell transfer generated from melanoma metastases. An increased frequency of Vδ1 T cells was found among the cell products from patients with an advanced disease stage. Vδ1 T cells...... displayed in vitro antitumor activities and sufficient proliferative potential to generate over 1 × 10(9) cells using current protocols for T cell transfer. Infusion of Vδ1 T cells together with high numbers of αβ TILs in a clinical trial was safe and well tolerated. These data suggest that Vδ1 T cells...

  3. IGF binding protein 2 is a cell-autonomous factor supporting survival and migration of acute leukemia cells

    OpenAIRE

    Chen, Xiaoli; Zheng, Junke; Zou, Yizhou; Song, Chun; Hu, Xuemei; Zhang, Cheng Cheng

    2013-01-01

    Background The role of IGF binding protein 2 (IGFBP2) in cancer development is intriguing. Previously we identified IGFBP2 as an extrinsic factor that supports the activity of hematopoietic stem cells (HSCs). Methods and results Here we investigated the role of IGFBP2 in in human leukemia cells and in the retroviral AML1-ETO9a transplantation acute myeloid leukemia (AML) mouse model. Results IGFBP2 is highly expressed in certain human AML and acute lymphoblastic leukemia (ALL) cells. Inhibiti...

  4. Aberrant Expression of Functional BAFF-System Receptors by Malignant B-Cell Precursors Impacts Leukemia Cell Survival

    OpenAIRE

    Maia, Sara; Pelletier, Marc; Ding, Jixin; Hsu, Yen-Ming; Rao, Sambasiva P.; Cardoso, Angelo A.; Sallan, Stephen Earl; Nadler, Lee Marshall

    2011-01-01

    Despite exhibiting oncogenic events, patient's leukemia cells are responsive and dependent on signals from their malignant bone marrow (BM) microenvironment, which modulate their survival, cell cycle progression, trafficking and resistance to chemotherapy. Identification of the signaling pathways mediating this leukemia/microenvironment interplay is critical for the development of novel molecular targeted therapies. We observed that primary leukemia B-cell precursors aberrantly express recept...

  5. Disseminated necrotizing leukoencephalopathy following irradiation and methotrexate therapy for central nervous system infiltration of leukemia and lymphoma

    International Nuclear Information System (INIS)

    The authors report four adult patients with disseminated necrotizing leukoencephalopathy (DNL) following therapy for central nervous system (CNS) involvement of leukemia and lymphoma. Five to fourteen months after starting therapy with 30.6-62.5 Gy of whole brain irradiation and 120-500 mg of intrathecal methotrexate (MTX), DNL developed. Brain CT scans demonstrated a characteristic symmetrical white matter low density area. Furthermore, the brain CT scans disclosed tumorous lesions with contrast enhancement in three cases. In two of the three cases autopsy proved the tumorous lesions to be necrotic foci but not leukemic tumors. Post-mortem neuropathological studies of three patients disclosed characteristic features of DNL: multiple coagulative necrosis in the white matter with myelin degeneration, swollen axons, prominent calcification, and enlarged reactive astrocytes. Three of the four patients obviously received greater doses of whole brain irradiation and intrathecal MTX than patients who remained free from DNL after treatment with whole brain irradiation and/or MTX. Analysis of the etiological factors in this series underscores the prevailing danger of treatment of neoplastic CNS involvement with excessive doses of whole brain irradiation combined with intrathecal MTX. (author)

  6. CD117 expression on blast cells in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Goryainova N.V.

    2015-09-01

    Full Text Available The aim of the present work was to analyze the frequency of CD117 (c-KIT antigen expression on the blast cells in acute myeloid leukemia (AML, evaluation of the presence of the relationship between the expression of the c-KIT and leukemia according to the FAB classification and definition of co-expression of the antigen CD117, antigens CD33 and CD34. The data of 47 patients with AML were diagnosed. M0 AML variant was established in 3 (6% patients, M1 – in 2 (4%, M2 – in 9 (20%, M4 – in 22 (47% and M5 – in 11 (23%. For immunophenotypic stu¬dies monoclonal antibodies (mAb that detect antigens of anti-CD34, anti-CD33 and anti-CD117 (Becton Dickinson, USA were used. The presence of the antigen CD117 was detected in 39 people, accounting for 83% of all surveyed. Antigen c-KIT was present in 48.117.0% cells on average: in all 3 cases – AML M0, in2 cases of AML M1, in 6 cases – AML M2, 20 of 22 cases – AML M4 and in 8 of 11 AML M5 cases. Average levels of CD117 in investigated leukemia cases statistically differed significantly (p=0.0067. Among 39 CD117- positive patients in 25 (53% co-expression of CD117+/CD34+ was revealed. Expression of CD117+/CD34- was observed in 14 cases (30%, CD117-/CD34+ – in 4 cases (8,5%, CD117-/CD34- – in 4 cases (8.5%. CD34 had of 64% of cells of myeloid origin. A high positive cor¬relation between expression of CD117 and CD34 (r=+0,5169 was determined, being statistically significant (p0,0067.

  7. Blocking p55PIK signaling inhibits proliferation and induces differentiation of leukemia cells.

    Science.gov (United States)

    Wang, G; Deng, Y; Cao, X; Lai, S; Tong, Y; Luo, X; Feng, Y; Xia, X; Gong, J; Hu, J

    2012-11-01

    p55PIK, a regulatory subunit of phosphatidylinositol 3-kinases, promotes cell cycle progression by interacting with cell cycle modulators such as retinoblastoma protein (Rb) via its unique amino-terminal 24 amino-acid residue (N24). Overexpression of N24 specifically inhibits these interactions and leads to cell cycle arrest. Herein, we describe the generation of a fusion protein (Tat transactivator protein (TAT)-N24) that contains the protein transduction domain and N24, and examined its effects on the proliferation and differentiation of leukemia cells. TAT-N24 not only blocks cell proliferation but remarkably induces differentiation of leukemia cells in vitro and in vivo. Systemically administered TAT-N24 also significantly decreases growth of leukemia cell tumors in animal models. Furthermore, overexpression of p55PIK in leukemia cells leads to increased proliferation; however, TAT-N24 blocks this effect and concomitantly induces differentiation. There is significant upregulation of p55PIK mRNA and protein expression in leukemia cells from patients. TAT-N24 inhibits cell cycle progression and induces differentiation of bone marrow cells derived from patients with several different types of leukemia. These results show that cell-permeable N24 peptide induces leukemia cell differentiation and suggest that p55PIK may be a novel drug target for the treatment of hematopoetic malignancies. PMID:22722333

  8. Abacavir, an anti–HIV-1 drug, targets TDP1-deficient adult T cell leukemia

    OpenAIRE

    Tada, Kohei; Kobayashi, Masayuki; Takiuchi, Yoko; Iwai, Fumie; Sakamoto, Takashi; Nagata, Kayoko; Shinohara, Masanobu; Io, Katsuhiro; Shirakawa, Kotaro; Hishizawa, Masakatsu; Shindo, Keisuke; Kadowaki, Norimitsu; Hirota, Kouji; Yamamoto, Junpei; Iwai, Shigenori

    2015-01-01

    Adult T cell leukemia (ATL) is an aggressive T cell malignancy caused by human T cell leukemia virus type 1 (HTLV-1) and has a poor prognosis. We analyzed the cytotoxic effects of various nucleoside analog reverse transcriptase inhibitors (NRTIs) for HIV-1 on ATL cells and found that abacavir potently and selectively kills ATL cells. Although NRTIs have minimal genotoxicities on host cells, the therapeutic concentration of abacavir induced numerous DNA double-strand breaks (DSBs) in the chrom...

  9. Advanced lymphoblastic clones detection in T-cell leukemia.

    Science.gov (United States)

    Minervina, A A; Komkov, A Y; Mamedov, I Z; Lebedev, Y B

    2016-03-01

    T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant neoplasm of the lymphocyte precursors that suffered malignant transformation arresting the lymphoid cell differentiation. Clinical studies revealed monoor, more rarely, oligoclonal nature of the disease. A precise identification of malignant clone markers is both the crucial stage of early diagnostics and the essential prognostic factor for therapeutic treatment. Here we present an improved system for unbiased detection of lymphoblastic clones in bone marrow aspirates of T-ALL patients. The system based on multiplex PCR of rearranged T-cell receptor locus (TRB) and straightforward sequencing of the resulted PCR fragments. Testing of the system on genomic DNA from Jurkat cell line and four clinical bone marrow aspirates revealed a set of unique TRB rearrangements that precisely characterize each of tested samples. Therefore, the outcome of the system produces highly informative molecular genetic markers for further monitoring of minimal residual disease in T-ALL patients. PMID:27193704

  10. Patient-individualized CD8⁺ cytolytic T-cell therapy effectively combats minimal residual leukemia in immunodeficient mice.

    Science.gov (United States)

    Distler, Eva; Albrecht, Jana; Brunk, Ariane; Khan, Shamsul; Schnürer, Elke; Frey, Michaela; Mottok, Anja; Jordán-Garrote, Ana-Laura; Brede, Christian; Beilhack, Andreas; Mades, Andreas; Tomsitz, Dirk; Theobald, Matthias; Herr, Wolfgang; Hartwig, Udo F

    2016-03-01

    Adoptive transfer of donor-derived cytolytic T-lymphocytes (CTL) has evolved as a promising strategy to improve graft-versus-leukemia (GvL) effects in allogeneic hematopoietic stem-cell transplantation. However, durable clinical responses are often hampered by limited capability of transferred T cells to establish effective and sustained antitumor immunity in vivo. We therefore analyzed GvL responses of acute myeloid leukemia (AML)-reactive CD8(+) CTL with central and effector memory phenotype in a new allogeneic donor-patient specific humanized mouse model. CTL lines and clones obtained upon stimulation of naive CD45RA(+) donor CD8(+) T cells with either single HLA antigen-mismatched or HLA-matched primary AML blasts, respectively, elicited strong leukemia reactivity during cytokine-optimized short to intermediate (i.e., 2-8 weeks) culture periods. Single doses of CTL were intravenously infused into NOD/scidIL2Rcg(null) mice when engraftment with patient AML reached bone marrow infiltration of 1-5%, clinically defining minimal residual disease status. This treatment resulted in complete regression of HLA-mismatched and strong reduction of HLA-matched AML infiltration, respectively. Most importantly, mice receiving AML-reactive CTL showed significantly prolonged survival. Transferred CTL were detectable in murine bone marrow and spleen and demonstrated sustained AML-reactivity ex vivo. Moreover, injections with human IL-15 clearly promoted CTL persistence. In summary, we show that naive donor-derived CD8(+) CTL effectively combat patient AML blasts in immunodeficient mice. The donor-patient specific humanized mouse model appears suitable to evaluate therapeutic efficacy of AML-reactive CTL before adoptive transfer into patients. It may further help to identify powerful leukemia rejection antigens and T-cell receptors for redirecting immunity to leukemias even in a patient-individualized manner. PMID:26376181

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

    Science.gov (United States)

    2016-07-29

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

  12. Arginase-1 is expressed exclusively by infiltrating myeloid cells in CNS injury and disease.

    Science.gov (United States)

    Greenhalgh, Andrew D; Passos Dos Santos, Rosmarini; Zarruk, Juan Guillermo; Salmon, Christopher K; Kroner, Antje; David, Samuel

    2016-08-01

    Resident microglia and infiltrating myeloid cells play important roles in the onset, propagation, and resolution of inflammation in central nervous system (CNS) injury and disease. Identifying cell type-specific mechanisms will help to appropriately target interventions for tissue repair. Arginase-1 (Arg-1) is a well characterised modulator of tissue repair and its expression correlates with recovery after CNS injury. Here we assessed the cellular localisation of Arg-1 in two models of CNS damage. Using microglia specific antibodies, P2ry12 and Fc receptor-like S (FCRLS), we show the LysM-EGFP reporter mouse is an excellent model to distinguish infiltrating myeloid cells from resident microglia. We show that Arg-1 is expressed exclusively in infiltrating myeloid cells but not microglia in models of spinal cord injury (SCI) and experimental autoimmune encephalomyelitis (EAE). Our in vitro studies suggest that factors in the CNS environment prevent expression of Arg-1 in microglia in vivo. This work suggests different functional roles for these cells in CNS injury and repair and shows that such repair pathways can be switched on in infiltrating myeloid cells in pro-inflammatory environments. PMID:27126514

  13. Current status of haploidentical stem cell transplantation for leukemia

    Directory of Open Access Journals (Sweden)

    Huang Xiao-jun

    2008-12-01

    Full Text Available Abstract Haploidentical hematopoietic stem cell transplantation has made tremendous progress over the past 20 years and has become a feasible option for leukemia patients without a HLA identical sibling donor. The early complications of severe graft-versus-host disease (GVHD, graft failure and delayed engraftment, as well as disease recurrence have limited the use of this approach. Newer strategies have been applied and overcome some of the problems, including the use of T-cell depleted graft, "mega" dose of stem cells, intensive post-transplant immunosuppression and manipulation of the graft. These have decreased the transplant related mortality and GVHD associated with haploidentical transplantation, however, the major problems of disease relapse and infection, which related to late immune reconstitution, limit the development of haploidentical HSCT. Future challenges remain in improving post-transplant immune reconstitution and finding the best approach to reduce the incidence and severity of GVHD, while preserving graft-versus-leukemia effect to prevent the recurrence of underlying malignancy.

  14. Development of a Test Cell to Evaluate Embankment Infiltration

    International Nuclear Information System (INIS)

    Envirocare of Utah, Inc. (Envirocare) has developed and constructed a test pad to evaluate potential infiltration through the designed cover system over the low-level radioactive waste disposal embankments incorporated at the facility. The general design of the test pad follows the recommendations set forth in the Alternative Cover Assessment Program (ACAP) that is currently funded by the U.S. Environmental Protection Agency (EPA) to assess potential alternatives to conventional landfill cover designs. The bulk of the test pad is below grade with dimensions approximately 16 feet wide by 28 feet long. The base of the test pad is a lysimeter built to the same dimensions as compliance lysimeters within the disposal embankments at Envirocare. The lysimeter collects all liquids to a single low point and directs the liquids through monitoring instruments within a manhole outside the test pad. The lysimeter is constructed to simulate the ''top of waste'' condition in Envirocare's embankments; consequently, the top of the lysimeter is sloped at an angle of approximately 2.8 percent, the design top slope of the embankment. A replica of the embankment cover is constructed directly above the lysimeter. This cover is constructed exactly the same as final cover is constructed upon the waste disposal embankments, utilizing the same QA/QC measures. Permanent monitoring equipment has been placed during construction at specific intervals throughout the test pad. Monitoring equipment consists of water content reflectometers (WCRs), matric water potential sensors (heat dissipation units; HDUs), and temperature probes. The monitoring equipment provides cross-sectional data of the moisture content and temperatures throughout the constructed cover. Additionally, surface water runoff is collected through a drainage trough and measured in order to perform a water balance over the entire test pad. To aid in the assessment, data collected from the site meteorological stat ion will be used

  15. Development of a Test Cell to Evaluate Embankment Infiltration

    Energy Technology Data Exchange (ETDEWEB)

    Orton, T. L.

    2002-02-25

    Envirocare of Utah, Inc. (Envirocare) has developed and constructed a test pad to evaluate potential infiltration through the designed cover system over the low-level radioactive waste disposal embankments incorporated at the facility. The general design of the test pad follows the recommendations set forth in the Alternative Cover Assessment Program (ACAP) that is currently funded by the U.S. Environmental Protection Agency (EPA) to assess potential alternatives to conventional landfill cover designs. The bulk of the test pad is below grade with dimensions approximately 16 feet wide by 28 feet long. The base of the test pad is a lysimeter built to the same dimensions as compliance lysimeters within the disposal embankments at Envirocare. The lysimeter collects all liquids to a single low point and directs the liquids through monitoring instruments within a manhole outside the test pad. The lysimeter is constructed to simulate the ''top of waste'' condition in Envirocare's embankments; consequently, the top of the lysimeter is sloped at an angle of approximately 2.8 percent, the design top slope of the embankment. A replica of the embankment cover is constructed directly above the lysimeter. This cover is constructed exactly the same as final cover is constructed upon the waste disposal embankments, utilizing the same QA/QC measures. Permanent monitoring equipment has been placed during construction at specific intervals throughout the test pad. Monitoring equipment consists of water content reflectometers (WCRs), matric water potential sensors (heat dissipation units; HDUs), and temperature probes. The monitoring equipment provides cross-sectional data of the moisture content and temperatures throughout the constructed cover. Additionally, surface water runoff is collected through a drainage trough and measured in order to perform a water balance over the entire test pad. To aid in the assessment, data collected from the site

  16. Nature of the inflammatory cell infiltrate in duodenitis.

    OpenAIRE

    M. Hasan; Hay, F; Sircus, W; Ferguson, A.

    1983-01-01

    Counts of lamina propria and intraepithelial cells, lymphoid and polymorphonuclear, have been performed on semithin sections of endoscopic biopsies from the duodenum of patients with ulcer-associated duodenitis, with non-specific duodenitis, and from controls. In both types of duodenitis there were significant increases in lamina propria counts of plasma cells, lymphocytes and eosinophils, and in intraepithelial lymphocyte counts, when compared with controls. In control specimens, neutrophil ...

  17. Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissue

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Hansen, Ulla; Christensen, Ib Jarle;

    1999-01-01

    prognostic value of individual white cell counts in the peritumoural inflammatory infiltrate in colorectal cancer was assessed. Intra-operative tumour tissue samples from 584 patients undergoing elective surgery for colorectal cancer were included. None of the patients received pre- or post......-operative adjuvant chemotherapy. Tissue blocks were cut from the periphery of the tumours and embedded in paraffin. All blocks included both tumour tissue and normal bowel tissue. Serial sections of 4 microm were analysed for tumour tissue inflammatory cell infiltration using a computer- and video......-assisted microscope, which allowed semi-automated quantification of cells within a fixed area. Total white cells and individual counts of eosinophils, neutrophils, mast cells, lymphocytes, and plasma cells were evaluated in every tumour specimen. Stratification into four groups with similar numbers of events was used...

  18. Assessment of Tumor Cells in a Mouse Model of Diffuse Infiltrative Glioma by Raman Spectroscopy

    Directory of Open Access Journals (Sweden)

    Kuniaki Tanahashi

    2014-01-01

    Full Text Available Glioma of infiltrative nature is challenging for surgeons to achieve tumor-specific and maximal resection. Raman spectroscopy provides structural information on the targeted materials as vibrational shifts. We utilized Raman spectroscopy to distinguish invasive tumors from normal tissues. Spectra obtained from replication-competent avian sarcoma-(RCAS- based infiltrative glioma cells and glioma tissues (resembling low-grade human glioma were compared with those obtained from normal mouse astrocytes and normal tissues. In cell analysis, the spectra at 950–1000, 1030, 1050–1100, 1120–1130, 1120–1200, 1200–1300, 1300–1350, and 1450 cm−1 were significantly higher in infiltrative glioma cells than in normal astrocytes. In brain tissue analysis, the spectra at 1030, 1050–1100, and 1200–1300 cm−1 were significantly higher in infiltrative glioma tissues than in normal brain tissues. These spectra reflect the structures of proteins, lipids, and DNA content. The sensitivity and specificity to predict glioma cells by distinguishing normal cells were 98.3% and 75.0%, respectively. Principal component analysis elucidated the significance of spectral difference between tumor tissues and normal tissues. It is possible to distinguish invasive tumors from normal tissues by using Raman spectroscopy.

  19. Cordycepin regulates GSK-3β/β-catenin signaling in human leukemia cells.

    Directory of Open Access Journals (Sweden)

    Bor-Sheng Ko

    Full Text Available BACKGROUND: Leukemia stem cells (LSCs are a limitless cell source for the initiation and maintenance of leukemia. Activation of the Wnt/β-catenin pathway is required for the survival and development of LSCs. Therefore, targeting β-catenin is considered a therapeutic strategy for the treatment of leukemia. The goal of this study was to explore whether cordycepin, an active component of the traditional medicine Cordyceps sinensis, regulates β-catenin expression in leukemia cells. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we found that cordycepin significantly suppressed cell proliferation in all malignant cancer cells, including U937, K562, A549, HepG2, SK-Hep1 and MCF7 in a dose-dependent manner. However, cordycepin reduced β-catenin levels in U937, K562 and THP1 leukemia cells and had no effect on other solid cancer cells. In addition, treatment with cordycepin significantly suppressed leukemia colony formation in soft agar assay. Cordycepin enhanced proteasome-dependent degradation and inhibited nuclear translocation of β-catenin in leukemia cells. Cordycepin-reduced β-catenin stability was restored by the addition of a pharmacological inhibitor of GSK-3β, indicating that cordycepin-suppressed β-catenin stability is mediated by the activation of GSK-3β. Furthermore, cordycepin abolished the effect of Wnt3a-induced β-catenin in leukemia cells. In addition, cordycepin-impaired β-catenin is regulated by Akt activation but is not significantly influenced by AMPK or mTOR signal pathways. SIGNIFICANCE: Our findings show for the first time that codycepin selectively reduces β-catenin stability in leukemia but not in other solid tumor cells. This suppressive effect is mediated by regulating GSK-3β. A synergistic combination of cordycepin with other treatments should be used as a novel strategy to eradicate leukemia via elimination of LSCs.

  20. Reducing the serine availability complements the inhibition of the glutamine metabolism to block leukemia cell growth

    Science.gov (United States)

    Polet, Florence; Corbet, Cyril; Pinto, Adan; Rubio, Laila Illan; Martherus, Ruben; Bol, Vanesa; Drozak, Xavier; Grégoire, Vincent; Riant, Olivier; Feron, Olivier

    2016-01-01

    Leukemia cells are described as a prototype of glucose-consuming cells with a high turnover rate. The role of glutamine in fueling the tricarboxylic acid cycle of leukemia cells was however recently identified confirming its status of major anaplerotic precursor in solid tumors. Here we examined whether glutamine metabolism could represent a therapeutic target in leukemia cells and whether resistance to this strategy could arise. We found that glutamine deprivation inhibited leukemia cell growth but also led to a glucose-independent adaptation maintaining cell survival. A proteomic study revealed that glutamine withdrawal induced the upregulation of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT), two enzymes of the serine pathway. We further documented that both exogenous and endogenous serine were critical for leukemia cell growth and contributed to cell regrowth following glutamine deprivation. Increase in oxidative stress upon inhibition of glutamine metabolism was identified as the trigger of the upregulation of PHGDH. Finally, we showed that PHGDH silencing in vitro and the use of serine-free diet in vivo inhibited leukemia cell growth, an effect further increased when glutamine metabolism was blocked. In conclusion, this study identified serine as a key pro-survival actor that needs to be handled to sensitize leukemia cells to glutamine-targeting modalities. PMID:26625201

  1. 3 Tesla proton MRI for the diagnosis of pneumonia/lung infiltrates in neutropenic patients with acute myeloid leukemia: Initial results in comparison to HRCT

    International Nuclear Information System (INIS)

    Purpose: To evaluate the diagnostic accuracy of 3 Tesla proton MRI for the assessment of pneumonia/lung infiltrates in neutropenic patients with acute myeloid leukemia. Material and methods: In a prospective study, 3 Tesla MRI was performed in 19 febrile neutropenic patients (5 women, 14 men; mean age 61 years ± 14.2; range 23–77 years). All patients underwent high-resolution CT less than 24 h prior to MRI. The MRI protocol (Magnetom Tim Trio, Siemens) included a T2-weighted HASTE sequence (TE/TR: 49 ms/∞, slice thickness 6 mm) and a high-resolution 3D VIBE sequence with an ultra-short TE < 1 ms (TE/TR 0.8/2.9 ms, slice thickness 2 mm). The VIBE sequence was examined before and after intravenous injection of 0.1 mmol/kg gadoterate meglumine (Dotarem, Guerbet). The presence of pulmonary abnormalities, their location within the lung, and lesion type (nodules, consolidations, glass opacity areas) were analyzed by one reader and compared to the findings of HRCT, which was evaluated by a second independent radiologist who served as the reference standard. The findings were compared per lobe in each patient and rated as true positive (TP) findings if all three characteristics (presence, location, and lesion type) listed above were concordant to HRCT. Results: Pulmonary abnormalities were characterized by 3 Tesla MRI with a sensitivity of 82.3% and a specificity of 78.6%, resulting in an overall accuracy of 88% (NPV/PPV 66.7%/89.5%). In 51 lobes (19 of 19 patients), pulmonary abnormalities visualized by MR were judged to be concordant in their location and in the lesion type identified by both readers. In 22 lobes (11 of 19 patients), no abnormalities were present on either MR or HRCT (true negative). In 6 lobes (5 of 19 patients), ground glass opacity areas were detected on MRI but were not visible on HRCT (false positives). In 11 lobes (7 of 19 patients), MRI failed to detect ground glass opacity areas identified by HRCT. However, since the abnormalities were

  2. 3 Tesla proton MRI for the diagnosis of pneumonia/lung infiltrates in neutropenic patients with acute myeloid leukemia: Initial results in comparison to HRCT

    Energy Technology Data Exchange (ETDEWEB)

    Attenberger, U.I., E-mail: ulrike.attenberger@umm.de [Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim (Germany); Morelli, J.N. [Scott and White Hospital, Texas A and M Health Sciences Center, Temple (United States); Henzler, T. [Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim (Germany); Buchheidt, D. [Department of Hematology and Oncology, University Medical Center Mannheim (Germany); Fink, C. [Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim (Germany); Department of Radiology, AKH Celle, Celle (Germany); Schoenberg, S.O.; Reichert, M. [Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim (Germany)

    2014-01-15

    Purpose: To evaluate the diagnostic accuracy of 3 Tesla proton MRI for the assessment of pneumonia/lung infiltrates in neutropenic patients with acute myeloid leukemia. Material and methods: In a prospective study, 3 Tesla MRI was performed in 19 febrile neutropenic patients (5 women, 14 men; mean age 61 years ± 14.2; range 23–77 years). All patients underwent high-resolution CT less than 24 h prior to MRI. The MRI protocol (Magnetom Tim Trio, Siemens) included a T2-weighted HASTE sequence (TE/TR: 49 ms/∞, slice thickness 6 mm) and a high-resolution 3D VIBE sequence with an ultra-short TE < 1 ms (TE/TR 0.8/2.9 ms, slice thickness 2 mm). The VIBE sequence was examined before and after intravenous injection of 0.1 mmol/kg gadoterate meglumine (Dotarem, Guerbet). The presence of pulmonary abnormalities, their location within the lung, and lesion type (nodules, consolidations, glass opacity areas) were analyzed by one reader and compared to the findings of HRCT, which was evaluated by a second independent radiologist who served as the reference standard. The findings were compared per lobe in each patient and rated as true positive (TP) findings if all three characteristics (presence, location, and lesion type) listed above were concordant to HRCT. Results: Pulmonary abnormalities were characterized by 3 Tesla MRI with a sensitivity of 82.3% and a specificity of 78.6%, resulting in an overall accuracy of 88% (NPV/PPV 66.7%/89.5%). In 51 lobes (19 of 19 patients), pulmonary abnormalities visualized by MR were judged to be concordant in their location and in the lesion type identified by both readers. In 22 lobes (11 of 19 patients), no abnormalities were present on either MR or HRCT (true negative). In 6 lobes (5 of 19 patients), ground glass opacity areas were detected on MRI but were not visible on HRCT (false positives). In 11 lobes (7 of 19 patients), MRI failed to detect ground glass opacity areas identified by HRCT. However, since the abnormalities were

  3. Prognostic significance of cell surface phenotype in acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Shiek Aejaz Aziz

    2015-01-01

    Full Text Available Context: To find out the phenotypic character of lymphoblasts of acute lymphoblastic leukemia (ALL patients in our study cohort and their possible effect on the prognosis. Aims: To investigate the phenotype in ALL in our demographic population and to prognosticate various upfront current protocols employed in our hospital. Settings and Design: The study spanned over a period of 4 years with retrospective and prospective data of January 2008 through December 2011. Materials and Methods: 159 patients of all age groups were enrolled for the study, of which flow cytometry was done in 144 patients. Statistical Analysis Used: Analysis was done using the variables on SPSS (statistical package for social sciences software on computer. Survival curves were estimated by method of Kaplan-Meir. Results: Majority of the patients were of B-cell (68.1% and 30.6% patients were of T-cell lineage. Of these, 80.6% patients were having cALLa positivity. Complete remission (CR was achieved in 59.1%, 16.4% relapsed, and 20.1% patients died. Conclusions: Phenotyping has become an important and integral part of diagnosis, classification, management and prognosticating in ALL. B-cell has been found to have a better survival over T-cell lymphoblastic leukemia. cALLa antigen positivity has good impact in achieving CR in only B-cell lineage, myeloid coexpression has no significant effect on the outcome. BFM (Berlin-Frankfurt-Münster based protocols though showed a higher CR and survival vis-a-vis UKALL-XII. However, patients enrolled in former group being of low risk category and lesser in numbers cannot be compared statistically with a fair degree of confidence.

  4. Thermal aging stability of infiltrated solid oxide fuel cell electrode microstructures: A three-dimensional kinetic Monte Carlo simulation

    Science.gov (United States)

    Zhang, Yanxiang; Ni, Meng; Yan, Mufu; Chen, Fanglin

    2015-12-01

    Nanostructured electrodes are widely used for low temperature solid oxide fuel cells, due to their remarkably high activity. However, the industrial applications of the infiltrated electrodes are hindered by the durability issues, such as the microstructure stability against thermal aging. Few strategies are available to overcome this challenge due to the limited knowledge about the coarsening kinetics of the infiltrated electrodes and how the potentially important factors affect the stability. In this work, the generic thermal aging kinetics of the three-dimensional microstructures of the infiltrate electrodes is investigated by a kinetic Monte Carlo simulation model considering surface diffusion mechanism. Effects of temperature, infiltration loading, wettability, and electrode configuration are studied and the key geometric parameters are calculated such as the infiltrate particle size, the total and percolated quantities of three-phase boundary length and infiltrate surface area, and the tortuosity factor of infiltrate network. Through parametric study, several strategies to improve the thermal aging stability are proposed.

  5. BK K+ channel blockade inhibits radiation-induced migration/brain infiltration of glioblastoma cells.

    Science.gov (United States)

    Edalat, Lena; Stegen, Benjamin; Klumpp, Lukas; Haehl, Erik; Schilbach, Karin; Lukowski, Robert; Kühnle, Matthias; Bernhardt, Günther; Buschauer, Armin; Zips, Daniel; Ruth, Peter; Huber, Stephan M

    2016-03-22

    Infiltration of the brain by glioblastoma cells reportedly requires Ca2+ signals and BK K+ channels that program and drive glioblastoma cell migration, respectively. Ionizing radiation (IR) has been shown to induce expression of the chemokine SDF-1, to alter the Ca2+ signaling, and to stimulate cell migration of glioblastoma cells. Here, we quantified fractionated IR-induced migration/brain infiltration of human glioblastoma cells in vitro and in an orthotopic mouse model and analyzed the role of SDF-1/CXCR4 signaling and BK channels. To this end, the radiation-induced migratory phenotypes of human T98G and far-red fluorescent U-87MG-Katushka glioblastoma cells were characterized by mRNA and protein expression, fura-2 Ca2+ imaging, BK patch-clamp recording and transfilter migration assay. In addition, U-87MG-Katushka cells were grown to solid glioblastomas in the right hemispheres of immunocompromised mice, fractionated irradiated (6 MV photons) with 5 × 0 or 5 × 2 Gy, and SDF-1, CXCR4, and BK protein expression by the tumor as well as glioblastoma brain infiltration was analyzed in dependence on BK channel targeting by systemic paxilline application concomitant to IR. As a result, IR stimulated SDF-1 signaling and induced migration of glioblastoma cells in vitro and in vivo. Importantly, paxilline blocked IR-induced migration in vivo. Collectively, our data demonstrate that fractionated IR of glioblastoma stimulates and BK K+ channel targeting mitigates migration and brain infiltration of glioblastoma cells in vivo. This suggests that BK channel targeting might represent a novel approach to overcome radiation-induced spreading of malignant brain tumors during radiotherapy. PMID:26893360

  6. Retinoic acid. Inhibition of the clonal growth of human myeloid leukemia cells.

    OpenAIRE

    Douer, D; Koeffler, H P

    1982-01-01

    Vitamin A and its analogues (retinoids) affect normal and malignant hematopoietic cells. We examined the effect of retinoids on the clonal growth in vitro of myeloid leukemia cells. Retinoic acid inhibited the clonal growth of the KG-1, acute myeloblastic leukemia, and the HL-60, acute promyelocytic leukemia, human cell lines. The KG-1 cells were extremely sensitive to retinoic acid, with 50% of the colonies inhibited by 2.4-nM concentrations of the drug. A 50% growth inhibition of HL-60 was ...

  7. Aptamer-Functionalized Fluorescent Silica Nanoparticles for Highly Sensitive Detection of Leukemia Cells

    Science.gov (United States)

    Tan, Juntao; Yang, Nuo; Hu, Zixi; Su, Jing; Zhong, Jianhong; Yang, Yang; Yu, Yating; Zhu, Jianmeng; Xue, Dabin; Huang, Yingying; Lai, Zongqiang; Huang, Yong; Lu, Xiaoling; Zhao, Yongxiang

    2016-06-01

    A simple, highly sensitive method to detect leukemia cells has been developed based on aptamer-modified fluorescent silica nanoparticles (FSNPs). In this strategy, the amine-labeled Sgc8 aptamer was conjugated to carboxyl-modified FSNPs via amide coupling between amino and carboxyl groups. Sensitivity and specificity of Sgc8-FSNPs were assessed using flow cytometry and fluorescence microscopy. These results showed that Sgc8-FSNPs detected leukemia cells with high sensitivity and specificity. Aptamer-modified FSNPs hold promise for sensitive and specific detection of leukemia cells. Changing the aptamer may allow the FSNPs to detect other types of cancer cells.

  8. Aptamer-Functionalized Fluorescent Silica Nanoparticles for Highly Sensitive Detection of Leukemia Cells.

    Science.gov (United States)

    Tan, Juntao; Yang, Nuo; Hu, Zixi; Su, Jing; Zhong, Jianhong; Yang, Yang; Yu, Yating; Zhu, Jianmeng; Xue, Dabin; Huang, Yingying; Lai, Zongqiang; Huang, Yong; Lu, Xiaoling; Zhao, Yongxiang

    2016-12-01

    A simple, highly sensitive method to detect leukemia cells has been developed based on aptamer-modified fluorescent silica nanoparticles (FSNPs). In this strategy, the amine-labeled Sgc8 aptamer was conjugated to carboxyl-modified FSNPs via amide coupling between amino and carboxyl groups. Sensitivity and specificity of Sgc8-FSNPs were assessed using flow cytometry and fluorescence microscopy. These results showed that Sgc8-FSNPs detected leukemia cells with high sensitivity and specificity. Aptamer-modified FSNPs hold promise for sensitive and specific detection of leukemia cells. Changing the aptamer may allow the FSNPs to detect other types of cancer cells. PMID:27299653

  9. A rare case of plasma cell leukemia in a 35 year old

    OpenAIRE

    Dosi, Rupal V; Annirudh Ambaliya; Patell, Rushad D.; Harshal J Joshi

    2010-01-01

    Plasma cell leukemia is a rare, aggressive form of multiple myeloma. A 35-year-old male presented with backache, generalized weakness, and facial puffiness. His complete blood count showed anemia and a high WBC count with atypical cells on peripheral smear. Bone marrow examination showed more than 90% of atypical plasma cells, confirming a diagnosis of plasma cell leukemia. Patient also had azotemia, hypercalcemia, and hyperuricemia. The patient was started on chemotherapy along with supporti...

  10. The expression of PML in chronic myeloid leukemia and effect on cell proliferation

    Institute of Scientific and Technical Information of China (English)

    吴洁

    2013-01-01

    Objective To investigate whether PML is expressed differently in chronic myeloid leukemia (CML) patients and healthy controls,then explore the effect of PML on proliferation in leukemia cell lines K562.Methods Realtime PCR was used to detect the PML expression in

  11. Tumor infiltrating lymphocyte therapy for ovarian cancer and renal cell carcinoma

    DEFF Research Database (Denmark)

    Andersen, Rikke; Donia, Marco; Westergaard, Marie Christine Wulff;

    2015-01-01

    expressed by the patients' tumors and that the presence of these "neo-antigen" specific T-cells may be related to a high number of mutations in the tumor. In melanoma, treatment with autologous tumor-infiltrating lymphocytes (TILs) can mediate durable complete responses. Previous trials investigating TIL...... therapy in solid tumors other than melanoma have shown limited success, however none of these early trials used current preparative chemotherapy regimens, and the methods for in vitro lymphocyte expansion have changed considerably. New advances and understandings in T cell based immunotherapies have...... stimulated the interest in developing this approach for other indications. Here, we summarize the early clinical data in the field of adoptive cell transfer therapy (ACT) using tumor-infiltrating lymphocytes for patients with renal cell carcinoma (RCC) and ovarian cancer (OC). In addition we describe the...

  12. Enhanced microglial clearance of myelin debris in T cell-infiltrated central nervous system

    DEFF Research Database (Denmark)

    Nielsen, Helle Hvilsted; Ladeby, Rune; Fenger, Christina;

    2009-01-01

    Acute multiple sclerosis lesions are characterized by accumulation of T cells and macrophages, destruction of myelin and oligodendrocytes, and axonal damage. There is, however, limited information on neuroimmune interactions distal to sites of axonal damage in the T cell-infiltrated central nervous...... system. We investigated T-cell infiltration, myelin clearance, microglial activation, and phagocytic activity distal to sites of axonal transection through analysis of the perforant pathway deafferented dentate gyrus in SJL mice that had received T cells specific for myelin basic protein (TMBP) or...... with TMBP but not TOVA enhanced the microglial response to axonal transection and microglial phagocytosis of myelin debris associated with the degenerating axons. Because myelin antigen-specific immune responses may provoke protective immunity, increased phagocytosis of myelin debris might enhance...

  13. What Is Chronic Myeloid Leukemia?

    Science.gov (United States)

    ... leukemia? Next Topic Normal bone marrow and blood What is chronic myeloid leukemia? Cancer starts when cells ... their treatment is the same as for adults. What is leukemia? Leukemia is a cancer that starts ...

  14. Current and emerging treatment options for hairy cell leukemia

    Directory of Open Access Journals (Sweden)

    López-Rubio M

    2015-08-01

    Full Text Available Montserrat López-Rubio,1 Jose Antonio Garcia-Marco2 1Department of Hematology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, 2Department of Hematology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain Abstract: Hairy cell leukemia (HCL is a lymphoproliferative B-cell disorder characterized by pancytopenia, splenomegaly, and characteristic cytoplasmic hairy projections. Precise diagnosis is essential in order to differentiate classic forms from HCL variants, such as the HCL-variant and VH4-34 molecular variant, which are more resistant to available treatments. The current standard of care is treatment with purine analogs (PAs, such as cladribine or pentostatin, which provide a high rate of long-lasting clinical remissions. Nevertheless, ~30%–40% of the patients relapse, and moreover, some of these are difficult-to-treat refractory cases. The use of the monoclonal antibody rituximab in combination with PA appears to produce even higher responses, and it is often employed to minimize or eliminate residual disease. Currently, research in the field of HCL is focused on identifying novel therapeutic targets and potential agents that are safe and can universally cure the disease. The discovery of the BRAF mutation and progress in understanding the biology of the disease has enabled the scientific community to explore new therapeutic targets. Ongoing clinical trials are assessing various treatment strategies such as the combination of PA and anti-CD20 monoclonal antibodies, recombinant immunotoxins targeting CD22, BRAF inhibitors, and B-cell receptor signal inhibitors. Keywords: hairy cell leukemia, purine analogs, rituximab, immunotoxins, vemurafenib, ibrutinib

  15. Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia in Adults.

    Science.gov (United States)

    Speziali, Craig; Paulson, Kristjan; Seftel, Matthew

    2016-06-01

    The majority of adults with acute lymphoblastic leukemia will achieve a first complete remission (CR). However relapse is the most common cause of treatment failure. Outcomes after relapse remain poor, with long-term survival in the order of 10 %. Treatment decisions made at the time of first complete remission are thus critical to ensuring long-term survival. Allogeneic hematopoietic cell transplant (HCT) is effective at preventing relapse in many transplant recipients but is also associated with significant treatment related morbidity and mortality. Alternatively, ongoing systemic chemotherapy offers lower toxicity at the expense of increased relapse rates. Over the past decades, both the safety of transplant and the efficacy of non-transplant chemotherapy have improved. Emerging data show substantially improved outcomes for young adults treated with pediatric-inspired chemotherapy regimens that question the role of HCT in the upfront setting. In this review, we review the data supporting the role of allogeneic transplantation in adult acute lymphoblastic leukemia (ALL), and we propose a therapeutic algorithm for upfront therapy of adults with ALL. PMID:26984203

  16. Carbon and Redox Tolerant Infiltrated Oxide Fuel-Electrodes for Solid Oxide Cells

    DEFF Research Database (Denmark)

    Skafte, Theis Løye; Sudireddy, Bhaskar Reddy; Blennow, P.;

    2016-01-01

    To solve issues of coking and redox instability related to the presence of nickel in typical fuel electrodes in solid oxide cells,Gd-doped CeO2 (CGO) electrodes were studied using symmetriccells. These electrodes showed high electro-catalytic activity, butlow electronic conductivity. When infiltr...... deposition in a CO/CO2-atmosphere, while none of the non-nickel cells catalyzed carbon.Stability towards redox cycles was also proven....

  17. Red cell ferritin and iron stores in chronic granulocytic leukemia

    International Nuclear Information System (INIS)

    Basic red cell ferritin was investigated in 28 patients with different phases of chronic granulocytic leukemia (GCL). Red cell ferritin was significantly decreased in remission after busulphan treatment and significantly elevated in the blast crisis as compared to healthy controls. Bone marrow stainable iron was decreased or absent in 86% of patients in the initial phase at the time of diagnosis and in 92% of those in remission. Red cell ferritin correlated with serum ferritin, however, serum ferritin level remained above normal range during all phases of the disease. A negative correlation between red cell ferritin and hemoglobin (Hb) (r = -0.605, p < 0.001) suggested that red cell ferritin level reflected the rate of iron utilization for heme synthesis. Decrease red cell iron observed in the remission may be explained by regression of dyserythropoiesis and by restoration of normal Hb synthesis after busulphan treatment. A progressive dyserythropoiesis in the blast crisis may lead to an increased red cell ferritin level. (author)

  18. Reprogramming of Melanoma Tumor-Infiltrating Lymphocytes to Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Hidehito Saito

    2016-01-01

    Full Text Available Induced pluripotent stem cells (iPSCs derived from somatic cells of patients hold great promise for autologous cell therapies. One of the possible applications of iPSCs is to use them as a cell source for producing autologous lymphocytes for cell-based therapy against cancer. Tumor-infiltrating lymphocytes (TILs that express programmed cell death protein-1 (PD-1 are tumor-reactive T cells, and adoptive cell therapy with autologous TILs has been found to achieve durable complete response in selected patients with metastatic melanoma. Here, we describe the derivation of human iPSCs from melanoma TILs expressing high level of PD-1 by Sendai virus-mediated transduction of the four transcription factors, OCT3/4, SOX2, KLF4, and c-MYC. TIL-derived iPSCs display embryonic stem cell-like morphology, have normal karyotype, express stem cell-specific surface antigens and pluripotency-associated transcription factors, and have the capacity to differentiate in vitro and in vivo. A wide variety of T cell receptor gene rearrangement patterns in TIL-derived iPSCs confirmed the heterogeneity of T cells infiltrating melanomas. The ability to reprogram TILs containing patient-specific tumor-reactive repertoire might allow the generation of patient- and tumor-specific polyclonal T cells for cancer immunotherapy.

  19. Establishment and genetic characterization of a novel mixed-phenotype acute leukemia cell line with EP300-ZNF384 fusion

    OpenAIRE

    Ping, Nana; Qiu, Huiying; Wang, Qian; Dai, Haiping; Ruan, Changgeng; Ehrentraut, Stefan; Drexler, Hans G.; MacLeod, Roderick A. F.; Chen, Suning

    2015-01-01

    Herein, we describe the establishment and characterization of the first mixed-phenotype acute leukemia cell line (JIH-5). The JIH-5 cell line was established from leukemia cells with B lymphoid/myeloid phenotype from a female mixed-phenotype acute leukemia patient. JIH-5 cells exhibit an immunophenotype comprised of myeloid and B lymphoid antigens. Whole-exome sequencing revealed somatic mutations in nine genes in JIH-5 cells. Transcriptional sequencing of JIH-5 cells identified EP300-ZNF384 ...

  20. Induction of neuro-protective/regenerative genes in stem cells infiltrating post-ischemic brain tissue

    Directory of Open Access Journals (Sweden)

    Yilmaz Gokhan

    2010-05-01

    Full Text Available Abstract Background- Although the therapeutic potential of bone marrow-derived stromal stem cells (BMSC has been demonstrated in different experimental models of ischemic stroke, it remains unclear how stem cells (SC induce neuroprotection following stroke. In this study, we describe a novel method for isolating BMSC that infiltrate postischemic brain tissue and use this method to identify the genes that are persistently activated or depressed in BMSC that infiltrate brain tissue following ischemic stroke. Methods- Ischemic strokes were induced in C57BL/6 mice by middle cerebral artery occlusion for 1 h, followed by reperfusion. BMSC were isolated from H-2 Kb-tsA58 (immortomouse™ mice, and were administered (i.v. 24 h after reperfusion. At the peak of therapeutic improvement (14 days after the ischemic insult, infarcted brain tissue was isolated, and the BMSC were isolated by culturing at 33°C. Microarray analysis and RT-PCR were performed to compare differential gene expression between naïve and infiltrating BMSC populations. Results- Z-scoring revealed dramatic differences in the expression of extracellular genes between naïve and infiltrating BMSC. Pair-wise analysis detected 80 extracellular factor genes that were up-regulated (≥ 2 fold, P Conclusions- BMSC infiltrating the post-ischemic brain exhibit persistent epigenetic changes in gene expression for numerous extracellular genes, compared to their naïve counterparts. These genes are relevant to the neuroprotection, regeneration and angiogenesis previously described following stem cell therapy in animal models of ischemic stroke.

  1. Prognostic relevance of RUNX1 mutations in T-cell acute lymphoblastic leukemia

    OpenAIRE

    Grossmann, Vera; Kern, Wolfgang; Harbich, Stefan; Alpermann, Tamara; Jeromin, Sabine; Schnittger, Susanne; Haferlach, Claudia; Haferlach, Torsten; Kohlmann, Alexander

    2011-01-01

    The runt-related transcription factor 1, RUNX1, is crucial in the development of myeloid and lymphoid cell lineages and has been reported to be mutated in myeloid malignancies in approximately 30% of cases. In this study, the mutational status of RUNX1 was investigated in 128 acute lymphoblastic leukemia patients. We detected a mutation rate of 18.3% (13 of 71) in patients with T-cell acute lymphoblastic leukemia, 3.8% (2 of 52) in patients with B-cell acute lymphoblastic leukemia and no muta...

  2. Acute myelogenous leukemia cells with the MLL-ELL translocation convert morphologically and functionally into adherent myofibroblasts

    International Nuclear Information System (INIS)

    Bone marrow-myofibroblasts, a major component of bone marrow-stroma, are reported to originate from hematopoietic stem cells. We show in this paper that non-adherent leukemia blasts can change into myofibroblasts. When myeloblasts from two cases of acute myelogenous leukemia with a fusion product comprising mixed lineage leukemia and RNA polymerase II elongation factor, were cultured long term, their morphology changed to that of myofibroblasts with similar molecular characteristics to the parental myeloblasts. The original leukemia blasts, when cultured on the leukemia blast-derived myofibroblasts, grew extensively. Leukemia blasts can create their own microenvironment for proliferation.

  3. Ultrasound and MR Findings of Aleukemic Leukemia Cutis in a Patient with Complete Remission of Acute Lymphoblastic Leukemia: A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Min Sung; Jee, Won Hee; Kim, Sun Ki; Lee, So Yeon; Lim, Gye Yeon; Park, Gyeong Sin; Lee, Seok [Catholic University of Korea College of Medicine, Seoul (Korea, Republic of)

    2010-12-15

    Aleukemic leukemia cutis is an extremely rare condition characterized by the infiltration of leukemic cells in skin without blasts in the peripheral blood. Leukemia cutis is considered a grave prognostic sign, thus early diagnosis is important. Leukemia cutis usually occurs in patients with myeloid leukemia. To the best of our knowledge, there has been no report regarding the radiological findings of aleukemic leukemia cutis, which is probably due to the presence of the skin changes in most patients. We report the ultrasound and MR findings of aleukemic leukemia cutis, even without the skin manifestation in patients with a history of complete remission of the acute lymphoblastic leukemia following an allogeneic peripheral blood stem cell transplantation

  4. Diagnosis of a T-lineage acute lymphoblastic leukemia through digitalized cell analysis of the pleural effusion

    Directory of Open Access Journals (Sweden)

    Peruzzi B

    2013-11-01

    Full Text Available Benedetta Peruzzi,1 Ilaria Cutini,2 Anna Maria Grazia Gelli,1 Tommaso Rondelli,1 Marinella Statello,1 Sara Bencini,2 Francesco Mannelli,2 Roberto Caporale,1 Alberto Bosi,2 Alessandra Fanelli1 1General Laboratory Unit (Microscopy and Clinical Cytometry Unit, 2Hematology Unit, Azienda Ospedaliero–Universitaria Careggi, Firenze, Italy Introduction: Pleural effusion as the first clinical manifestation of acute lymphoblastic leukemia (ALL is a relatively rare event. An early and accurate diagnosis of this clinical picture is very important for adequate patient management. Case presentation: We report the atypical onset of T-lineage ALL in a 31-year-old man. The patient was admitted to the emergency room due to lung failure; at that moment, the patient's initial blood count was normal; the chest X-ray radiography showed a massive pleural effusion and a thoracentesis was carried out. Routine investigations performed on the pleural fluid using a new technology system and digitalized cell analysis demonstrated infiltration by immature cells. Therefore, bone marrow aspirate and flow cytometry analyses were performed, leading to the diagnosis of T-lineage ALL. A cord blood transplantation procedure was performed at the first hematological remission following chemotherapy regimens. The patient died of septic shock. Conclusion: The case we reported underlines the usefulness of using automated instruments to identify abnormal lymphoid cells in body fluids. Keywords: pleural effusion, digital morphology, leukemia

  5. Myeloid-derived suppressor cells in Chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Cesarina eGiallongo

    2015-05-01

    Full Text Available The suppression of the immune system create a permissive environment for development and progression of cancer. One population of immunosuppressive cells that have become the focus of intense study is myeloid derived suppressor cells (MDSCs, immature myeloid cells able to induce immune-escape, angiogenesis and tumor progression. Two different subpopulations have been identified and studied: granulocytic and monocytic MDSCs, with a different immunophenotype and immunosuppressive properties. Recently, an accumulation of both Gr-MDSCs and Mo-MDSCs cells has been found in the peripheral blood of chronic myeloid leukemia (CML patients. They are part of the tumor clone showing BCR/ABL expression. Imatinib therapy decreases both MDSCs and arginase 1 levels to normal ones. This review will focus on actual knowledge for human MDSCs and their immunosuppressive activity in CML patients with a critical attention to comparison of Gr-MDSCs and polymorphonuclear cells (PMNs. We will then suggest the monitoring of MDSCs in patients who have discontinued tyrosine kinase inhibitors (TKIs therapy to evaluate if their increase could correlate with disease relapse.

  6. Maintenance of leukemia-initiating cells is regulated by the CDK inhibitor Inca1.

    Directory of Open Access Journals (Sweden)

    Nicole Bäumer

    Full Text Available Functional differences between healthy progenitor and cancer initiating cells may provide unique opportunities for targeted therapy approaches. Hematopoietic stem cells are tightly controlled by a network of CDK inhibitors that govern proliferation and prevent stem cell exhaustion. Loss of Inca1 led to an increased number of short-term hematopoietic stem cells in older mice, but Inca1 seems largely dispensable for normal hematopoiesis. On the other hand, Inca1-deficiency enhanced cell cycling upon cytotoxic stress and accelerated bone marrow exhaustion. Moreover, AML1-ETO9a-induced proliferation was not sustained in Inca1-deficient cells in vivo. As a consequence, leukemia induction and leukemia maintenance were severely impaired in Inca1-/- bone marrow cells. The re-initiation of leukemia was also significantly inhibited in absence of Inca1-/- in MLL-AF9- and c-myc/BCL2-positive leukemia mouse models. These findings indicate distinct functional properties of Inca1 in normal hematopoietic cells compared to leukemia initiating cells. Such functional differences might be used to design specific therapy approaches in leukemia.

  7. Perineural Infiltration of Cutaneous Squamous Cell Carcinoma and Basal Cell Carcinoma Without Clinical Features

    International Nuclear Information System (INIS)

    Purpose: To review the factors that influence outcome and patterns of relapse in patients with cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with perineural infiltration (PNI) without clinical or radiologic features, treated with surgery and radiotherapy. Methods and Materials: Between 1991 and 2004, 222 patients with SCC or BCC with PNI on pathologic examination but without clinical or radiologic PNI features were identified. Charts were reviewed retrospectively and relevant data collected. All patients were treated with curative intent; all had radiotherapy, and most had surgery. The primary endpoint was 5-year relapse-free survival from the time of diagnosis. Results: Patients with SCC did significantly worse than those with BCC (5-year relapse-free survival, 78% vs. 91%; p < 0.01). Squamous cell carcinoma with PNI at recurrence did significantly worse than de novo in terms of 5-year local failure (40% vs. 19%; p < 0.01) and regional relapse (29% vs. 5%; p < 0.01). Depth of invasion was also a significant factor. Of the PNI-specific factors for SCC, focal PNI did significantly better than more-extensive PNI, but involved nerve diameter or presence of PNI at the periphery of the tumor were not significant factors. Conclusions: Radiotherapy in conjunction with surgery offers an acceptable outcome for cutaneous SCC and BCC with PNI. This study suggests that focal PNI is not an adverse feature.

  8. Perineural Infiltration of Cutaneous Squamous Cell Carcinoma and Basal Cell Carcinoma Without Clinical Features

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Charles, E-mail: Charles_Lin@health.qld.gov.au [Cancer Care Services, Royal Brisbane and Women' s Hospital, Brisbane, Queensland (Australia); Tripcony, Lee; Keller, Jacqui [Cancer Care Services, Royal Brisbane and Women' s Hospital, Brisbane, Queensland (Australia); Poulsen, Michael [Mater Hospital, Brisbane, Queensland (Australia); Martin, Jarad [St. Andrews Hospital, Toowoomba, Queensland (Australia); Jackson, James; Dickie, Graeme [Cancer Care Services, Royal Brisbane and Women' s Hospital, Brisbane, Queensland (Australia)

    2012-01-01

    Purpose: To review the factors that influence outcome and patterns of relapse in patients with cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with perineural infiltration (PNI) without clinical or radiologic features, treated with surgery and radiotherapy. Methods and Materials: Between 1991 and 2004, 222 patients with SCC or BCC with PNI on pathologic examination but without clinical or radiologic PNI features were identified. Charts were reviewed retrospectively and relevant data collected. All patients were treated with curative intent; all had radiotherapy, and most had surgery. The primary endpoint was 5-year relapse-free survival from the time of diagnosis. Results: Patients with SCC did significantly worse than those with BCC (5-year relapse-free survival, 78% vs. 91%; p < 0.01). Squamous cell carcinoma with PNI at recurrence did significantly worse than de novo in terms of 5-year local failure (40% vs. 19%; p < 0.01) and regional relapse (29% vs. 5%; p < 0.01). Depth of invasion was also a significant factor. Of the PNI-specific factors for SCC, focal PNI did significantly better than more-extensive PNI, but involved nerve diameter or presence of PNI at the periphery of the tumor were not significant factors. Conclusions: Radiotherapy in conjunction with surgery offers an acceptable outcome for cutaneous SCC and BCC with PNI. This study suggests that focal PNI is not an adverse feature.

  9. Bone marrow niche-mediated survival of leukemia stem cells in acute myeloid leukemia: Yin and Yang

    Science.gov (United States)

    Zhou, Hong-Sheng; Carter, Bing Z.; Andreeff, Michael

    2016-01-01

    Acute myeloid leukemia (AML) is characterized by the accumulation of circulating immature blasts that exhibit uncontrolled growth, lack the ability to undergo normal differentiation, and have decreased sensitivity to apoptosis. Accumulating evidence shows the bone marrow (BM) niche is critical to the maintenance and retention of hematopoietic stem cells (HSC), including leukemia stem cells (LSC), and an increasing number of studies have demonstrated that crosstalk between LSC and the stromal cells associated with this niche greatly influences leukemia initiation, progression, and response to therapy. Undeniably, stromal cells in the BM niche provide a sanctuary in which LSC can acquire a drug-resistant phenotype and thereby evade chemotherapy-induced death. Yin and Yang, the ancient Chinese philosophical concept, vividly portrays the intricate and dynamic interactions between LSC and the BM niche. In fact, LSC-induced microenvironmental reprogramming contributes significantly to leukemogenesis. Thus, identifying the critical signaling pathways involved in these interactions will contribute to target optimization and combinatorial drug treatment strategies to overcome acquired drug resistance and prevent relapse following therapy. In this review, we describe some of the critical signaling pathways mediating BM niche-LSC interaction, including SDF1/CXCL12, Wnt/β-catenin, VCAM/VLA-4/NF-κB, CD44, and hypoxia as a newly-recognized physical determinant of resistance, and outline therapeutic strategies for overcoming these resistance factors.

  10. Influence of race on microsatellite instability and CD8+ T cell infiltration in colon cancer.

    Directory of Open Access Journals (Sweden)

    John M Carethers

    Full Text Available African American patients with colorectal cancer show higher mortality than their Caucasian counterparts. Biology might play a partial role, and prior studies suggest a higher prevalence for microsatellite instability (MSI among cancers from African Americans, albeit patients with MSI cancers have improved survival over patients with non-MSI cancers, counter to the outcome observed for African American patients. CD8+ T cell infiltration of colon cancer is postively correlated with MSI tumors, and is also related to improved outcome. Here, we utilized a 503-person, population-based colon cancer cohort comprising 45% African Americans to determine, under blinded conditions from all epidemiological data, the prevalence of MSI and associated CD8+ T cell infiltration within the cancers. Among Caucasian cancers, 14% were MSI, whereas African American cancers demonstrated 7% MSI (P = 0.009. Clinically, MSI cancers between races were similar; among microsatellite stable cancers, African American patients were younger, female, and with proximal cancers. CD8+ T cells were higher in MSI cancers (88.0 vs 30.4/hpf, P<0.0001, but was not different between races. Utilizing this population-based cohort, African American cancers show half the MSI prevalence of Caucasians without change in CD8+ T cell infiltration which may contribute towards their higher mortality from colon cancer.

  11. Ayanin diacetate-induced cell death is amplified by TRAIL in human leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Marrero, Maria Teresa; Estevez, Sara; Negrin, Gledy; Quintana, Jose [Departamento de Bioquimica, Unidad Asociada al Consejo Superior de Investigaciones Cientificas, Universidad de Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria (Spain); Lopez, Mariana; Perez, Francisco J.; Triana, Jorge [Departamento de Quimica, Universidad de Las Palmas de Gran Canaria, Instituto Canario de Investigacion del Cancer, 35017 Las Palmas de Gran Canaria (Spain); Leon, Francisco [Instituto de Productos Naturales y Agrobiologia, Consejo Superior de Investigaciones Cientificas, Avda. Astrofisico F. Sanchez 3, 38206 La Laguna, Tenerife (Spain); Estevez, Francisco, E-mail: festevez@dbbf.ulpgc.es [Departamento de Bioquimica, Unidad Asociada al Consejo Superior de Investigaciones Cientificas, Universidad de Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria (Spain)

    2012-11-09

    Highlights: Black-Right-Pointing-Pointer Ayanin diacetate as apoptotic inducer in leukemia cells. Black-Right-Pointing-Pointer Cell death was prevented by caspase inhibitors and by the overexpression of Bcl-x{sub L}. Black-Right-Pointing-Pointer The intrinsic and the extrinsic pathways are involved in the mechanism of action. Black-Right-Pointing-Pointer Death receptors are up-regulated and TRAIL enhances apoptotic cell death. -- Abstract: Here we demonstrate that the semi-synthetic flavonoid ayanin diacetate induces cell death selectively in leukemia cells without affecting the proliferation of normal lymphocytes. Incubation of human leukemia cells with ayanin diacetate induced G{sub 2}-M phase cell cycle arrest and apoptosis which was prevented by the non-specific caspase inhibitor z-VAD-fmk and reduced by the overexpression of Bcl-x{sub L}. Ayanin diacetate-induced cell death was found to be associated with: (i) loss of inner mitochondrial membrane potential, (ii) the release of cytochrome c, (iii) the activation of multiple caspases, (iv) cleavage of poly(ADP-ribose) polymerase and (v) the up-regulation of death receptors for TRAIL, DR4 and DR5. Moreover, the combined treatment with ayanin diacetate and TRAIL amplified cell death, compared to single treatments. These results provide a basis for further exploring the potential applications of this combination for the treatment of cancer.

  12. Targeting aberrant glutathione metabolism to eradicate human acute myelogenous leukemia cells.

    Science.gov (United States)

    Pei, Shanshan; Minhajuddin, Mohammad; Callahan, Kevin P; Balys, Marlene; Ashton, John M; Neering, Sarah J; Lagadinou, Eleni D; Corbett, Cheryl; Ye, Haobin; Liesveld, Jane L; O'Dwyer, Kristen M; Li, Zheng; Shi, Lei; Greninger, Patricia; Settleman, Jeffrey; Benes, Cyril; Hagen, Fred K; Munger, Joshua; Crooks, Peter A; Becker, Michael W; Jordan, Craig T

    2013-11-22

    The development of strategies to eradicate primary human acute myelogenous leukemia (AML) cells is a major challenge to the leukemia research field. In particular, primitive leukemia cells, often termed leukemia stem cells, are typically refractory to many forms of therapy. To investigate improved strategies for targeting of human AML cells we compared the molecular mechanisms regulating oxidative state in primitive (CD34(+)) leukemic versus normal specimens. Our data indicate that CD34(+) AML cells have elevated expression of multiple glutathione pathway regulatory proteins, presumably as a mechanism to compensate for increased oxidative stress in leukemic cells. Consistent with this observation, CD34(+) AML cells have lower levels of reduced glutathione and increased levels of oxidized glutathione compared with normal CD34(+) cells. These findings led us to hypothesize that AML cells will be hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as parthenolide (PTL) or piperlongumine that induce almost complete glutathione depletion and severe cell death in CD34(+) AML cells. Importantly, these compounds only induce limited and transient glutathione depletion as well as significantly less toxicity in normal CD34(+) cells. We further determined that PTL perturbs glutathione homeostasis by a multifactorial mechanism, which includes inhibiting key glutathione metabolic enzymes (GCLC and GPX1), as well as direct depletion of glutathione. These findings demonstrate that primitive leukemia cells are uniquely sensitive to agents that target aberrant glutathione metabolism, an intrinsic property of primary human AML cells. PMID:24089526

  13. ESAM is a novel human hematopoietic stem cell marker associated with a subset of human leukemias.

    Science.gov (United States)

    Ishibashi, Tomohiko; Yokota, Takafumi; Tanaka, Hirokazu; Ichii, Michiko; Sudo, Takao; Satoh, Yusuke; Doi, Yukiko; Ueda, Tomoaki; Tanimura, Akira; Hamanaka, Yuri; Ezoe, Sachiko; Shibayama, Hirohiko; Oritani, Kenji; Kanakura, Yuzuru

    2016-04-01

    Reliable markers are essential to increase our understanding of the biological features of human hematopoietic stem cells and to facilitate the application of hematopoietic stem cells in the field of transplantation and regenerative medicine. We previously identified endothelial cell-selective adhesion molecule (ESAM) as a novel functional marker of hematopoietic stem cells in mice. Here, we found that ESAM can also be used to purify human hematopoietic stem cells from all the currently available sources (adult bone marrow, mobilized peripheral blood, and cord blood). Multipotent colony-forming units and long-term hematopoietic-reconstituting cells in immunodeficient mice were found exclusively in the ESAM(High) fraction of CD34(+)CD38(-) cells. The CD34(+)CD38(-) fraction of cord blood and collagenase-treated bone marrow contained cells exhibiting extremely high expression of ESAM; these cells are likely to be related to the endothelial lineage. Leukemia cell lines of erythroid and megakaryocyte origin, but not those of myeloid or lymphoid descent, were ESAM positive. However, high ESAM expression was observed in some primary acute myeloid leukemia cells. Furthermore, KG-1a myeloid leukemia cells switched from ESAM negative to ESAM positive with repeated leukemia reconstitution in vivo. Thus, ESAM is a useful marker for studying both human hematopoietic stem cells and leukemia cells. PMID:26774386

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

    Science.gov (United States)

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

    1992-11-01

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

  15. Macrophage-independent T cell infiltration to the site of injury-induced brain inflammation

    DEFF Research Database (Denmark)

    Fux, Michaela; van Rooijen, Nico; Owens, Trevor

    2008-01-01

    We have addressed the role of macrophages in glial response and T cell entry to the CNS after axonal injury, by using intravenous injection of clodronate-loaded mannosylated liposomes, in C57BL6 mice. As expected, clodronate-liposome treatment resulted in depletion of peripheral macrophages which...... was confirmed by F4/80(-) and MOMA-1(-) stainings in spleen. Sequential clodronate-liposome treatment 4, 2 and 0 days before axotomy resulted in significant reduction of infiltrating CD45(high) CD11b(+) macrophages in the hippocampus at 1, 2 and 3 days post-lesion, measured by flow cytometry. There...... was a slight delay in the expansion of CD45(dim) CD11b(+) microglia in clodronate-liposome treated mice, but macrophage depletion had no effect on the percentage of infiltrating T cells in the lesion-reactive hippocampus. Lesion-induced TNFalpha mRNA expression was not affected by macrophage depletion...

  16. Autoimmune pancreatitis metachronously associated with retroperitoneal fibrosis with IgG4-positive plasma cell infiltration

    Institute of Scientific and Technical Information of China (English)

    Terumi Kamisawa; Pong Yui Chen; Yuyang Tu; Hitoshi Nakajima; Naoto Egawa

    2006-01-01

    Retroperitoneal fibrosis is an uncommon disorder characterized by the formation of a dense plaque of fibrous tissue in the retroperitoneum, and its etiology remains unknown. Autoimmune pancreatitis is a rare type of chronic pancreatitis characterized by fibrosis with abundant infiltration of IgG4-positive plasma cells and lymphocytes and obliterative phlebitis in the pancreas. We present a case of autoimmune pancreatitis that developed 10 mo after the occurrence of retroperitoneal fibrosis. Histological findings of the resected retroperitoneal mass were marked periureteral fibrosis with abundant infiltration of IgG4-positive plasma cells and lymphocytes and obliterative phlebitis.These findings suggest a common pathophysiological mechanism for retroperitoneal fibrosis and autoimmune pancreatitis in this case. Some cases of retroperitoneal fibrosis might be a retroperitoneal lesion of IgG4-related sclerosing disease.

  17. 单核母细胞肉瘤的临床病理观察及免疫表型分析%Extramedullary infiltration of acute monocytic leukemia / monoblastic sarcoma:a clinicopathologic and immunophenotype analysis of 5 cases

    Institute of Scientific and Technical Information of China (English)

    左卓; 刘卫平; 于建渤; 李吉满; 廖殿英

    2008-01-01

    Objective To study the clinieopathologic features,diagnosis and differential diagnosis of extramedullary infiltration of acute monocytic leukemia/monoblastic sarcoma.Methods Five cases of extramedullary infiltration of acute monocytie leukemia/monoblastic sarcoma were selected from 102 cases of myeloid sarcoma diagnosed during the period from 1990 to 2006.The clinicopathologic findings and follow-up data were retrospectively analyzed.Immunohistochemical study was also carried out with SP method.Reslllts Among the 5 cases studied,3 were males and 2 were females,including 2 children and 3 aduhs.Generalized lymphadenopathy was found in 4 patients and skin lesions were observed in 2 patients.The tumor cells in all cases were positive for CD68(KP1),CD68(PGM1),lysozyme and CD45.They were negative for MPO,CD15,CD163,TdT,CD117,T and B cell markers.The Ki-67 index ranged from 40%to 80%.Follow-up data were available in all the 5 patients.Four of the 5 patients died of the disease,with the average survival time being 6.25 months.Conclusions Monoblastic sarcoma is a rare disease with poorprognosis.It is almost impossible to distinguish monoblastic sarcoma from granuloeytic sarcoma and other types of small round cell tumors on the basis of morphologie examination alone.Immunohistochemistry is mandatory for a correct diagnosis.%目的 探讨单核母细胞肉瘤的临床病理特征、诊断和鉴别诊断.方法 从1990-2006年诊断的102例髓系肉瘤患者中筛选出5例单核母细胞肉瘤,进行临床病理回顾性研究和随访,以SP法检测其免疫表型.结果 5例中男性3人,女性2人,2例为儿童,3例为成人.病程1周~12个月不等.4例有多处浅表淋巴结肿大;2例有多发性皮肤病变.免疫表型:5例瘤细胞均表达CD68(KP1)、CD68(PGM1)、溶菌酶和CD45;均不表达髓过氧化物酶、CD15、CD163、脱氧核苷酸转移酶、CD117以及T和B细胞分化抗原.Ki-67指数为40%-80%.5例患者均有随访,4例死亡,1

  18. Solving cell infiltration limitations of electrospun nanofiber meshes for tissue engineering applications

    OpenAIRE

    Guimarães, Ana; Martins, Albino; Pinho, Elisabete D.; Faria, Susana; Reis, R. L.; Neves, N. M.

    2010-01-01

    AIM: Utilize the dual composition strategy to increase the pore size and solve the low cell infiltration capacity on random nanofiber meshes, an intrinsic limitation of electrospun scaffolds for tissue engineering applications. MATERIALS & METHODS: Polycaprolactone and poly(ethylene oxide) solutions were electrospun simultaneously to obtain a dual composition nanofiber mesh. Selective dissolution of the poly(ethylene oxide) nanofiber fraction was performed. The biologic performance of these e...

  19. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer

    OpenAIRE

    Goeppert, B; Frauenschuh, L; Zucknick, M; Stenzinger, A; Andrulis, M; Klauschen, F; Joehrens, K; Warth, A; Renner, M.; Mehrabi, A; Hafezi, M.; Thelen, A; Schirmacher, P; Weichert, W

    2013-01-01

    Background: Biliary tract cancers (BTC) are relatively rare malignant tumours with poor prognosis. It is known from other solid neoplasms that antitumour inflammatory response has an impact on tumour behaviour and patient outcome. The aim of this study was to provide a comprehensive characterisation of antitumour inflammatory response in human BTC. Methods: Tumour-infiltrating T lymphocytes (CD4+, CD8+, and Foxp3+), natural killer cells (perforin+), B lymphocytes (CD20+), macrophages (CD68+) ...

  20. Synergistic interactions between HDAC and sirtuin inhibitors in human leukemia cells.

    Directory of Open Access Journals (Sweden)

    Michele Cea

    Full Text Available Aberrant histone deacetylase (HDAC activity is frequent in human leukemias. However, while classical, NAD(+-independent HDACs are an established therapeutic target, the relevance of NAD(+-dependent HDACs (sirtuins in leukemia treatment remains unclear. Here, we assessed the antileukemic activity of sirtuin inhibitors and of the NAD(+-lowering drug FK866, alone and in combination with traditional HDAC inhibitors. Primary leukemia cells, leukemia cell lines, healthy leukocytes and hematopoietic progenitors were treated with sirtuin inhibitors (sirtinol, cambinol, EX527 and with FK866, with or without addition of the HDAC inhibitors valproic acid, sodium butyrate, and vorinostat. Cell death was quantified by propidium iodide cell staining and subsequent flow-cytometry. Apoptosis induction was monitored by cell staining with FITC-Annexin-V/propidium iodide or with TMRE followed by flow-cytometric analysis, and by measuring caspase3/7 activity. Intracellular Bax was detected by flow-cytometry and western blotting. Cellular NAD(+ levels were measured by enzymatic cycling assays. Bax was overexpressed by retroviral transduction. Bax and SIRT1 were silenced by RNA-interference. Sirtuin inhibitors and FK866 synergistically enhanced HDAC inhibitor activity in leukemia cells, but not in healthy leukocytes and hematopoietic progenitors. In leukemia cells, HDAC inhibitors were found to induce upregulation of Bax, a pro-apoptotic Bcl2 family-member whose translocation to mitochondria is normally prevented by SIRT1. As a result, leukemia cells become sensitized to sirtuin inhibitor-induced apoptosis. In conclusion, NAD(+-independent HDACs and sirtuins cooperate in leukemia cells to avoid apoptosis. Combining sirtuin with HDAC inhibitors results in synergistic antileukemic activity that could be therapeutically exploited.

  1. Highly durable anode supported solid oxide fuel cell with an infiltrated cathode

    DEFF Research Database (Denmark)

    Samson, Alfred Junio; Hjalmarsson, Per; Søgaard, Martin; Hjelm, Johan; Bonanos, Nikolaos

    2012-01-01

    , consisting of a Nieyttria stabilized zirconia (YSZ) anode support, a Niescandia-doped yttria-stabilized zirconia (ScYSZ) anode, a ScYSZ electrolyte, and a CGO barrier layer. LSC was introduced into the CGO backbone by multiple infiltrations of an aqueous nitrate solution followed by firing. The cell was...... tested at 700 deg. C under a current density of 0.5 A cm-2 for 1500 h using air as oxidant and humidified hydrogen as fuel. The electrochemical performance of the cell was analyzed by impedance spectroscopy and current evoltage relationships. No measurable degradation in the cell voltage or increase in...

  2. A novel cell growth-promoting factor identified in a B cell leukemia cell line, BALL-1

    International Nuclear Information System (INIS)

    A novel leukemia cell growth-promoting activity has been identified in the culture supernatant from a human B cell leukemia cell line, BALL-1. The supernatant from unstimulated cultures of the BALL-1 cells significantly promoted the growth of 16 out of 24 leukemia/lymphoma cell lines of different lineages (T, B and non-lymphoid) in a minimal concentration of fetal bovine serum (FBS), and 5 out of 12 cases of fresh leukemia cells in FBS-free medium. The growth-promoting sieve filtration and dialysis. The MW of the factor was less than 10 kDa. The growth-promoting activity was heat and acid stable and resistant to trypsin treatment. The factor isolated from the BALL-1 supernatant was distinct from known polypeptide growth factors with MW below 10 kDa, such as epidermal growth factor, transforming growth factor α, insulin-like growth factor I (IGF-I), IGF-II and insulin, as determine by specific antibodies and by cell-growth-promoting tests. The factor is the BALL-1 supernatant did not promote the proliferation of normal human fresh peripheral blood lymphocytes or mouse fibroblast cell line, BALB/C 3T3. In addition to the BALL-1 supernatant, a similar growth-promoting activity was found in the culture supernatant from 13 of 17 leukemia/lymphoma cell lines tested. The activity in these culture supernatant promoted the growth of leukemia/lymphoma cell lines in autocrine and/or paracrine fashions. These observations suggest that the low MW cell growth-promoting activity found in the BALL-1 culture supernatant is mediated by a novel factor which may be responsible for the clonal expansion of particular leukemic clones. (author)

  3. Leukemia Inhibitory Factor Decreases the Arylamine N-Acetyltransferase Activity in Human Cumulus Granulosa Cells

    OpenAIRE

    Chang, Chi-Chen; Hsieh, Yao-Yuan; CHUNG, JING-GUNG; Tsai, Horng-Der; Tsai, Chang-Hai

    2001-01-01

    Purpose: To evaluate the activities of acetyl coenzyme A (AcCoA): arylamine N-acetyltransferase (NAT) of intact cumulus granulosa cells and the role of leukemia inhibitory factor (LIF) upon their NAT activities.

  4. Simple solid-phase radioimmunoassay for human leukemia-associated cell membrane antigens

    International Nuclear Information System (INIS)

    In the present study, a simple solid-phase radioimmunoassay was developed to determine detergent-extracted human leukemia-associated cell membrane antigens. In the assay, 96-well microtiter plates are coated with human leukemia cell membrane antigens containing a T cell leukemia or a non-T cell leukemia antigen in the presence of a detergent, and treated with 1.6% bovine serum albumin solution. The coated antigens were reacted with an appropriate murine monoclonal antibody (mAb). The bound mAb is determined by a second reaction with 125I-labeled F(ab')2 of goat anti-mouse Ig. The best antigen dose-dependent antibody binding results were obtained using the plates coated with antigens in the presence of taurocholate. In addition, the usefulness of the present assay with taurocholate during the purification of the antigens was demonstrated. (Auth.)

  5. Ginseng Extract Enhances Anti-cancer Effect of Cytarabine on Human Acute Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Yiju Hou

    2015-02-01

    Full Text Available Ginseng as a traditional medicine is well known to exhibit various pharmacological effects. Ginsenoside Rg3 is the active ingredient extracted from ginseng. The pharmacological modulatory effects of Rg3 on multidrug resistant cancer cells are reported in the present study. Cytarabine is a chemotherapeutic agent for the treatment of acute leukemia. However, this compound has serious side effects at high doses, for example hematopoiesis depression. In this study, using hl60 human leukemia cells, we investigated the possible synergistic anti-cancer effects between ginseng extract Rg3 and cytarabine on acute myeloid leukemia cells. Results of this study demonstrate that Rg3 can enhance the anti-proliferation effect of cytarabine on hl60 cells and may decrease the dosage of cytarabine needed for acute myeloid leukemia treatment.

  6. Characterisation of the Leukemic Stem Cell in a Murine Model of CALM/AF10 Positive Myeloid Leukemia

    OpenAIRE

    Deshpande, Aniruddha

    2006-01-01

    We have demonstrated, that an acute leukemia with a predominantly myeloid phenotype can be propagated by a progenitor with lymphoid characteristics in a mouse model of the t(10;11) (p13;q14) translocation. Mice transplanted with bone marrow retrovirally engineered to express the leukemia specific CALM/AF10 fusion gene consistently developed an acute leukemia with a short latency. The leukemia showed characteristic myeloid features such as the presence of myeloid marker positive cells infilt...

  7. Phase 1 Study of Terameprocol (EM-1421) in Patients With Leukemia

    Science.gov (United States)

    2016-02-20

    Leukemias; Acute Myeloid Leukemia (AML); Acute Lymphocytic Leukemia (ALL); Adult T Cell Leukemia (ATL); Chronic Myeloid Leukemia (CML-BP); Chronic Lymphocytic Leukemia (CLL); Myelodysplastic Syndrome (MDS); Chronic Myelomonocytic Leukemia (CMML)

  8. Acute lymphoblastic leukemia cells that survive combination chemotherapy in vivo remain sensitive to allogeneic immune effects

    OpenAIRE

    Jansson, Johan; Hsu, Yu-Chiao; Kuzin, Igor I.; Campbell, Andrew; Mullen, Craig A.

    2010-01-01

    Allogeneic hematopoietic stem cell transplantation is often performed for patients with acute lymphoblastic leukemia (ALL) whose disease has relapsed after chemotherapy treatment. However, graft versus leukemia (GVL) effects in ALL are generally weak and the mechanisms of this weakness are unknown. These studies tested the hypothesis that ALL cells that have survived conventional chemotherapy in vivo acquire relative resistance to the allogeneic GVL effect. C57BL/6 mice were injected with mur...

  9. Ginseng Extract Enhances Anti-cancer Effect of Cytarabine on Human Acute Leukemia Cells

    OpenAIRE

    Yiju Hou; Xiaodong Liu; Zhonghai Yuan; Yan Li

    2015-01-01

    Ginseng as a traditional medicine is well known to exhibit various pharmacological effects. Ginsenoside Rg3 is the active ingredient extracted from ginseng. The pharmacological modulatory effects of Rg3 on multidrug resistant cancer cells are reported in the present study. Cytarabine is a chemotherapeutic agent for the treatment of acute leukemia. However, this compound has serious side effects at high doses, for example hematopoiesis depression. In this study, using hl60 human leukemia cells...

  10. Induced transdifferentiation of human B-leukemia/lymphoma cell lines and inhibition of leukemogenicity

    OpenAIRE

    Rapino, Francesca

    2013-01-01

    B-cell malignancies encompass a wide variety of distinct diseases including Non Hodgkin lymphoma (NHL) and leukemia. Currently, chemotherapy, radiation and anti-CD20 antibody treatment are the mainstays of B-cell lymphoma and leukemia therapy. However, the fact that a large number of patients are eventually not cured justifies the search for novel and more effective therapeutic approaches. Although induction of differentiation has been shown to be effective in several tum...

  11. Up-regulation of TIMP-2 expression promotes SHI-1 leukemic cells proliferation and infiltration in immunodeficiency mice

    Institute of Scientific and Technical Information of China (English)

    Li Zhenjiang; Chen Zixing; Cen Jiannong; He Jun; Qiu Qiaocheng; Xue Yongquan

    2014-01-01

    Background MMPs and TIMPs play important roles in tumor angiogenesis and invasion.Studies have shown that TIMP-2 has two roles in tumor invasion.However,its role in leukemic infiltration has not been well investigated.This study explored the roles of TIMP-2 in extramedullary infiltration of acute monocytic leukemic SHI-1 cells both in vitro and in vitro.Methods A retroviral vector carrying the human TIMP-2 cDNA was constructed and transfected into the monocytic leukemic cell line SHI-1.The expression of TIMP-2 in the positive clones was determined.The proliferation of SHI-1 cells was examined by MTT assay.Trans-Matrigel invasion assays were used to investigate the infiltration ability in vitro.SHI-1 cells were intravenously injected into pre-treated nu/nu mice to investigate the infiltration ability feature in vitro.Results The expression of TIMP-2 on the cell membrane was significantly elevated in SHI-1/TIMP-2 cells.Over-expression of TIMP-2 promoted the cells proliferation and the invasions in vitro.The SHI-1/TIMP-2 cells demonstrated higher infiltration ability when intravenously injected into nu/nu mice.Conclusion Over-expression of TIMP-2,especially on the cell membrane,may play important roles in promoting the proliferation and infiltration of SHI-1 leukemic cells.

  12. Flow cytometric immunophenotypic characteristics of plasma cell leukemia

    Directory of Open Access Journals (Sweden)

    Barbara Kruk

    2011-04-01

    Full Text Available The aim of this prospective study was to define the flow cytometric characteristics of simultaneously investigated bone marrow and peripheral blood plasma cells antigens expression in 36 plasma cell leukemia (PCL patients. The immunophenotypic profile of plasma cells was determined with a panel of monoclonal antibodies. The antigen expression intensity was calculated as relative fluorescence intensity (RFI. Bone marrow plasma cells showed expression of particular antigens in the following proportion of cases: CD49d 100%, CD29 94%, CD54 93%, CD44 83%, CD56 60%, CD18 26%, CD11b 29%, CD11a 19%, CD117 27%, CD71 30%, CD126 100% and CD19 0%, while the expression of those antigens on peripheral blood plasma cells was present in the following percentage of patients: CD49d 100%, CD29 96%, CD54 93%, CD44 95%, CD56 56%, CD18 50%, CD11b 53%, CD11a 29%, CD117 26%, CD71 28%, CD126 100% and CD19 0%. The expression of CD54 was significantly higher than that of adhesion molecules belonging to the integrin b2 family: CD11a, CD18 and CD11b, on both bone marrow and peripheral blood cells (p < 0.01. Expression of CD18, CD11a and CD11b was differential between two cell compartments: lower on bone marrow and higher on peripheral blood cells. We found that plasma cells in the bone marrow of patients with plasma cell leukaemia showed significantly greater granularity and size than those in the peripheral blood (p = 0.0001 and p = 0.04, respectively. However, no differences in cell size or granularity were revealed between bone marrow plasma cells from patients with PCL and multiple myeloma. In conclusion, impaired expression of adhesion molecules such as CD11a/CD18 (LFA-1 or CD56 may explain hematogenic dissemination characterizing PCL. The following pattern of adhesion molecule expression according to the proportion of plasma cells expressing a given antigen in peripheral blood and bone marrow and arranged in diminishing order may be established: CD49d > CD44 > CD54

  13. Ultra-Localization of Foxp3+ T Cells within Renal Allografts Shows Infiltration of Tubules Mimicking Rejection

    OpenAIRE

    Brown, Kathryn; Moxham, Victoria; Karegli, Julieta; Phillips, Richard; Sacks, Steven H.; Wong, Wilson

    2007-01-01

    Kidney transplant recipients are monitored for rejection by measurement of serum creatinine and graft biopsies. Biopsy samples are evaluated according to the Banff classification, which states that infiltration of tubules by mononuclear cells is an indicator of acute rejection. However, regulatory T cells play a crucial role in the overall immune response and are also present within transplanted tissue. We hypothesize that infiltration of mononuclear cells within kidney grafts is not always a...

  14. Parvovirus B19 infection presenting as pre-B-cell acute lymphoblastic leukemia: a transient and progressive course in two children.

    Science.gov (United States)

    Yetgin, Sevgi; Cetin, Mualla; Aslan, Deniz; Ozyurek, Emel; Oyürek, Emel; Anlar, Banu; Uçkan, Duygu

    2004-10-01

    Parvovirus B19 is the causative agent of various forms of hematologic diseases such as aplastic crisis in patients with hemolytic anemia, aplastic anemia, hypoplastic anemia, and idiopathic thrombocytopenic purpura. In addition, parvovirus B19 infection may precede or be associated with acute lymphoblastic leukemia (ALL). The authors present two cases of parvovirus B19 infection and bone marrow infiltration with pre-B-cell lymphoblasts; one patients was diagnosed as having ALL, and the other patient, with neurologic findings, showed total resolution of the blastic morphology and phenotype. PMID:15454845

  15. Chronic Lymphocytic Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. ...

  16. Chronic Myeloid Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. ...

  17. The receptors for gibbon ape leukemia virus and amphotropic murine leukemia virus are not downregulated in productively infected cells

    Directory of Open Access Journals (Sweden)

    Eiden Maribeth V

    2011-07-01

    Full Text Available Abstract Background Over the last several decades it has been noted, using a variety of different methods, that cells infected by a specific gammaretrovirus are resistant to infection by other retroviruses that employ the same receptor; a phenomenon termed receptor interference. Receptor masking is thought to provide an earlier means of blocking superinfection, whereas receptor down regulation is generally considered to occur in chronically infected cells. Results We used replication-competent GFP-expressing viruses containing either an amphotropic murine leukemia virus (A-MLV or the gibbon ape leukemia virus (GALV envelope. We also constructed similar viruses containing fluorescence-labeled Gag proteins for the detection of viral particles. Using this repertoire of reagents together with a wide range of antibodies, we were able to determine the presence and availability of viral receptors, and detect viral envelope proteins and particles presence on the cell surface of chronically infected cells. Conclusions A-MLV or GALV receptors remain on the surface of chronically infected cells and are detectable by respective antibodies, indicating that these receptors are not downregulated in these infected cells as previously proposed. We were also able to detect viral envelope proteins on the infected cell surface and infected cells are unable to bind soluble A-MLV or GALV envelopes indicating that receptor binding sites are masked by endogenously expressed A-MLV or GALV viral envelope. However, receptor masking does not completely prevent A-MLV or GALV superinfection.

  18. Reprogramming tumor-infiltrating dendritic cells for CD103+CD8+ mucosal T cell differentiation and breast cancer rejection

    Science.gov (United States)

    Wu, Te-Chia; Xu, Kangling; Banchereau, Romain; Marches, Florentina; Yu, Chun I; Martinek, Jan; Anguiano, Esperanza; Pedroza-Gonzalez, Alexander; Snipes, G. Jackson; O’Shaughnessy, Joyce; Nishimura, Stephen; Liu, Yong-Jun; Pascual, Virginia; Banchereau, Jacques; Oh, Sangkon; Palucka, Karolina

    2014-01-01

    Our studies showed that tumor-infiltrating dendritic cells (DC) in breast cancer drive inflammatory T helper 2 (iTh2) cells and protumor inflammation. Here we show that intratumoral delivery of the β-glucan curdlan, a ligand of dectin-1, blocks the generation of iTh2 cells, and prevents breast cancer progression in vivo. Curdlan reprograms tumor-infiltrating DC via the ligation of dectin-1, enabling the DC to become resistant to cancer-derived thymic stromal lymphopoietin (TSLP), to produce IL12p70, and to favor the generation of T helper 1 (Th1) cells. DC activated via dectin-1, but not those activated with TLR-7/8 ligand or poly IC, induce CD8+ T cells to express CD103 (αE integrin), a ligand for cancer cells E-cadherin. Generation of these mucosal CD8+ T cells is regulated by DC-derived integrin αvβ8 and TGF-β activation in a dectin-1-dependent fashion. These CD103+CD8+ mucosal T cells accumulate in the tumors thereby increasing cancer necrosis and inhibiting cancer progression in vivo in a humanized mouse model of breast cancer. Importantly, CD103+CD8+ mucosal T cells elicited by reprogrammed DC can reject established cancer. Thus, reprogramming tumor-infiltrating DC represents a new strategy for cancer rejection. PMID:24795361

  19. Resistance to cyclopentenylcytosine in murine leukemia L1210 cells.

    Science.gov (United States)

    Zhang, H; Cooney, D A; Zhang, M H; Ahluwalia, G; Ford, H; Johns, D G

    1993-12-01

    Cyclopentenyl cytosine (CPEC) exhibits oncological activity in murine and human tumor cells and has now entered Phase I clinical trials. Its mode of action as an antitumor agent appears to be inhibition by its triphosphate (CPEC-TP) of CTP synthase, the enzyme which converts UTP to CTP. In an attempt to elucidate the mechanism of resistance to CPEC, a murine leukemia cell line resistant to CPEC (L1210/CPEC) was developed by N-methyl-N-nitro-N-nitrosoguanidine-induced mutagenesis and subsequent selection by cultivation of the L1210 cells in the presence of 2 microM CPEC. Resistant clones were maintained in CPEC-free medium for 6 generations before biochemical studies were performed. The resistant clone selected for further studies was approximately 13,000-fold less sensitive to growth inhibition by CPEC than the parental cells, and the concentration of CPEC required to deplete CTP in the resistant cells was 50-fold higher than in the sensitive cells. A comparison of the kinetic properties of CTP synthase from sensitive and resistant cells indicated alteration in the properties of the enzyme from the latter; the median inhibitory concentration for CPEC-TP increased from 2 to 14 microM, Km for UTP decreased from 126 to 50 microM, and Vmax increased 12-fold from 0.2 to 2.3 nmol/mg/min. Northern blot analyses of polyadenylated RNA from the resistant and sensitive cells indicated a 3-fold increase in transcripts of the CTP synthase gene in the resistant line. Consistent with these alterations in the properties of the enzyme, the resistant cells exhibited significantly expanded CTP and dCTP pools (4- 5-fold) when compared with the sensitive cells. No change was observed, however, in the properties of uridine-cytidine kinase, the enzyme responsible for the initial phosphorylation of CPEC; despite this, however, cellular uptake of CPEC was greatly decreased, and phosphorylation of CPEC and its incorporation into RNA were 10-fold less than in the parental cells. These latter

  20. EFFECTS OF CURCUMIN ON PROLIFERATION AND APOPTOSIS IN ACUTE MYELOID LEUKEMIA CELLS HL-60

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    To investigate the curcumin killing leukemia cells in vitro,. Methods: The myeloid leukemic cell line HL-60 was studied by using cell culture, flow cytometrydetermining DNA content and TUNEL method measuring apoptotic cell percentage. Results: The data showed that curcumin selectively inhibited proliferation of acute myeloid leukemia (AML) HL-60 cell lines in a dose- and time-dependent manner. The growth inhibition rate was gradually increased and reached the peak at concentration of 25 m mol/L curcumin at 24h. The sub-G1 peak appeared after 12h treatment and was increased to 34.4% at 24h. The TUNEL method further certified that apoptotic cells reached 41% at the same phase. Conclusion: curcumin possesses obvious potent of anti-leukemia cell proliferation, which is contributed to the induction of HL-60 cells apoptosis. The concentration and action time of curcumin in vitro provide some reference for clinical use.

  1. Immunological reactivity of leukemia afflicted animals under the effect of gamma-ray sterilized malignant cells

    International Nuclear Information System (INIS)

    The employment of ionizing radiation or cytostatics for the treatment of malignant neoplasms leads to the cessation of the processes of division in part of the malignant cells. Cells sterilized in this manner interact with the malignant cells that have remained alive. To elucidate some mechanisms of this interrelationships studies were undertaken on mice with transplantational leukemia L 1210. Since the intraperitoneal administration of 107 sterile leukemia cells mixed with 104 live cells results in prolongation of survival of the mice in this group as compared with mice injected with live cells only. The question arises whether immune mechanisms are involved in these phenomena. Studies on the specific immunological activity indicate that in the group treated with a mixture of sterilized and live cells the number of positive cytotoxic reactions increases as regards leukemia cells; the nonspecific immune reactivity remains unaffected. (author)

  2. Infiltration patterns in monoclonal plasma cell disorders: correlation of magnetic resonance imaging with matched bone marrow histology

    International Nuclear Information System (INIS)

    Objectives: To investigate how plasma cell infiltration patterns detected by MRI match the plasma cell distribution in bone marrow biopsy. Methods: We assessed 50 patients with monoclonal plasma cell disorders of all clinical stages. MRI infiltration pattern was compared with matched BM histology from the same anatomic region. Results: MRI revealed a minimal (n = 11, 22%), focal (n = 5, 10%), diffuse (n = 14, 28%) and mixed (n = 20, 40%) infiltration pattern. Diffuse MRI pattern was predominant in smoldering myeloma patients whereas the MRI patterns with “focal component” (i.e. focal and mixed) were most common in symptomatic myeloma (p < 0.01). In histology an interstitial (n = 13, 26%), nodular (n = 23, 46%) and packed marrow (n = 14, 28%) was found respectively. All three histological types of infiltration were observed in patients with diffuse and mixed MRI patterns. Minimal MRI pattern was found in all MGUS patients and was associated with an interstitial BM infiltration. In two patients with minimal MRI pattern an extensive micro-nodular BM infiltration was found in histology. Conclusions: Infiltration patterns in MRI represent different histological growth patterns of plasma cells, but the MRI resolution is not sufficient to visualize micro-nodular aggregates of plasma cells

  3. Infiltration patterns in monoclonal plasma cell disorders: correlation of magnetic resonance imaging with matched bone marrow histology

    Energy Technology Data Exchange (ETDEWEB)

    Andrulis, Mindaugas [Institute of Pathology, University of Heidelberg, Heidelberg (Germany); Bäuerle, Tobias [Department of Diagnostic and Interventional Radiology, University of Hamburg, Hamburg (Germany); Goldschmidt, Hartmut [Department of Hematology and Oncology, University of Heidelberg, Heidelberg (Germany); Delorme, Stefan [Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg (Germany); Landgren, Ola [Multiple Myeloma Section, Metabolism Branch, National Cancer Institute, Bethesda (United States); Schirmacher, Peter [Institute of Pathology, University of Heidelberg, Heidelberg (Germany); Hillengass, Jens, E-mail: jens.hillengass@med.uni-heidelberg.de [Department of Hematology and Oncology, University of Heidelberg, Heidelberg (Germany); Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg (Germany)

    2014-06-15

    Objectives: To investigate how plasma cell infiltration patterns detected by MRI match the plasma cell distribution in bone marrow biopsy. Methods: We assessed 50 patients with monoclonal plasma cell disorders of all clinical stages. MRI infiltration pattern was compared with matched BM histology from the same anatomic region. Results: MRI revealed a minimal (n = 11, 22%), focal (n = 5, 10%), diffuse (n = 14, 28%) and mixed (n = 20, 40%) infiltration pattern. Diffuse MRI pattern was predominant in smoldering myeloma patients whereas the MRI patterns with “focal component” (i.e. focal and mixed) were most common in symptomatic myeloma (p < 0.01). In histology an interstitial (n = 13, 26%), nodular (n = 23, 46%) and packed marrow (n = 14, 28%) was found respectively. All three histological types of infiltration were observed in patients with diffuse and mixed MRI patterns. Minimal MRI pattern was found in all MGUS patients and was associated with an interstitial BM infiltration. In two patients with minimal MRI pattern an extensive micro-nodular BM infiltration was found in histology. Conclusions: Infiltration patterns in MRI represent different histological growth patterns of plasma cells, but the MRI resolution is not sufficient to visualize micro-nodular aggregates of plasma cells.

  4. Emodin Induces Apoptotic Death in Murine Myelomonocytic Leukemia WEHI-3 Cells In Vitro and Enhances Phagocytosis in Leukemia Mice In Vivo

    Directory of Open Access Journals (Sweden)

    Yuan-Chang Chang

    2011-01-01

    Full Text Available Emodin is one of major compounds in rhubarb (Rheum palmatum L., a plant used as herbal medicine in Chinese population. Although many reports have shown that emodin exhibits anticancer activity in many tumor cell types, there is no available information addressing emodin-affected apoptotic responses in the murine leukemia cell line (WEHI-3 and modulation of the immune response in leukemia mice. We investigated that emodin induced cytotoxic effects in vitro and affected WEHI-3 cells in vivo. This study showed that emodin decreased viability and induced DNA fragmentation in WEHI-3 cells. Cells after exposure to emodin for 24 h have shown chromatin condensation and DNA damage. Emodin stimulated the productions of ROS and Ca2+ and reduced the level of ΔΨm by flow cytometry. Our results from Western blotting suggest that emodin triggered apoptosis of WEHI-3 cells through the endoplasmic reticulum (ER stress, caspase cascade-dependent and -independent mitochondrial pathways. In in vivo study, emodin enhanced the levels of B cells and monocytes, and it also reduced the weights of liver and spleen compared with leukemia mice. Emodin promoted phagocytic activity by monocytes and macrophages in comparison to the leukemia mice group. In conclusions, emodin induced apoptotic death in murine leukemia WEHI-3 cells and enhanced phagocytosis in the leukemia animal model.

  5. Effects of High-Temperature-Pressure Polymerized Resin-Infiltrated Ceramic Networks on Oral Stem Cells

    Science.gov (United States)

    Nassif, Ali; Berbar, Tsouria; Le Goff, Stéphane; Berdal, Ariane; Sadoun, Michael; Fournier, Benjamin P. J.

    2016-01-01

    Objectives The development of CAD—CAM techniques called for new materials suited to this technique and offering a safe and sustainable clinical implementation. The infiltration of resin in a ceramic network under high pressure and high temperature defines a new class of hybrid materials, namely polymer infiltrated ceramics network (PICN), for this purpose which requires to be evaluated biologically. We used oral stem cells (gingival and pulpal) as an in vitro experimental model. Methods Four biomaterials were grinded, immersed in a culture medium and deposed on stem cells from dental pulp (DPSC) and gingiva (GSC): Enamic (VITA®), Experimental Hybrid Material (EHM), EHM with initiator (EHMi) and polymerized Z100™ composite material (3M®). After 7 days of incubation; viability, apoptosis, proliferation, cytoskeleton, inflammatory response and morphology were evaluated in vitro. Results Proliferation was insignificantly delayed by all the tested materials. Significant cytotoxicity was observed in presence of resin based composites (MTT assay), however no detectable apoptosis and some dead cells were detected like in PICN materials. Cell morphology, major cytoskeleton and extracellular matrix components were not altered. An intimate contact appeared between the materials and cells. Clinical Significance The three new tested biomaterials did not exhibit adverse effects on oral stem cells in our experimental conditions and may be an interesting alternative to ceramics or composite based CAD—CAM blocks. PMID:27196425

  6. Secondary infiltration of the central nervous system in patients with diffuse large B-cell lymphoma

    Directory of Open Access Journals (Sweden)

    Talita Maira Bueno da Silveira da Rocha

    2013-01-01

    Full Text Available OBJECTIVE: To investigate the incidence and risk factors of infiltration of the central nervous system after the initial treatment of diffuse large B-cell lymphoma in patients treated at Santa Casa de Misericórdia de São Paulo. METHODS: A total of 133 patients treated for diffuse large B-cell lymphoma from January 2001 to April 2008 were retrospectively analyzed in respect to the incidence and risk factors of secondary central nervous system involvement of lymphoma. Intrathecal prophylaxis was not a standard procedure for patients considered to be at risk. This analysis includes patients whether they received rituximab as first-line treatment or not. RESULTS: Nine of 133 (6.7% patients developed central nervous system disease after a mean observation time of 29 months. The median time to relapse or progression was 7.9 months after diagnosis and all but one patient died despite the treatment administered. Twenty-six (19.5% patients of this cohort received rituximab as first-line treatment and nine (7.1% received intrathecal chemoprophylaxis. Of the nine patients that relapsed, seven (77.7% had parenchymal central nervous system involvement; seven (77.7% had stage III or IV disease; one (11.1% had bone marrow involvement; two (22.2% had received intrathecal chemoprophylaxis; and 3 (33.3% had taken rituximab. In a multivariate analysis, the risk factors for this infiltration were being male, previous use of intrathecal chemotherapy and patients that were refractory to initial treatment. CONCLUSION: Central nervous system infiltration in this cohort is similar to that of previous reports in the literature. As this was a small cohort with a rare event, only three risk factors were important for this infiltration

  7. Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

    International Nuclear Information System (INIS)

    To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 μM drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug–drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis

  8. Graft-versus-leukemia effects associated with detectable Wilms tumor-1–specific T lymphocytes after allogeneic stem-cell transplantation for acute lymphoblastic leukemia

    OpenAIRE

    Rezvani, Katayoun; Yong, Agnes S.M.; Savani, Bipin N.; Mielke, Stephan; Keyvanfar, Keyvan; Gostick, Emma; Price, David A; Douek, Daniel C.; Barrett, A. John

    2007-01-01

    To determine whether the leukemia-associated Wilms tumor antigen (WT1) contributes to a graft-versus-leukemia (GVL) effect after allogeneic stem-cell transplantation (SCT) for acute lymphoblastic leukemia (ALL), we studied CD8+ T-cell responses to WT1 in 10 human lymphocyte antigen (HLA)–A*0201–positive ALL patients during the early phase of immune recovery after SCT (days 30-120). Seven of 10 patients had detectable WT1 expression in their peripheral blood (PB) before SCT by quantitative rev...

  9. Ezrin dephosphorylation/downregulation contributes to ursolic acid-mediated cell death in human leukemia cells

    International Nuclear Information System (INIS)

    Ezrin links the actin filaments with the cell membrane and has a functional role in the apoptotic process. It appears clear that ezrin is directly associated with Fas, leading to activation of caspase cascade and cell death. However, the exact role of ezrin in ursolic acid (UA)-induced apoptosis remains unclear. In this study, we show for the first time that UA induces apoptosis in both transformed and primary leukemia cells through dephosphorylation/downregulation of ezrin, association and polarized colocalization of Fas and ezrin, as well as formation of death-inducing signaling complex. These events are dependent on Rho-ROCK1 signaling pathway. Knockdown of ezrin enhanced cell death mediated by UA, whereas overexpression of ezrin attenuated UA-induced apoptosis. Our in vivo study also showed that UA-mediated inhibition of tumor growth of mouse leukemia xenograft model is in association with the dephosphorylation/downregulation of ezrin. Such findings suggest that the cytoskeletal protein ezrin may represent an attractive target for UA-mediated lethality in human leukemia cells

  10. Inhibitory effects of rapamycin on proliferation of chronic myelogenous leukemia cells and its mechanism

    Institute of Scientific and Technical Information of China (English)

    李杰

    2012-01-01

    Objective To explore the inhibitory effects of rapamycin on proliferation of chronic myelogenous leukemia (CML) cells and its possible mechanism. Methods The effects of rapamycin at various concentrations on cell proliferation of CML cell line K562 cells were analyzed by MTT. The expressions

  11. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias

    DEFF Research Database (Denmark)

    Nicolini, Franck Emmanuel; Basak, Grzegorz W; Soverini, Simona;

    2011-01-01

    , still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome-positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic...... myeloid leukemia. The occurrence of chronic GVHD had a positive impact on overall survival (P = .047). Transplant-related mortality rates were low. Multivariate analysis identified only blast phase at transplantation (hazard ratio 3.68, P = .0011) and unrelated stem cell donor (hazard ratio 2.98, P = .011...

  12. Transforming human blood stem and progenitor cells: A new way forward in leukemia modeling

    OpenAIRE

    Mulloy, James C.; Wunderlich, Mark; Zheng, Yi; Wei, Junping

    2008-01-01

    MLL-AF9 (MA9) is a leukemia fusion gene formed upon translocation of the AF9 gene on chromosome 9 and the MLL gene on chromosome 11. MA9 is commonly found in acute myeloid leukemia (AML) and occasionally in acute lymphoid leukemia and is associated with intermediate to poor outcome. The specific signaling pathways downstream of MA9 are still poorly understood. We have recently described a model system whereby we expressed the MA9 fusion gene in human CD34+ Umbilical Cord Blood (UCB) cells and...

  13. The relationships between serum cytokine levels and tumor infiltrating immune cells and their clinical significance in colorectal cancer.

    Science.gov (United States)

    Väyrynen, Juha P; Kantola, Tiina; Väyrynen, Sara A; Klintrup, Kai; Bloigu, Risto; Karhu, Toni; Mäkelä, Jyrki; Herzig, Karl-Heinz; Karttunen, Tuomo J; Tuomisto, Anne; Mäkinen, Markus J

    2016-07-01

    Increased inflammatory cell infiltration correlates to improved survival in colorectal cancer (CRC). Development and progression of CRC is associated with alterations in serum cytokine levels but their significance is not well defined. In this study, we investigated the relationships between the serum levels of 13 cytokines and the densities of eight types of tumor infiltrating inflammatory cells and their impact on disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) in a prospectively recruited group of 147 CRC patients. There were strong positive correlations between the serum concentrations of different cytokines, as well as between the different types of tumor infiltrating immune cells, whereas the associations between serum cytokines and tumor infiltrating immune cells were generally weak. High serum IL-12 levels associated with increased densities of peritumoral CD8(+) T cells, intraepithelial CD3(+) T cells and intratumoral neutrophils, while high serum CCL4 levels associated with increased densities of peritumoral CD68(+) cells. In multivariate survival models, increased infiltration of intraepithelial CD3(+) T cells and increased serum CCL4 associated with improved DFS, whereas higher intratumoral CD83(+) dendritic cell density and increased serum interferon gamma levels associated with improved CSS and OS. Also high density of peritumoral CD3(+) T cells associated with improved CSS. In conclusion, serum cytokines and tumor infiltrating immune cells in CRC represent entities with high intragroup correlations but relatively weak intergroup correlations. The results suggest that tumor infiltrating CD3(+) T cells, CD83(+) dendritic cells, serum CCL4 and serum interferon gamma represent relevant markers of disease outcome. PMID:26874795

  14. Donor cell leukemia after allogeneic peripheral blood stem cell transplantation: a case report and literature review.

    Science.gov (United States)

    Murata, Makoto; Ishikawa, Yuichi; Ohashi, Haruhiko; Terakura, Seitaro; Ozeki, Kazutaka; Kiyoi, Hitoshi; Naoe, Tomoki

    2008-07-01

    A 49-year-old male developed recurrent acute myeloid leukemia 27 months after allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical brother. The immunophenotype of the blastic cell population was incompatible with that of the pre-transplant blast cells; a mutation in C/EBPA gene was found in the pre-transplant blast cells that was not present in the post-transplant blast cells, and short tandem repeat analysis of marrow cells, which included 71% blasts, showed complete donor chimera. Thus, this recipient developed donor cell leukemia (DCL). The donor was healthy when DCL developed in the recipient as well as before donation of the peripheral blood stem cells. Only five cases of DCL after PBSCT have been reported in the literature. As a mechanism for the development of DCL, a vigorous proliferative demand on the donor cells, which often correlates with a higher likelihood of replication error or mutation, has been proposed. Peripheral blood stem cells might have an advantage in that they are associated with a low incidence of DCL development because PBSCT recipients receive a higher total cell dose than recipients of bone marrow or cord blood cells. PMID:18470599

  15. Anticancer activity of cryptotanshinone on acute lymphoblastic leukemia cells.

    Science.gov (United States)

    Wu, Ching-Fen; Klauck, Sabine M; Efferth, Thomas

    2016-09-01

    Cryptotanshinone, a well-known diterpene quinone from a widely used traditional Chinese herb named Salvia miltiorrhiza, has been reported for its therapeutical potentials on diverse activities. In this study, pharmacological effects of cryptotanshinone on acute lymphoblastic leukemia cells were investigated. IC50 values of 5.0 and 4.8 were obtained in CEM/ADR5000 and CCRF-CEM. Microarray-based mRNA expression revealed that cryptotanshinone regulated genes associated with cell cycle, DNA damage, reactive oxygen species (ROS), NFκB signaling and cellular movement. The involvement of these pathways in the mode of action of cryptotanshinone was subsequently validated by additional independent in vitro studies. Cryptotanshinone stimulated ROS generation and induced DNA damage. It arrested cells in G2/M phase of the cell cycle and induced apoptosis as measured by annexin V-FITC-conjugating fluorescence. The induction of the intrinsic apoptotic pathway by cryptotanshinone was proved by loss of mitochondrial membrane potential and increased cleavage of caspase 3/7, caspase 9 and poly ADP ribose polymerase (PARP). DNA-binding motif analysis of the microarray-retrieved deregulated genes in the promoter region revealed NFκB as potential transcription factor involved in cryptotanshinone's mode of action. Molecular docking and Western blotting provided supportive evidence, suggesting that cryptotanshinone binds to IKK-β and inhibits the translocation of p65 from the cytosol to the nucleus. In addition, cryptotanshinone inhibited cellular movement as shown by a fibronectin-based cellular adhesion assay, indicating that this compound exerts anti-invasive features. In conclusion, cryptotanshinone exerts profound cytotoxicity, which is caused by multispecific modes of actions, including G2/M arrest, apoptosis and inhibition of cellular movement. The inhibitory activities of this compound may be explained by inhibition of NFκB, which orchestrates all these mechanisms. PMID

  16. Knockdown of WAVE1 enhances apoptosis of leukemia cells by downregulating autophagy.

    Science.gov (United States)

    Zhang, Zhaoxia; Wu, Benqing; Chai, Wenwen; Cao, Lizhi; Wang, Yangping; Yu, Yan; Yang, Liangchun

    2016-06-01

    Chemoresistance of leukemia constitutes a great challenge for successful treatment of leukemia. Autophagy has recently attracted increasing attention for its role in conferring resistance to various conventional anti-neoplastic regiments. In the present study, the authors showed that WAVE1, a member of WASP family verprolin-homologous proteins, is a critical regulator of chemoresistance during autophagy. It is positively correlated with clinical status in pediatric acute myeloblastic leukemia (AML) and leukemia cell lines. The knockdown of WAVE1 expression decreased autophagy was accompanied by an upregulation of autophagic marker microtubule-associated protein light chain 3 (LC3)-Ⅱ, a degradation of SQSTM1/sequestosome 1 (p62) and the formation of autophagosomes. Moreover, a suppression of WAVE1 expression increased the sensitivity of leukemia cells to chemotherapy and apoptosis, and depletion of WAVE1 expression promoted the translocation of Bcl-2 from mitochondria into the cytoplasm. In addition, a knockdown of PI3K-Ⅲ expression significantly inhibited WAVE1-mediated autophagy. Furthermore, suppression of WAVE1 expression blocked the interactions between Beclin1 and PI3K-Ⅲ and the disassociation of Beclin1-Bcl-2 during enhanced autophagy. The above results suggested that WAVE1 is a critical pro-autophagic protein capable of enhancing cell survival and regulating chemoresistance in leukemia cells potentially through the Beclin1/Bcl-2 and Beclin1/PI3K-Ⅲ complex-dependent pathways. PMID:27035872

  17. Tumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancer

    OpenAIRE

    García-Martínez, Elena; Gil, Ginés Luengo; Benito, Asunción Chaves; González-Billalabeitia, Enrique; Conesa, María Angeles Vicente; García, Teresa García; García-Garre, Elisa; Vicente, Vicente; de la Peña, Francisco Ayala

    2014-01-01

    Introduction Tumor microenvironment immunity is associated with breast cancer outcome. A high lymphocytic infiltration has been associated with response to neoadjuvant chemotherapy, but the contribution to response and prognosis of immune cell subpopulations profiles in both pre-treated and post-treatment residual tumor is still unclear. Methods We analyzed pre- and post-treatment tumor-infiltrating immune cells (CD3, CD4, CD8, CD20, CD68, Foxp3) by immunohistochemistry in a series of 121 bre...

  18. RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Houcai; Yu, Jing; Zhang, Lixia; Xiong, Yuanyuan; Chen, Shuying; Xing, Haiyan; Tian, Zheng; Tang, Kejing; Wei, Hui; Rao, Qing; Wang, Min; Wang, Jianxiang, E-mail: wangjx@ihcams.ac.cn

    2014-04-18

    Highlights: • RPS27a expression was up-regulated in advanced-phase CML and AL patients. • RPS27a knockdown changed biological property of K562 and K562/G01 cells. • RPS27a knockdown affected Raf/MEK/ERK, P21 and BCL-2 signaling pathways. • RPS27a knockdown may be applicable for new combination therapy in CML patients. - Abstract: Ribosomal protein S27a (RPS27a) could perform extra-ribosomal functions besides imparting a role in ribosome biogenesis and post-translational modifications of proteins. The high expression level of RPS27a was reported in solid tumors, and we found that the expression level of RPS27a was up-regulated in advanced-phase chronic myeloid leukemia (CML) and acute leukemia (AL) patients. In this study, we explored the function of RPS27a in leukemia cells by using CML cell line K562 cells and its imatinib resistant cell line K562/G01 cells. It was observed that the expression level of RPS27a was high in K562 cells and even higher in K562/G01 cells. Further analysis revealed that RPS27a knockdown by shRNA in both K562 and K562G01 cells inhibited the cell viability, induced cell cycle arrest at S and G2/M phases and increased cell apoptosis induced by imatinib. Combination of shRNA with imatinib treatment could lead to more cleaved PARP and cleaved caspase-3 expression in RPS27a knockdown cells. Further, it was found that phospho-ERK(p-ERK) and BCL-2 were down-regulated and P21 up-regulated in RPS27a knockdown cells. In conclusion, RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells. It appears that drugs targeting RPS27a combining with tyrosine kinase inhibitor (TKI) might represent a novel therapy strategy in TKI resistant CML patients.

  19. Immunophenotyping of mature T/NK cell neoplasm presenting as leukemia

    Directory of Open Access Journals (Sweden)

    S Gujral

    2010-01-01

    Full Text Available Introduction : Mature T/NK cell lymphomas (MTNKL presenting as leukemia are rare and show considerable overlapping of clinical, morphological and immunophenotypic features. AIM: Critical analysis of the morphology and immunophenotypic profile of MTNKL. Materials and Methods : We reviewed 380 consecutive cases of mature lymphoid neoplasm that presented as leukemia and were diagnosed on morphology and immunophenotyping of bone marrow and/or peripheral blood samples. Results : Peripheral blood and bone marrow involvement was seen in all cases. MTNKL constituted 4% (nine cases of all mature lymphoid neoplasms presenting as leukemia. It included four cases of T-large granular leukemia (T-LGL, two of T-cell prolymphocytic leukemia small cell variant (T-PLL, two of adult T-cell leukemia/lymphoma (ATLL and one of primary cutaneous gamma delta T-cell lymphoma (PCGDTCL. T-LGL revealed CD4-/CD8+ phenotype in three, and CD4+/CD8+ phenotype in one case. CD56 was absent in all the cases of T-LGL. One case of T- PLL small cell variant showed CD4+/CD8- phenotype, while the other revealed CD4-/CD8+ phenotype. Both cases of ATLL showed CD4+/CD8+/CD25+ phenotype. The single case of PCGDTCL showed CD4-/CD8- phenotype pattern. CD3 and CD5 were expressed in all MTNKL. CD7 was absent in three cases of T-LGL. TCRα/β was performed in three cases of T-LGL and was positive in all. TCRα/β was also seen in both the cases of T-PLL small variant. However, TCRα/β was seen in the single case of PCGDTCL. Conclusion : Mature nodal T/NK cell neoplasms are rare and MTNKL presenting as leukemia are even rarer. There is an overlap between the immunophenotypic profiles of different MTNKL subtypes and elaborate T/NK cell panels are required for their evaluation.

  20. Farnesyltransferase inhibitor tipifarnib inhibits Rheb prenylation and stabilizes Bax in acute myelogenous leukemia cells

    OpenAIRE

    Ding, Husheng; McDonald, Jennifer S.; Yun, Seongseok; Schneider, Paula A.; Peterson, Kevin L.; Flatten, Karen S.; Loegering, David A.; Ann L Oberg; Riska, Shaun M.; Huang, Shengbing; Sinicrope, Frank A.; Adjei, Alex A.; Judith E Karp; Meng, X. Wei; Kaufmann, Scott H.

    2014-01-01

    Although farnesyltransferase inhibitors have shown promising activity in relapsed lymphoma and sporadic activity in acute myelogenous leukemia, their mechanism of cytotoxicity is incompletely understood, making development of predictive biomarkers difficult. In the present study, we examined the action of tipifarnib in human acute myelogenous leukemia cell lines and clinical samples. In contrast to the Ras/MEK/ERK pathway-mediated Bim upregulation that is responsible for tipifarnib-induced ki...

  1. Prdm14 initiates lymphoblastic leukemia after expanding a population of cells resembling common lymphoid progenitors

    OpenAIRE

    E J Dettman; Simko, Stephen J.; Ayanga, Bernard; Carofino, Brandi; Margolin, Judith; Morse, Herbert C.; Justice, Monica J.

    2011-01-01

    Understanding the heterogeneous genetic mechanisms of tumor initiation in lymphoid leukemias (LL) will lead to improvements in prognostic classification and treatment regimens. In previous studies of mouse leukemias, we showed that retroviral insertion at the Evi32 locus leads to increased expression of Prdm14, a pluripotency gene implicated in the self-renewal capacity of embryonic stem cells and the early stages of breast cancer. Here we show that PRDM14 is also overexpressed in ~25% of hum...

  2. Acute Lymphocytic Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, however, the bone marrow produces abnormal white blood ...

  3. Acute Myeloid Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, however, the bone marrow produces abnormal white blood ...

  4. Adenovirus-mediated CTLA4Ig gene inhibits infiltration of immune cells and cell apoptosis in rats after liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Guo-Ping Jiang; Zhen-Hua Hu; Shu-Sen Zheng; Chang-Ku Jia; Ai-Bin Zhang; Wei-Lin Wang

    2005-01-01

    AIM: To investigate the role of adenovirus-mediated CTLA4Ig gene therapy in inhibiting the infiltration of macrophages and CD8+T cells and cell apoptosis after liver transplantation.METHODS: The rat orthotopic liver transplantation model was applied. The rats were divided into three groups:group Ⅰ: rejection control (SD-to-Wistar); group Ⅱ: acute rejection treated with intramuscular injection of CsA injection of 1× 109 PFU adenovirus-mediated CTLA4Ig gene liquor in dorsal vein of penis 7 d before liver transplantation(SD-to-Wistar+CTLA4Ig). Immunohistochemistry and transferase-mediated dUTPnick-end labeling (TUNEL)were used to analyze the expression of CTLA4Ig gene in liver, infiltration of macrophages and CD8+T cells, cell apoptosis in grafts at different time-points after liver transplantation. Histopathological examination was done.RESULTS: CTLA4Ig gene expression was positive in liver on d 7 after administering adenovirus-mediated CTLA4Ig gene via vein, and remained positive until day 60 after liver transplantation. Infiltration of macrophages and CD8+T cells in CTLA4Ig-treated group was less than in rejection control group and CsA-treated group. The apoptotic index of rejection group on d 3, 5, and 7 were significantly higher than that of CTLA4Ig-treated group. A good correlation was found between severity of rejection reaction and infiltration of immune activator cells or cell apoptotic index in grafts.CONCLUSION: CTLA4Ig gene is constantly expressed in liver and plays an important role in inducing immune tolerance.

  5. Cytologic Phenotypes of B-Cell Acute Lymphoblastic Leukemia-

    Directory of Open Access Journals (Sweden)

    Ramyar Asghar

    2009-06-01

    Full Text Available Acute lymphoblastic leukemia (ALL is a malignant disorder of lymphoid precursor cells, which could be classified according to morphological and cytochemical methods as well as immunophenotyping. Twenty patients with ALL, who had been referred to the Children's Medical Center Hospital, during the year 2007, were enrolled in this study in order to evaluate the morphologic and immunophenotypic profile of these patients. Cytologic analysis of blood and bone marrow samples revealed that the frequency of ALL-L1 was 70%, followed by ALL-L2 and ALL-L3. The onset age of the patients with ALL-L1 was significantly lower than the patients with L2/L3. Severe anemia was significantly detected more in L1 group. Flow cytometic study of bone marrow showed that 10 cases had Pre-B1 ALL and 7 cases had Pre-B2 ALL, while three cases had Pro-B ALL. Comparisons of the characteristics and clinical manifestations among these groups did not show any appreciable difference. There were an increase percentage of CD20+ cells and a decrease CD10+ cells in pre-B2 group in comparison with pre-B1 group. Fifteen patients were in standard risk and five were in high risk. Although standard risk patients were more common in the group of pre-B1, this was not significant. Our results confirm the previous reports indicating heterogeneity of ALL. Immunophenotyping is not the only diagnostic test of importance, while morphological assessment still can be used in the diagnosis and classification of the disease.

  6. Childhood Leukemia

    Science.gov (United States)

    ... cells. It is the most common type of childhood cancer. Your blood cells form in your bone ... in the bones or joints Risk factors for childhood leukemia include having a brother or sister with ...

  7. Leukemia cutis resembling a flare-up of psoriasis

    OpenAIRE

    Ferreira, M; Caetano, M.; I. Amorim; Selores, M

    2006-01-01

    Abstract Leukemia cutis represents a skin infiltration by leukemic cells. Clinically it can mimic a wide variety of dermatoses. We describe the case of a 64-year-old man with psoriasis who presented with a 4-day history of erythematous, slightly scaly, asymptomatic plaques distributed on the trunk and upper-extremities, and associated asthenia, myalgias, and anorexia. A skin biopsy revealed a leukemic infiltrate. Studies of peripheral blood and bone marrow provided a diagnosis of acute mon...

  8. Role for protein geranylgeranylation in adult T-cell leukemia cell survival

    International Nuclear Information System (INIS)

    Adult T-cell leukemia (ATL) is a fatal lymphoproliferative disease that develops in human T-cell leukemia virus type I (HTLV-I)-infected individuals. Despite the accumulating knowledge of the molecular biology of HTLV-I-infected cells, effective therapeutic strategies remain to be established. Recent reports showed that the hydroxyl-3-methylglutaryl (HMG)-CoA reductase inhibitor statins have anti-proliferative and apoptotic effects on certain tumor cells through inhibition of protein prenylation. Here, we report that statins hinder the survival of ATL cells and induce apoptotic cell death. Inhibition of protein geranylgeranylation is responsible for these effects, since simultaneous treatment with isoprenoid precursors, geranylgeranyl pyrophosphate or farnesyl pyrophosphate, but not a cholesterol precursor squalene, restored the viability of ATL cells. Simvastatin inhibited geranylgeranylation of small GTPases Rab5B and Rac1 in ATL cells, and a geranylgeranyl transferase inhibitor GGTI-298 reduced ATL cell viability more efficiently than a farnesyl transferase inhibitor FTI-277. These results not only unveil an important role for protein geranylgeranylation in ATL cell survival, but also implicate therapeutic potentials of statins in the treatment of ATL

  9. Significance of mast cell renal infiltration in patients with anti-GBM nephritis.

    Science.gov (United States)

    Wu, Xiao-Mei; Zhang, Yi-Yan; Zhang, Ming-Chao; Zhang, Li-Hua; Zeng, Cai-Hong; Liu, Zhi-Hong; Tang, Zheng

    2016-07-01

    To investigate the role of mast cells (MCs) renal infiltration in the progression of human anti-GBM nephritis, 38 patients diagnosed with anti-GBM nephritis were enrolled. Renal biopsies were performed. Immunohistochemistry was conducted to detect MCs in renal tissues. Patients were divided into group 1 (MCs SCr 8.95 ± 3.66 vs. 4.75 ± 2.73 mg/dL, p < 0.001), urine retinol-binding protein (RBP 29.8 ± 13.9 vs. 15.7 ± 11.5 mg/dL, p = 0.005), and lower urinary osmotic pressure. Pathologically, patients of group 2 had a higher percentage of fibrous/fibrocellular crescents (66.7 ± 21.9 vs. 47.0 ± 33.6%, p = 0.037) but a lower percentage of cellular crescents. More CD8 (268 mm(-2) vs. 180 mm(-2), p = 0.045) and CD68 (268 mm(-2) vs. 180 mm(-2), p = 0.045) positive cells infiltrating the interstitium were observed in group 2. Furthermore, renal MCs correlated significantly with the total number of crescents and the tubular interstitial CD8 and CD68 positive cells. And, the number of MCs was associated with the histological types. The renal function was significantly different between the two groups at presentation. However, at 3 and 6 month follow-up, the patient outcome was associated with the histological types. Our study showed that MC infiltrations were associated with chronic lesions in anti-GBM nephritis and may be involved in the loss of renal function with pathological changes. PMID:27095326

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

    Science.gov (United States)

    2016-06-17

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

  11. Acute liver failure due to natural killer-like T-cell leukemia/lymphoma: A case report and review of the Literature

    Institute of Scientific and Technical Information of China (English)

    Evan S Dellon; Shannon R Morris; Wozhan Tang; Cherie H Dunphy; Mark W Russo

    2006-01-01

    Acute liver failure (ALF) is a medical emergency requiring immediate evaluation for liver transplantation. We describe an unusual case of a patient who presented with ascites, jaundice, and encephalopathy and was found to have ALF due to natural killer (NK)-like T cell leukemia/lymphoma. The key immunophenotype was CD2+, CD3+, CD7+, CD56+. This diagnosis, which was based on findings in the peripheral blood and ascitic fluid, was confirmed with liver biopsy, and was a contraindication to liver transplantation. A review of the literature shows that hematologic malignancies are an uncommon cause of fulminant hepatic failure, and that NK-like T-cell leukemia/lymphoma is a relatively recently recognized entity which is characteristically CD3+ and CD56+. This case demonstrates that liver biopsy is essential in diagnosing unusual causes of acute liver failure, and that infiltration of the liver with NK-like T-cell lymphoma/leukemia can cause acute liver failure.

  12. A rare case of plasma cell leukemia in a 35 year old

    Directory of Open Access Journals (Sweden)

    Rupal V Dosi

    2010-01-01

    Full Text Available Plasma cell leukemia is a rare, aggressive form of multiple myeloma. A 35-year-old male presented with backache, generalized weakness, and facial puffiness. His complete blood count showed anemia and a high WBC count with atypical cells on peripheral smear. Bone marrow examination showed more than 90% of atypical plasma cells, confirming a diagnosis of plasma cell leukemia. Patient also had azotemia, hypercalcemia, and hyperuricemia. The patient was started on chemotherapy along with supportive care. Patient improved dramatically and he was discharged on regular follow-up.

  13. ROLE OF PANCREATIC STELLATE CELLS AND GALECTIN-3 ON PROLIFERATION AND INFILTRATION OF HUMAN PANCREATIC CANCER CELL LINE SW1990

    Institute of Scientific and Technical Information of China (English)

    JIANG Hai-biao; XU Ming; WANG Xing-peng

    2008-01-01

    Objective To investigate the role of pancreatic stellate cells (PSCs) and galectin-3 (GAL-3)on the proliferation and infiltration of pancreatic cancer cell line SW1990. Methods Human pancreatic cancercell line SW1990 and PSCs were cultured in vitro. Supernatant of cultured PSCs and SW1990 cells was collected.Expressions of GAL-3 in SW1990 cells and PSCs were detected by ELISA, RT-PCR and Western blot. Theproliferation of those cultured PSCs and SW1990 cells were measured by MTT assay and flowcytometry. Infiltrationof SW1990 cells was detected by cell infiltration kit. Results SW1990 cells expressed GAL-3 and the expressionwas up-regulated by the supernatant fluid of cultured PSCs. PSCs did not express GAL-3. SW1990 cells couldstimulate the proliferation of PSCs via GAL-3. GAL-3 antibody could inhibit SW1990 cells proliferation andinfiltration, which indicated that supernatant of PSCs might stimulate the proliferation of SW1990 cells through theinteraction with GAL-3 protein. The supernatant fluid of PSCs could enhance the invasiveness of SW1990 cellsthrough the interaction with GAL-3. Conclusion GAL-3 and PSCs was involved in the proliferation andinfiltration process of pancreatic cancer.

  14. CNS Infiltration of Peripheral Immune Cells: D-Day for Neurodegenerative Disease?

    OpenAIRE

    Rezai-Zadeh, Kavon; Gate, David; Town, Terrence

    2009-01-01

    While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as “immune privilege,” it is now clear that immune responses do occur in the CNS—giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripher...

  15. Effect of DC-CIK cell on the proliferation, apoptosis and differentiation of leukemia cells

    Institute of Scientific and Technical Information of China (English)

    Hui-Qing Qu; Xiao-Sheng Zhou; Xiao-Long Zhou; Jian Wang

    2014-01-01

    Objective:To observe the effect of co-culture cytokine-induced killer cells(CIK) and homologous dendritic cells(DC) on the proliferative activity and phenotype change of theDC-CIK cell and the cell killing activity of leukemiaHL-60.Methods:50 mL cord blood sample was obtained from infants delivered by full term healthy woman and the cord blood mononuclear cells were isolated by density gradient centrifugation.Non-adherent cells were collectedfor the induction culture ofCIK, adherent cells were differentiated into matureDC; cultured matureDC was mixed with andCIK in the proportion of1:5 for12 d.Killing activity ofDC-CIK co-cultured cell on leukemiaHL-60 was detected byMTT assay.Results:Compared withCIKs, the co-culturedDC-CIKs presented a markedly higher proliferation and killing activity.Conclusions:Co-culture ofDC-CIK cells led to a significant increase of the proliferation and cytotoxicity of CIK.

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

    Science.gov (United States)

    Stilgenbauer, S; Lichter, P; Döhner, H

    2000-03-01

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

  17. Synergistic effect of green tea EGCG treatment with gamma radiation in leukemia cell necrosis

    International Nuclear Information System (INIS)

    During cancer therapy, gamma-ray irradiation and treatment of anti-cancer chemicals destroy the normal cells as well as cancer cells. In this study, we investigated the effect of epigallocathechin-gallate (EGCG) extracted from green tea, which is known to have anti-cancer and anti-oxident activities, in order to find out the feasible method to protect the normal cells and to kill the cancer cells efficiently. We investigated the effect of EGCG on the leukemia cell growth and cell necrosis, especially when treated along with gamma radiation. The EGCG inhibited the leukemia cell, HL-60, growth at the appropriate concentration while it exhibited no influence on the normal cell growth. More significantly, it enhanced leukemia cell necrosis when its treatment was combined with gamma irradiation. Simultaneous treatment of EGCG and gamma radiation increased leukemia cell necrosis up to 35% compared with separate treatments. These results suggest that drinking of green tea or co-treatment of EGCG during gamma irradiation therapy may result in better prognosis through enhancement of the tumor cell necrosis and protection of the normal cells

  18. Animals Models of Human T Cell Leukemia Virus Type I Leukemogenesis.

    Science.gov (United States)

    Niewiesk, Stefan

    2016-03-31

    Infection with human T cell leukemia virus type I (HTLV-I) causes adult T cell leukemia (ATL) in a minority of infected individuals after long periods of viral persistence. The various stages of HTLV-I infection and leukemia development are studied by using several different animal models: (1) the rabbit (and mouse) model of persistent HTLV-I infection, (2) transgenic mice to model tumorigenesis by HTLV-I specific protein expression, (3) ATL cell transfers into immune-deficient mice, and (4) infection of humanized mice with HTLV-I. After infection, virus replicates without clinical disease in rabbits and to a lesser extent in mice. Transgenic expression of both the transactivator protein (Tax) and the HTLV-I bZIP factor (HBZ) protein have provided insight into factors important in leukemia/lymphoma development. To investigate factors relating to tumor spread and tissue invasion, a number of immune-deficient mice based on the severe combined immunodeficiency (SCID) or non-obese diabetic/SCID background have been used. Inoculation of adult T cell leukemia cell (lines) leads to lymphoma with osteolytic bone lesions and to a lesser degree to leukemia development. These mice have been used extensively for the testing of anticancer drugs and virotherapy. A recent development is the use of so-called humanized mice, which, upon transfer of CD34(+)human umbilical cord stem cells, generate human lymphocytes. Infection with HTLV-I leads to leukemia/lymphoma development, thus providing an opportunity to investigate disease development with the aid of molecularly cloned viruses. However, further improvements of this mouse model, particularly in respect to the development of adaptive immune responses, are necessary. PMID:27034390

  19. Lineage Switching in Acute Leukemias: A Consequence of Stem Cell Plasticity?

    Directory of Open Access Journals (Sweden)

    Elisa Dorantes-Acosta

    2012-01-01

    Full Text Available Acute leukemias are the most common cancer in childhood and characterized by the uncontrolled production of hematopoietic precursor cells of the lymphoid or myeloid series within the bone marrow. Even when a relatively high efficiency of therapeutic agents has increased the overall survival rates in the last years, factors such as cell lineage switching and the rise of mixed lineages at relapses often change the prognosis of the illness. During lineage switching, conversions from lymphoblastic leukemia to myeloid leukemia, or vice versa, are recorded. The central mechanisms involved in these phenomena remain undefined, but recent studies suggest that lineage commitment of plastic hematopoietic progenitors may be multidirectional and reversible upon specific signals provided by both intrinsic and environmental cues. In this paper, we focus on the current knowledge about cell heterogeneity and the lineage switch resulting from leukemic cells plasticity. A number of hypothetical mechanisms that may inspire changes in cell fate decisions are highlighted. Understanding the plasticity of leukemia initiating cells might be fundamental to unravel the pathogenesis of lineage switch in acute leukemias and will illuminate the importance of a flexible hematopoietic development.

  20. Characterization of miRNomes in Acute and Chronic Myeloid Leukemia Cell Lines

    Institute of Scientific and Technical Information of China (English)

    Qian Xiong; Jiangwei Yan; Songnian Hu; Xiangdong Fang; Yadong Yang; Hai Wang; Jie Li; Shaobin Wang; Yanming Li; Yaran Yang; Kan Cai; Xiuyan Ruan

    2014-01-01

    Myeloid leukemias are highly diverse diseases and have been shown to be associated with microRNA (miRNA) expression aberrations. The present study involved an in-depth miRNome analysis of two human acute myeloid leukemia (AML) cell lines, HL-60 and THP-1, and one human chronic myeloid leukemia (CML) cell line, K562, via massively parallel signature sequenc-ing. mRNA expression profiles of these cell lines that were established previously in our lab facil-itated an integrative analysis of miRNA and mRNA expression patterns. miRNA expression profiling followed by differential expression analysis and target prediction suggested numerous miRNA signatures in AML and CML cell lines. Some miRNAs may act as either tumor suppres-sors or oncomiRs in AML and CML by targeting key genes in AML and CML pathways. Expres-sion patterns of cell type-specific miRNAs could partially reflect the characteristics of K562, HL-60 and THP-1 cell lines, such as actin filament-based processes, responsiveness to stimulus and phag-ocytic activity. miRNAs may also regulate myeloid differentiation, since they usually suppress dif-ferentiation regulators. Our study provides a resource to further investigate the employment of miRNAs in human leukemia subtyping, leukemogenesis and myeloid development. In addition, the distinctive miRNA signatures may be potential candidates for the clinical diagnosis, prognosis and treatment of myeloid leukemias.

  1. DNA Damage, Cell Cycle Arrest, and Apoptosis Induction Caused by Lead in Human Leukemia Cells

    OpenAIRE

    Yedjou, Clement G.; Tchounwou, Hervey M.; Tchounwou, Paul B.

    2015-01-01

    In recent years, the industrial use of lead has been significantly reduced from paints and ceramic products, caulking, and pipe solder. Despite this progress, lead exposure continues to be a significant public health concern. The main goal of this research was to determine the in vitro mechanisms of lead nitrate [Pb(NO3)2] to induce DNA damage, apoptosis, and cell cycle arrest in human leukemia (HL-60) cells. To reach our goal, HL-60 cells were treated with different concentrations of Pb(NO3)...

  2. Inhibition of MerTK increases chemosensitivity and decreases oncogenic potential in T-cell acute lymphoblastic leukemia

    OpenAIRE

    Brandao, L N; Winges, A; Christoph, S; Sather, S; Migdall-Wilson, J; Schlegel, J.; McGranahan, A; Gao, D.; Liang, X; DeRyckere, D; Graham, D K

    2013-01-01

    Pediatric leukemia survival rates have improved dramatically over the past decades. However, current treatment protocols are still largely ineffective in cases of relapsed leukemia and are associated with a significant rate of chronic health conditions. Thus, there is a continued need for new therapeutic options. Here, we show that mer receptor tyrosine kinase (MerTK) was abnormally expressed in approximately one half of pediatric T-cell leukemia patient samples and T-cell acute lymphoblastic...

  3. Hypergranular precursor B-cell acute lymphoblastic leukemia in a 16-year-old boy

    Directory of Open Access Journals (Sweden)

    Tembhare Prashant

    2009-07-01

    Full Text Available Presence of cytoplasmic granules in the blasts is a well known feature of myeloid leukemia. ALL presenting with the numerous cytoplasmic granules in blasts is a rarity and may be misdiagnosed as acute myeloid leukemia. We describe a rare case of hypergranular precursor B-cell acute lymphoblastic leukemia (ALL in an adolescent male expressing CD10, CD19, CytoCD22, CD34, as well as CD13 and CD117. The blasts were cytochemically negative for myeloperoxidase (MPO, and acid phosphatase (ACP but were positive for non-specific esterase (NSE. In centers where immunophenotypic panel is usually decided on the basis of morphology with limited antibodies may result in an erroneous typing of such rare diseases. Hence it is important to be aware of this rare entity and to confirm the lineage of acute leukemia by using a comprehensive panel of antibodies for immunophenotypic analysis.

  4. Role of exosomes released by chronic myelogenous leukemia cells in angiogenesis

    OpenAIRE

    Taverna, S; Flugy Papè, AM; SAIEVA, L; Kohn, EC; A. Santoro; Meraviglia, S; De Leo, G; ALESSANDRO, R

    2011-01-01

    The present study is designed to assess if exosomes released from Chronic Myelogenous Leukemia (CML) cells may modulate angiogenesis. We have isolated and characterized the exosomes generated from LAMA84 CML cells and demonstrated that addition of exosomes to human vascular endothelial cells (HUVEC) induces an increase of both ICAM-1 and VCAM-1 cell adhesion molecules and interleukin-8 expression. The stimulation of cell-cell adhesion molecules was paralleled by a dose-dependent increase of a...

  5. CD52 expression in T-cell large granular lymphocyte leukemia--implications for treatment with alemtuzumab.

    Science.gov (United States)

    Osuji, N; Del Giudice, I; Matutes, E; Morilla, A; Owusu-Ankomah, K; Morilla, R; Dunlop, A; Catovksy, D

    2005-05-01

    Few reports on the successful treatment of T-cell large granular lymphocyte (LGL) leukemia with the humanized anti-CD52 monoclonal antibody alemtuzumab are emerging in the literature. The expression of CD52 by LGLs has not been previously investigated. Using semi-quantitative 2- and 3-color flow cytometry, we documented the expression of CD52 in 100% of abnormal cells in T-cell LGL leukemia (n = 11) and natural killer (NK) cell LGL leukemia (n = 2), and showed no significant difference in CD52 expression between T-cell prolymphocytic leukemia (PLL) and T-cell LGL leukemia. Higher CD52 expression has been noted in responders to alemtuzumab in T-cell PLL and in chronic lymphocytic leukemia (CLL), a B-cell disorder. The strong and consistent expression of CD52 shown here highlights the potential role of alemtuzumab in the treatment of refractory T-cell LGL leukemia and possibly aggressive NK cell leukemia. PMID:16019510

  6. PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation.

    Science.gov (United States)

    Kong, Y; Zhang, J; Claxton, D F; Ehmann, W C; Rybka, W B; Zhu, L; Zeng, H; Schell, T D; Zheng, H

    2015-01-01

    Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1(hi)TIM-3(+) cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1(hi)TIM-3(+) T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1(hi)TIM-3(+) cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation. PMID:26230954

  7. PD-1hiTIM-3+ T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation

    International Nuclear Information System (INIS)

    Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1hiTIM-3+ cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1hiTIM-3+ T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1hiTIM-3+ cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation

  8. Oral Manifestations of T-Cell Large Granular Lymphocytic Leukemia: a Case Report

    Directory of Open Access Journals (Sweden)

    Ioanna-Eirini Arvanitidou

    2011-06-01

    Full Text Available Background: T-cell large granular lymphocytic (T-LGL leukemia is a rare, chronic, often indolent lymphoproliferative disorder of mature T cells (CD3+. Severe neutropenia and other cytopenias are common features in patients with T-LGL leukemia and may cause infections, thus representing a major cause of morbidity in this disease. Immunosuppressive therapy with low-dose regimes of methotrexate, cyclophosphamide, corticosteroids or cyclosporine A is the treatment of choice. Amongst the variety of T-LGL leukemia complications, oral manifestations such as ulcers have been rarely reported. The purpose of this paper is to report a case of T-cell large granular lymphocyte leukemia with oral manifestations and to discuss their pathogenesis and management.Methods: In the present case, a 65 year old female with a two-month history of diagnosed T-LGL leukemia presented with oral lesions, including ulcerations on the ventral tongue and soft palate as well as swollen, erythematous and ulcerated gingiva. The patient was under treatment with methotrexate, granulocyte colony-stimulating factor (G-CSF and erythropoietin.Results: Considering patients’ medical history and clinical appearance of the lesions, a clinical diagnosis of a neutropenic ulcer of the tongue was established. The oral lesions resolved after treatment with antibiotics, topical steroids and antiseptics combined with improvement of the hematological condition. The pertinent literature related to T-LGL leukemia ethiopathology, diagnostics and treatment was discussed.Conclusions: Although rare, T-cell large granular lymphocytic leukemia should be included in the list of lymphoproliferative disorders, which may present with oral manifestations as a result of the disease and its treatment complications.

  9. Antiproliferative effect of rapamycin on human T-cell leukemia cell line Jurkat by cell cycle arrest and telomerase inhibition

    Institute of Scientific and Technical Information of China (English)

    Yan-min ZHAO; Qian ZHOU; Yun XU; Xiao-yu LAI; He HUANG

    2008-01-01

    Aim:To examine the ability of rapamycin to suppress growth and regulate telomerase activity in the human T-cell leukemia cell line Jurkat. Methods:Cell proliferation was assessed after exposure to rapamycin by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle progression and apoptosis were determined by flow cytometry. The proteins important for cell cycle progres-sion and Akt/mammalian target of rapamycin signaling cascade were assessed by Western blotting. Telomerase activity was quantified by telomeric repeat amplication protocol assay. The human telomerase reverse transcriptase (hTERT) mRNA levels were determined by semi-quantitative RT-PCR. Results:Rapamycin inhibited the proliferation of Jurkat, induced G1 phase arrest, unregulated the pro-tein level of p21 as well as p27, and downregulated cyclinD3, phospho-p70s6k, and phospho-s6, but had no effect on apoptosis. Treatment with rapamycin reduced telomerase activity, and reduced hTERT mRNA and protein expression. Conclusion:Rapamycin displayed a potent antileukemic effect in the human T-cell leukemia cell line by inhibition of cell proliferation through G1 cell cycle arrest and also through the suppression of telomerase activity, suggesting that rapamycin may have potential clinical implications in the treatment of some leukemias.

  10. Triptolide induces apoptotic cell death of human cholangiocarcinoma cells through inhibition of myeloid cell leukemia-1

    International Nuclear Information System (INIS)

    Cholangiocarcinoma (CCA), a devastating neoplasm, is highly resistant to current chemotherapies. CCA cells frequently overexpress the antiapoptotic protein myeloid cell leukemia-1(Mcl-1), which is responsible for its extraordinary ability to evade cell death. Triptolide, a bioactive ingredient extracted from Chinese medicinal plant, has been shown to inhibit cell proliferation and induce apoptosis in several cancers. CCK-8 assay was performed to detect cell survival rate in vitro. DAPI staining and Flow cytometry were used to analyze apoptosis. Western blot was performed to determine the expression levels of caspase-3, caspase-7, caspase-9, PARP, and Mcl-1. Quantitative real-time PCR and immunofluorescence were used to detect the expression levels of Mcl-1. The nude mice xenograft model was used to evaluate the antitumor effect of triptolide in vivo. Triptolide reduced cell viability in cholangiocarcinoma cell lines in a dose- and time-dependent manner, with IC50 values of 12.6 ± 0.6 nM, 20.5 ± 4.2 nM, and 18.5 ± 0.7 nM at 48 h for HuCCT1, QBC939, and FRH0201 respectively. Triptolide induced apoptosis in CCA cell lines in part through mitochondrial pathway. Using quantitative real-time PCR, western blot and immunofluorescence, we have shown that triptolide downregulates Mcl-1 mRNA and protein levels. Furthermore, triptolide inhibited the CCA growth in vivo. Triptolide has profound antitumor effect on CCA, probably by inducing apoptosis through inhibition of Mcl-1. Triptolide would be a promising therapeutic agent for CCA

  11. Quantitation, in vitro propagation, and characterization of preleukemic cells induced by radiation leukemia virus

    International Nuclear Information System (INIS)

    Intrathymic (i.t.) inoculation of radiation leukemia virus into C57BL/6 mice induces a population of preleukemic (PL) cells that can progress into mature thymic lymphomas upon transfer into syngeneic recipients. A minimum of 10(3) PL thymic cells are required to induce lymphomas in the recipient. Most of the individual lymphomas developed in mice which were inoculated with cells of a single PL thymus, derived from different T-cell precursors. PL thymic cells could be grown in vitro on a feeder layer consisting of splenic stromal cells. Growth medium was supplemented with supernatant harvested from an established radiation leukemia virus-induced lymphoma cell line (SR4). The in vitro-grown PL cells were characterized as Thy-1+, CD4+, CD8- T-cells, most of which expressed radiation leukemia virus antigens. Cultured PL cells were found to be nontumorigenic, based on their inability to form s.c. tumors. However, these cells could develop into thymic lymphomas if inoculated i.t. into syngeneic recipients. A culture of PL cells, maintained for 2 mo, showed clonal T-cell receptor arrangement. Lymphomas which developed in several recipient mice upon injection with these PL cells were found to possess the same T-cell receptor arrangement. These results indicate that PL cells can be adapted for in vitro growth while maintaining their preleukemic character

  12. Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in adult T-cell leukemia cells.

    Science.gov (United States)

    Kozako, Tomohiro; Soeda, Shuhei; Yoshimitsu, Makoto; Arima, Naomichi; Kuroki, Ayako; Hirata, Shinya; Tanaka, Hiroaki; Imakyure, Osamu; Tone, Nanako; Honda, Shin-Ichiro; Soeda, Shinji

    2016-05-01

    Adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1), requires new treatments. Drug repositioning, reuse of a drug previously approved for the treatment of another condition to treat ATL, offers the possibility of reduced time and risk. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate peroxisome proliferator-activated receptor-γ, which plays various roles in lipid metabolism, cellular differentiation, and apoptosis. Here, telmisartan reduced cell viability and enhanced apoptotic cells via caspase activation in ex vivo peripheral blood monocytes from asymptomatic HTLV-1 carriers (ACs) or via caspase-independent cell death in acute-type ATL, which has a poor prognosis. Telmisartan also induced significant growth inhibition and apoptosis in leukemia cell lines via caspase activation, whereas other angiotensin II receptor blockers did not induce cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation and autophagy. Thus, telmisartan simultaneously caused caspase activation and autophagy. A hypertension medication with antiproliferation effects on primary and leukemia cells is intriguing. Patients with an early diagnosis of ATL are generally monitored until the disease progresses; thus, suppression of progression from AC and indolent ATL to acute ATL is important. Our results suggest that telmisartan is highly effective against primary cells and leukemia cell lines in caspase-dependent and -independent manners, and its clinical use may suppress acute transformation and improve prognosis of patients with this mortal disease. This is the first report demonstrating a cell growth-inhibitory effect of telmisartan in fresh peripheral blood mononuclear cells from leukemia patients. PMID:27419050

  13. Composite vascular grafts with high cell infiltration by co-electrospinning.

    Science.gov (United States)

    Tan, Zhikai; Wang, Hongjie; Gao, Xiangkai; Liu, Tong; Tan, Yongjun

    2016-10-01

    There is an increasing demand for functional small-diameter vascular grafts (diameterpolycaprolactone, gelatin, and polyvinyl alcohol (PVA) by co-electrospinning, and the scaffolds were further functionalized by immobilizing heparin on them. The PVA fibers degraded rapidly in vivo and generated electrospun scaffolds with high porosity, which significantly enhanced cell proliferation and infiltration. The mechanical properties of the grafts are suitable for use in artery replacement. Heparin functionalization of the grafts yielded a good antithrombogenic effect, which was demonstrated in platelet adhesion tests. Moreover, in vitro and in vivo results demonstrated that the heparin release from the grafts enhanced the growth of endothelial cells, which is important for the endothelium of implanted grafts. The results of this study indicate that our method is effective and controllable for the fabrication of vascular grafts that meet the clinical requirements for blood vessel transplantation. PMID:27287133

  14. Identification of a novel SEPT9-ABL1 fusion gene in a patient with T-cell prolymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Rikio Suzuki

    2014-01-01

    Full Text Available T-cell prolymphocytic leukemia (T-PLL, a rare type of peripheral T-cell leukemia, is characterized by marked splenomegaly with rapidly progressive lymphocytosis and a poor prognosis. Nine kinds of ABL1 chimeric genes have been identified in various kinds of hematological malignancies, such as chronic myeloid leukemia and B- or T-lymphoblastic leukemia. However, there have been no reports describing T-PLL cases with ABL1 rearrangements. We herein report a case of T-PLL with a novel SEPT9-ABL1 fusion gene which induced strong resistance to tyrosine kinase inhibitors such as imatinib and dasatinib.

  15. Concise Review: Preleukemic Stem Cells: Molecular Biology and Clinical Implications of the Precursors to Leukemia Stem Cells

    OpenAIRE

    Pandolfi, Ashley; Barreyro, Laura; Steidl, Ulrich

    2013-01-01

    Despite the established use of poly-chemotherapy, relapse continues to be the most common cause of death in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The therapeutic elimination of all leukemia stem cells (LSC) and pre-LSC will be essential for achieving lasting cures. This article reviews recent and ongoing advances in understanding the roles of pre-LSC, and the aberrations that lead to pre-LSC formation and subsequent LSC transformation.

  16. Radiation exposure as a possible etiologic factor in hairy cell leukemia (leukemic reticuloendotheliosis).

    Science.gov (United States)

    Stewart, D J; Keating, M J

    1980-10-01

    The frequency of prior occupational, accidental, or therapeutic radiation exposure was significantly higher for hairy cell leukemia patients than for a control group of solid tumor patients (8/23 vs. 4/56, P risk of radiation exposure such as chemist, engineer, physicist, and health care facility worker (7/23 vs. 4/56, P < 0.01). The observation that the incidence of thyroid disorders among hairy cell leukemia patients was also unusually high (5/23 vs. 2/56, P < 0.05) was interpreted as further indirect evidence of excessive radiation exposure. It appears that radiation exposure may be an important contribution factor in the development of some case of hairy cell leukemia. PMID:7417955

  17. Signal transduction pathways and transcription factors triggered by arsenic trioxide in leukemia cells

    International Nuclear Information System (INIS)

    Arsenic trioxide (As2O3) is widely used to treat acute promyelocytic leukemia (APL). Several lines of evidence have indicated that As2O3 affects signal transduction and transactivation of transcription factors, resulting in the stimulation of apoptosis in leukemia cells, because some transcription factors are reported to associate with the redox condition of the cells, and arsenicals cause oxidative stress. Thus, the disturbance and activation of the cellular signaling pathway and transcription factors due to reactive oxygen species (ROS) generation during arsenic exposure may explain the ability of As2O3 to induce a complete remission in relapsed APL patients. In this report, we review recent findings on ROS generation and alterations in signal transduction and in transactivation of transcription factors during As2O3 exposure in leukemia cells.

  18. Interleukin 1 as an autocrine growth factor for acute myeloid leukemia cells

    International Nuclear Information System (INIS)

    Production of interleukin 1 (IL-1) by leukemic cells was studied in 13 cases of acute myeloid leukemia. Intracytoplasmic immunofluorescence studies showed that the cells invariably contained the cytokine. Endogenous labeling studies demonstrated that acute myeloid leukemia cells produced either only the 33-kDa propeptide or both the propeptide and the 17-kDa mature form of IL-1β. The 33-kDa propeptide IL-1α was always produced but was less frequently released. Involvement of IL-1 in leukemic cell growth was investigated using two antibodies specific for IL-1 subtypes, which inhibited spontaneous cell proliferation in the six cases studied. After acid treatment of the cells, a surface receptor for IL-1 could be demonstrated, which mediated 125I-labeled IL-1-specific uptake by leukemic cells. Furthermore, recombinant IL-1α or IL-1β induced significant cell proliferation in 10 12 cases. The above findings were uncorrelated with the cytologic type (French-American-British classification) of leukemia. The studies suggest that IL-1 may act as an autocrine growth factor in most cases of acute myeloid leukemia

  19. Establishment and characterization of a human monocytoid leukemia cell line, CTV-1.

    Science.gov (United States)

    Chen, P; Chiu, C; Chiou, T; Maeda, S; Chiang, H; Tzeng, C; Sugiyama, T; Chiang, B N

    1984-08-01

    A new human monocytoid leukemic cell line, CTV-1, was established from a patient with relapsed acute monoblastic leukemia. The characteristics of this cell line were evaluated by morphologic and cytochemical analyses, electron-microscopy, chromosome study, surface marker analysis and a study of differentiation potential with tumor-promoting agents. PMID:6593267

  20. Acute myeloid leukemia arising from a donor derived premalignant hematopoietic clone: A possible mechanism for the origin of leukemia in donor cells

    Directory of Open Access Journals (Sweden)

    Mark A. Dickson

    2014-01-01

    Full Text Available During recent years, it has become increasingly evident that donor leukemia following allogeneic transplant may be more common then realized in the past. We identified five cases of potential donor leukemia cases during past five years. The precise mechanism of the origin of such leukemias, however, remains poorly defined. In this short communication, we report a well documented case of donor-derived de novo acute myeloid leukemia (AML that developed fourteen years after allogeneic stem cell transplantation for treatment induced AML for his primary malignancy Immunoblastic lymphoma. This case allows us to postulate a possible mechanism of the origin of donor leukemia. The de novo AML clone contained a distinct cytogenetic abnormality, trisomy 11, which was simultaneously detected in preserved peripheral blood obtained at the time of transplantation as well as in the current bone marrow from an otherwise clinically and phenotypically normal donor. The findings from this unique case, provides insight into the process of leukemogenesis, and suggests that the sequence of events leading to leukemogenesis in this patient involved the senescence/apoptosis of normal donor hematopoietic cells due to telomere shortening resulting in the selective proliferation and transformation of this clone with MLL (mixed-lineage leukemia gene amplification.

  1. Lapatinib induces autophagic cell death and differentiation in acute myeloblastic leukemia

    Directory of Open Access Journals (Sweden)

    Chen YJ

    2016-07-01

    Full Text Available Yu-Jen Chen,1–4 Li-Wen Fang,5 Wen-Chi Su,6,7 Wen-Yi Hsu,1 Kai-Chien Yang,1 Huey-Lan Huang8 1Department of Medical Research, 2Department of Radiation Oncology, Mackay Memorial Hospital, 3Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, 4Institute of Pharmacology, Taipei Medical University, Taipei, 5Department of Nutrition, I-Shou University, Kaohsiung, 6Research Center for Emerging Viruses, China Medical University Hospital, 7Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 8Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan, Republic of China Abstract: Lapatinib is an oral-form dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR or ErbB/Her superfamily members with anticancer activity. In this study, we examined the effects and mechanism of action of lapatinib on several human leukemia cells lines, including acute myeloid leukemia (AML, chronic myeloid leukemia (CML, and acute lymphoblastic leukemia (ALL cells. We found that lapatinib inhibited the growth of human AML U937, HL-60, NB4, CML KU812, MEG-01, and ALL Jurkat T cells. Among these leukemia cell lines, lapatinib induced apoptosis in HL-60, NB4, and Jurkat cells, but induced nonapoptotic cell death in U937, K562, and MEG-01 cells. Moreover, lapatinib treatment caused autophagic cell death as shown by positive acridine orange staining, the massive formation of vacuoles as seen by electronic microscopy, and the upregulation of LC3-II, ATG5, and ATG7 in AML U937 cells. Furthermore, autophagy inhibitor 3-methyladenine and knockdown of ATG5, ATG7, and Beclin-1 using short hairpin RNA (shRNA partially rescued lapatinib-induced cell death. In addition, the induction of phagocytosis and ROS production as well as the upregulation of surface markers CD14 and CD68 was detected in lapatinib-treated U937 cells, suggesting the induction of

  2. Dose- and Time-Dependent Response of Human Leukemia (HL-60 Cells to Arsenic Trioxide Treatment

    Directory of Open Access Journals (Sweden)

    Paul B. Tchounwou

    2006-06-01

    Full Text Available The treatment of acute promyelocytic leukemia (APL has been based on the administration of all-trans retinoic acid plus anthracycline chemotherapy, which is very effective as first line therapy; however 25 to 30% of patients will relapse with their disease becoming refractory to conventional therapy. Recently, studies have shown arsenic trioxide to be effective in the treatment of acute promyelocytic leukemia. In this study, we used the human leukemia (HL-60 cell line as a model to evaluate the cytoxicity of arsenic trioxide based on the MTT assay. Data obtained from this assay indicated that arsenic trioxide significantly reduced the viability of HL-60 cells, showing LD50 values of 14.26 + 0.5μg/mL, 12.54 + 0.3μg/mL, and 6.4 + 0.6μg/mL upon 6, 12, and 24 hours of exposure, respectively; indicating a dose- and time-dependent response relationship. Findings from the present study indicate that arsenic trioxide is highly cytotoxic to human leukemia (HL-60 cells, supporting its use as an effective therapeutic agent in the management of acute promyelocytic leukemia.

  3. Infiltrating Mast Cells Correlate with Angiogenesis in Bone Metastases from Gastric Cancer Patients

    Directory of Open Access Journals (Sweden)

    Michele Ammendola

    2015-02-01

    Full Text Available While gastric cancer is a well established angiogenesis driven tumor, no data has been published regarding angiogenesis stimulated by mast cells (MCs positive for tryptase in bone metastases from gastric cancer patients (BMGCP. It is well established that MCs play a role in immune responses and more recently it was demonstrated that MCs have been involved in tumor angiogenesis. We analyzed infiltrating MCs and neovascularization in BMGCP diagnosed by histology. A series of 15 stage T3-4N2-3M1 (by AJCC for Gastric Cancer Staging 7th Edition BMGCP from bone biopsies were selected. Tumour tissue samples were evaluated by mean of immunohistochemistry and image analysis methods in terms of MCs density positive to tryptase (MCDPT, MCs area positive to tryptase (MCAPT, microvascular density (MVD and endothelial area (EA. A significant correlation between MCDPT, MCAPT, MVD and EA groups to each other was found by Pearson and t-test analysis (r ranged from 0.68 to 0.82; p-value ranged from 0.00 to 0.02. Our very preliminary data suggest that infiltrating MCs positive for tryptase may play a role in BMGCP angiogenesis, and could be further evaluated as a novel target of anti-angiogenic therapy.

  4. Infiltrated lanthanum strontium chromite anodes for solid oxide fuel cells: Structural and catalytic aspects

    Science.gov (United States)

    Oh, Tae-Sik; Yu, Anthony S.; Adijanto, Lawrence; Gorte, Raymond J.; Vohs, John M.

    2014-09-01

    Infiltration is a widely used fabrication method for solid oxide fuel cell (SOFC) composite electrodes. Here we report a study of the structure and electrocatalytic properties of SOFC anodes composed of a layer of lanthanum, strontium chromite (La0.8Sr0.2CrO3, LSCr), both with and without added transition metal dopants, infiltrated into a porous yttria-stabilized zirconia (YSZ) matrix. The structural evolution of the electrode upon reduction and under typical SOFC operating conditions is compared to that reported previously for La0.8Sr0.2Cr0.5Mn0.5O3-YSZ composite anodes. For the transition metal doped materials, a portion of the metal dopants were found to be exsolved from the LSCr lattice upon reduction and to be effective in promoting electro-oxidation of hydrogen. Exsolved cobalt particles were also found to be relatively stable when exposed to hydrocarbon fuels with low activity for the formation of carbon deposits.

  5. Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype

    Science.gov (United States)

    Gabrusiewicz, Konrad; Rodriguez, Benjamin; Wei, Jun; Hashimoto, Yuuri; Healy, Luke M.; Maiti, Sourindra N.; Thomas, Ginu; Zhou, Shouhao; Wang, Qianghu; Elakkad, Ahmed; Liebelt, Brandon D.; Yaghi, Nasser K.; Ezhilarasan, Ravesanker; Huang, Neal; Weinberg, Jeffrey S.; Prabhu, Sujit S.; Rao, Ganesh; Sawaya, Raymond; Langford, Lauren A.; Bruner, Janet M.; Fuller, Gregory N.; Bar-Or, Amit; Li, Wei; Colen, Rivka R.; Curran, Michael A.; Bhat, Krishna P.; Antel, Jack P.; Cooper, Laurence J.; Sulman, Erik P.; Heimberger, Amy B.

    2016-01-01

    Glioblastomas are highly infiltrated by diverse immune cells, including microglia, macrophages, and myeloid-derived suppressor cells (MDSCs). Understanding the mechanisms by which glioblastoma-associated myeloid cells (GAMs) undergo metamorphosis into tumor-supportive cells, characterizing the heterogeneity of immune cell phenotypes within glioblastoma subtypes, and discovering new targets can help the design of new efficient immunotherapies. In this study, we performed a comprehensive battery of immune phenotyping, whole-genome microarray analysis, and microRNA expression profiling of GAMs with matched blood monocytes, healthy donor monocytes, normal brain microglia, nonpolarized M0 macrophages, and polarized M1, M2a, M2c macrophages. Glioblastoma patients had an elevated number of monocytes relative to healthy donors. Among CD11b+ cells, microglia and MDSCs constituted a higher percentage of GAMs than did macrophages. GAM profiling using flow cytometry studies revealed a continuum between the M1- and M2-like phenotype. Contrary to current dogma, GAMs exhibited distinct immunological functions, with the former aligned close to nonpolarized M0 macrophages. PMID:26973881

  6. What Is Chronic Lymphocytic Leukemia?

    Science.gov (United States)

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

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

    OpenAIRE

    Buddula, Aravind; Assad, Daniel

    2011-01-01

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

  8. 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.

  9. Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission

    DEFF Research Database (Denmark)

    Nagler, Arnon; Rocha, Vanderson; Labopin, Myriam;

    2013-01-01

    Cyclophosphamide (Cy) combined with total-body irradiation (TBI) or with busulfan (Bu) are currently the most common myeloablative regimens used in allogeneic stem-cell transplantation (alloSCT) in adults with acute myelogenous leukemia (AML). Intravenous (IV) Bu has more predictable bioavailabil......Cyclophosphamide (Cy) combined with total-body irradiation (TBI) or with busulfan (Bu) are currently the most common myeloablative regimens used in allogeneic stem-cell transplantation (alloSCT) in adults with acute myelogenous leukemia (AML). Intravenous (IV) Bu has more predictable...

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

    International Nuclear Information System (INIS)

    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

  11. Acute Hepatitis A Induction of Precursor B-Cell Acute Lymphoblastic Leukemia: A Causal Relationship?

    OpenAIRE

    Senadhi, V.; Emuron, D.; R. Gupta

    2010-01-01

    Background Precursor B-cell acute lymphoblastic leukemia accounts for 2% of all lymphoid neoplasms in the United States and occurs most frequently in childhood, but can also occur in adults with a median age of 39 years. It is more commonly seen in males and in Caucasians. Case Report We present a case of a 51-year-old Caucasian female with the development of precursor B-cell acute lymphoblastic leukemia after suffering acute hepatitis A 4 weeks prior to her diagnosis. She presented with mala...

  12. A model with competition between the cell lines in leukemia under treatment

    Energy Technology Data Exchange (ETDEWEB)

    Halanay, A.; Cândea, D.; Rădulescu, R. [POLITEHNICA University of Bucharest Department of Mathematics and Informatics Splaiul Independentei 313 RO-060042 Bucharest (Romania)

    2014-12-10

    The evolution of leukemia is modeled with a delay differential equation model of four cell populations: two populations (healthy and leukemic) ) of stem-like cells involving a larger category consisting of proliferating stem and progenitor cells with self-renew capacity and two populations (healthy and leukemic) of mature cells, considering the competition of healthy vs. leukemic cell populations and three types of division that a stem-like cell can exhibit: self-renew, asymmetric division and differentiation. In the model it is assumed that the treatment acts on the proliferation rate of the leukemic stem cells and on the apoptosis of stem and mature cells. The emphasis in this model is on establishing relevant parameters for chronic and acute manifestations of leukemia. Stability of equilibria is investigated and sufficient conditions for local asymptotic stability will be given using a Lyapunov-Krasovskii functional.

  13. 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

    Fetal hematopoietic cells that express the common acute lymphoblastic leukemia antigen (CALLA) were purified from both fetal liver and fetal bone marrow by immune rosetting with sheep erythrocytes coated with rabbit anti-mouse immunoglobulin and by fluorescence-activated cell sorting. Dual...... antigen. Furthermore, using methanol-fixed cells, it could be shown that approximately 20% contained intracytoplasmic mu chains (cyto-mu) and that approximately 15% were positive for the terminal transferase enzyme (TdT) marker. The CALLA+ fetal cells thus closely resemble the childhood acute...... 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...

  14. A model with competition between the cell lines in leukemia under treatment

    International Nuclear Information System (INIS)

    The evolution of leukemia is modeled with a delay differential equation model of four cell populations: two populations (healthy and leukemic) ) of stem-like cells involving a larger category consisting of proliferating stem and progenitor cells with self-renew capacity and two populations (healthy and leukemic) of mature cells, considering the competition of healthy vs. leukemic cell populations and three types of division that a stem-like cell can exhibit: self-renew, asymmetric division and differentiation. In the model it is assumed that the treatment acts on the proliferation rate of the leukemic stem cells and on the apoptosis of stem and mature cells. The emphasis in this model is on establishing relevant parameters for chronic and acute manifestations of leukemia. Stability of equilibria is investigated and sufficient conditions for local asymptotic stability will be given using a Lyapunov-Krasovskii functional

  15. Unusual immunophenotype of T-cell large granular lymphocytic leukemia: Report of two cases

    Directory of Open Access Journals (Sweden)

    Nikhil Rabade

    2015-01-01

    Full Text Available Large granular lymphocytes (LGL leukemias are commonly of the T-cell or NK-cell type. T-cell LGL leukemia is typically a disorder of mature CD3, CD8 and T-cell receptor TCR (TCR - T cell receptor-αβ positive cytotoxic T-cells. Rare variants include TCRγδ+ variants and CD4 + TCRαβ+ cases. We report a case of each of these rare variants. An 83-year-old female presented with anemia and lymphocytosis with LGLs on peripheral smear. Six-color multiparametric flowcytometric analysis showed expression of CD3, heterogeneous CD7, dim CD2 and TCRγδ and lacked expression of CD5, TCRαβ, CD56, CD4 and CD8. A final diagnosis of TCRγδ+ T-cell LGL leukemia was made. Differentiation between TCRγδ+ T-cell LGL leukemia and other γδ+ T-cell malignancies is of utmost importance due to the indolent nature of the former as compared to the highly aggressive behavior of the latter. An 85-year-old male diagnosed with liposarcoma was identified to have lymphocytosis during preoperative evaluation. Peripheral smear showed presence of LGLs. Flowcytometric immunophenotyping showed expression of TCRαβ, CD3, CD2, CD5, CD4, dim CD8, CD56 with aberrant loss of CD7 expression. Vβ repertoire analysis by flowcytometry showed 97% cells with Vβ14 clonality. A final diagnosis of TCRαβ+ CD4 + T-cell LGL leukemia was made. CD4 + T-cell large granular lymphocytic leukemias have an indolent, less aggressive course when compared to their CD8 + counterparts and are not necessarily associated with cytopenias. However, their association with secondary neoplasia (29% of the cases warrants a high degree of suspicion in the diagnosis as also noted in the index case. Use of a wide panel of antibodies and newer modalities such as Vβ repertoire analysis helps in accurate subtyping of LGL leukemia.

  16. Interleukin 21 therapy increases the density of tumor infiltrating CD8+ T cells and inhibits the growth of syngeneic tumors

    DEFF Research Database (Denmark)

    Søndergaard, Henrik; Frederiksen, Klaus S; Thygesen, Peter; Galsgaard, Elisabeth D; Skak, Kresten; Kristjansen, Paul E G; Odum, Niels; Kragh, Michael

    2007-01-01

    infiltrating T cells. We treated mice bearing established subcutaneous B16 melanomas or RenCa renal cell carcinomas with intraperitoneal (i.p.) or subcutaneous (s.c.) IL-21 protein therapy and subsequently scored the densities of tumor infiltrating CD4(+) and CD8(+) T cells by immunohistochemistry. Whereas.......c. administration, which could account for the apparent increase in anti-tumor activity. Specific depletion of CD8(+) T cells with monoclonal antibodies completely abrogated the anti-tumor activity, whereas NK1.1(+) cell depletion did not affect tumor growth. In accordance, both routes of IL-21 administration...... significantly increased the density of tumor infiltrating CD8(+) T cells in both B16 and RenCa tumors; and in the RenCa model s.c. administration of IL-21 led to a significantly higher density of tumor infiltrating CD8(+) T cells compared to i.p. administration. The densities of CD4(+) T cells were unchanged...

  17. CTGF promotes inflammatory cell infiltration of the renal interstitium by activating NF-kappaB.

    Science.gov (United States)

    Sánchez-López, Elsa; Rayego, Sandra; Rodrigues-Díez, Raquel; Rodriguez, Javier Sánchez; Rodrigues-Díez, Raúl; Rodríguez-Vita, Juan; Carvajal, Gisselle; Aroeira, Luiz Stark; Selgas, Rafael; Mezzano, Sergio A; Ortiz, Alberto; Egido, Jesús; Ruiz-Ortega, Marta

    2009-07-01

    Connective tissue growth factor (CTGF) is an important profibrotic factor in kidney diseases. Blockade of endogenous CTGF ameliorates experimental renal damage and inhibits synthesis of extracellular matrix in cultured renal cells. CTGF regulates several cellular responses, including adhesion, migration, proliferation, and synthesis of proinflammatory factors. Here, we investigated whether CTGF participates in the inflammatory process in the kidney by evaluating the nuclear factor-kappa B (NF-kappaB) pathway, a key signaling system that controls inflammation and immune responses. Systemic administration of CTGF to mice for 24 h induced marked infiltration of inflammatory cells in the renal interstitium (T lymphocytes and monocytes/macrophages) and led to elevated renal NF-kappaB activity. Administration of CTGF increased renal expression of chemokines (MCP-1 and RANTES) and cytokines (INF-gamma, IL-6, and IL-4) that recruit immune cells and promote inflammation. Treatment with a NF-kappaB inhibitor, parthenolide, inhibited CTGF-induced renal inflammatory responses, including the up-regulation of chemokines and cytokines. In cultured murine tubuloepithelial cells, CTGF rapidly activated the NF-kappaB pathway and the cascade of mitogen-activated protein kinases, demonstrating crosstalk between these signaling pathways. CTGF, via mitogen-activated protein kinase and NF-kappaB activation, increased proinflammatory gene expression. These data show that in addition to its profibrotic properties, CTGF contributes to the recruitment of inflammatory cells in the kidney by activating the NF-kappaB pathway. PMID:19423687

  18. TRAIL-mediated killing of acute lymphoblastic leukemia by plasmacytoid dendritic cell-activated natural killer cells.

    Science.gov (United States)

    Lelaidier, Martin; Dìaz-Rodriguez, Yildian; Cordeau, Martine; Cordeiro, Paulo; Haddad, Elie; Herblot, Sabine; Duval, Michel

    2015-10-01

    Acute lymphoblastic leukemia (ALL) still frequently recurs after hematopoietic stem cell transplantation (HSCT), underscoring the need to improve the graft-versus-leukemia (GvL) effect. Natural killer (NK) cells reconstitute in the first months following HSCT when leukemia burden is at its lowest, but ALL cells have been shown to be resistant to NK cell-mediated killing. We show here that this resistance is overcome by NK cell stimulation with TLR-9-activated plasmacytoid dendritic cells (pDCs). NK cell priming with activated pDCs resulted in TRAIL and CD69 up-regulation on NK cells and IFN-γ production. NK cell activation was dependent on IFN-α produced by pDCs, but was not reproduced by IFN-α alone. ALL killing was further enhanced by inhibition of KIR engagement. We showed that ALL lysis was mainly mediated by TRAIL engagement, while the release of cytolytic granules was involved when ALL expressed NK cell activating receptor ligands. Finally, adoptive transfers of activated-pDCs in ALL-bearing humanized mice delayed the leukemia onset and cure 30% of mice. Our data therefore demonstrate that TLR-9 activated pDCs are a powerful tool to overcome ALL resistance to NK cell-mediated killing and to reinforce the GvL effect of HSCT. These results open new therapeutic avenues to prevent relapse in children with ALL. PMID:26320191

  19. T315 Decreases Acute Myeloid Leukemia Cell Viability through a Combination of Apoptosis Induction and Autophagic Cell Death

    Science.gov (United States)

    Chiu, Chang-Fang; Weng, Jing-Ru; Jadhav, Appaso; Wu, Chia-Yung; Sargeant, Aaron M.; Bai, Li-Yuan

    2016-01-01

    T315, an integrin-linked kinase (ILK) inhibitor, has been shown to suppress the proliferation of breast cancer, stomach cancer and chronic lymphocytic leukemia cells. Here we demonstrate that T315 decreases cell viability of acute myeloid leukemia (AML) cell lines (HL-60 and THP-1) and primary leukemia cells from AML patients in a dose-responsive manner. Normal human bone marrow cells are less sensitive than leukemia cells to T315. T315 down regulates protein kinase B (Akt) and p-Akt and induces caspase activation, poly-ADP-ribose polymerase (PARP) cleavage, apoptosis and autophagy through an ILK-independent manner. Interestingly, pretreatment with autophagy inhibitors rescues cells from apoptosis and concomitant PARP cleavage, which implicates a key role of autophagic cell death in T315-mediated cytotoxicity. T315 also demonstrates efficacy in vivo, suppressing the growth of THP-1 xenograft tumors in athymic nude mice when administered intraperitoneally. This study shows that autophagic cell death and apoptosis cooperatively contribute to the anticancer activity of T315 in AML cells. In conclusion, the complementary roles of apoptotic and autophagic cell death should be considered in the future assessment of the translational value of T315 in AML therapy. PMID:27537872

  20. Human monoclonal antibody directed against an envelope glycoprotein of human T-cell leukemia virus type I.

    OpenAIRE

    Matsushita, S; Robert-Guroff, M; Trepel, J. (Jane); Cossman, J; Mitsuya, H; Broder, S

    1986-01-01

    We report the production and characterization of a human monoclonal antibody reactive against the major envelope glycoprotein of human T-cell leukemia virus type I (HTLV-I), a virus linked to the etiology of adult T-cell leukemia. We exposed lymph-node cells derived from a patient with adult T-cell leukemia to the Epstein-Barr virus in vitro and obtained a B-cell clone (designated 0.5 alpha) by a limiting dilution technique. The secreted product of 0.5 alpha is a monoclonal antibody (also des...

  1. Mesenchymal stem cells enhance ovarian cancer cell infiltration through IL6 secretion in an amniochorionic membrane based 3D model

    Directory of Open Access Journals (Sweden)

    Touboul Cyril

    2013-01-01

    Full Text Available Abstract Background The early peritoneal invasion of epithelial ovarian cancer (EOC by tumoral aggregates presents in ascites is a major concern. The role of the microenvironment seems to be important in this process but the lack of adequate models to study cellular interactions between cancer cells and stromal cells does not allow to uncover the molecular pathways involved. Our goal was to study the interactions between ovarian cancer cells (OCC and mesenchymal stem cells (MSC using a 3D model. Methods We used millimetric pieces of amniochorionic membrane - referred to as amniotic membrane scaffold (AMS - to create 3D peritoneal nodules mimicking EOC early invasion. We were able to measure the distribution and the depth of infiltration using confocal microsopy. We extracted MSC from the amniochorionic membrane using the markers CD34-, CD45-, CD73+, CD90+, CD105+ and CD29+ at the Fluorescence Activated Cell Sorting (FACS analysis. We used transwell and wound healing tests to test OCC migration and invasion in vitro. Results Here we show that OCC tumors were located in regions rich in MSC (70%. The tumors infiltrated deeper within AMS in regions rich in MSC (p Conclusions The use of tridimensional models using AMS could be a useful tool to decipher early molecular events in ovarian cancer metastasis. Cytokine inhibitors interrupting the cross-talk between OCCs and MSCs such as IL6 should be investigated as a new therapeutic approach in ovarian cancer.

  2. B-cell infiltration and frequency of cytokine producing cells differ between localized and disseminated human cutaneous leishmaniases

    Directory of Open Access Journals (Sweden)

    MGS Vieira

    2002-10-01

    Full Text Available Biopsies from human localized cutaneous lesions (LCL n = 7 or disseminated lesions (DL n = 8 cases were characterized according to cellular infiltration,frequency of cytokine (IFN-g, TNF-alpha or iNOS enzyme producing cells. LCL, the most usual form of the disease with usually one or two lesions, exhibits extensive tissue damage. DL is a rare form with widespread lesions throughout the body; exhibiting poor parasite containment but less tissue damage. We demonstrated that LCL lesions exhibit higher frequency of B lymphocytes and a higher intensity of IFN-gamma expression. In both forms of the disease CD8+ were found in higher frequency than CD4+ T cells. Frequency of TNF-alpha and iNOS producing cells, as well as the frequency of CD68+ macrophages, did not differ between LCL and DL. Our findings reinforce the link between an efficient control of parasite and tissue damage, implicating higher frequency of IFN-gamma producing cells, as well as its possible counteraction by infiltrated B cells and hence possible humoral immune response in situ.

  3. Microgliosis in the Injured Brain: Infiltrating Cells and Reactive Microglia Both Play a Role.

    Science.gov (United States)

    Li, Ting; Zhang, Shengxiang

    2016-04-01

    Microgliosis is an intense reaction of CNS microglia to pathogenic insults. One of the characteristic features of microgliosis is an increase in the number of activated microglia at the site of lesion. Ontogenically, microglia are considered to be of mesodermal lineage in the adult CNS, but the origin of the accumulated microglia in pathological conditions remains controversial. Some studies indicate that circulating cells from the bloodstream can infiltrate the CNS and contribute to microglial pool, but some studies suggest that local expansion of reactive microglia is the sole source for parenchymal microglia. Recent data suggest that latent progenitors may also exist in the CNS. Available evidence suggests that multiple sources of microglia may exist under various neurological conditions. In this review, we compare the prevalent views and supporting evidence from different experimental models and provide an overview on the origins of microgliosis. PMID:25672621

  4. Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Portell CA

    2013-04-01

    Full Text Available Craig A Portell, Candice M Wenzell, Anjali S Advani Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA Abstract: Acute lymphoblastic leukemia (ALL in adults remains a challenging disease to treat, and novel therapies are needed. Precursor-B ALL comprises 80% of cases, and the CD19 antigen is expressed in nearly all precursor-B ALL patients. Bispecific T-cell-engaging antibodies are novel bioengineered proteins. The bispecific T-cell-engaging antibody blinatumomab engages polyclonal T cells to CD19-expressing B cells. By binding to both CD3 and CD19, blinatumomab physically brings these T cells in close proximity to malignant B cells and potentiates T-cell-induced cytotoxic cell kill. Blinatumomab requires continuous intravenous infusion due to its short half-life, the need for continuous exposure for the drug to exert sufficient efficacy, and lessened toxicity. A phase II trial of B-cell ALL patients with persistent or relapsed minimal residual disease demonstrated an 80% rate of complete molecular remission. Cytokine-release syndrome and central nervous system events, such as seizures and encephalopathy, are reversible toxicities. Promising results in B-cell ALL with minimal residual disease have led to further evaluation of this drug in newly diagnosed and relapsed B-cell ALL. Keywords: blinatumomab, B-cell acute lymphoblastic leukemia, CD19, BiTE antibodies

  5. Peptide aptamer identified by molecular docking targeting translationally controlled tumor protein in leukemia cells.

    Science.gov (United States)

    Kadioglu, Onat; Efferth, Thomas

    2016-08-01

    Bioinformatics screening and molecular docking analyses were utilized to select high affinity peptides targeting translationally controlled tumor protein (TCTP). Selected peptide aptamers were tested towards cancer cell lines with different levels of TCTP expression. One peptide (WGQWPYHC) revealed specific cytotoxicity according to the TCTP expression in tumor cells without affecting normal cells. Western blot analysis showed peptide-induced down-regulation of TCTP as primary target as well as of cell-cycle related downstream proteins (CDK2, CDK6, Cyclin D3) in MOLT-4 leukemia cells. "WGQWPYHC" deserves further analysis for targeted therapy of TCTP-expressing tumor cells. Graphical abstract Molecular docking on TCTP, cytotoxicity toward MOLT-4 leukemia cell line and downregulation of CDK2, CDK6, CyclinD3 and TCTP proteins. PMID:26972431

  6. Evidence that high-migration drug-surviving MOLT4 leukemia cells exhibit cancer stem cell-like properties.

    Science.gov (United States)

    Huang, Xiaoxing; Xiong, Meng; Jin, Yujie; Deng, Chaohua; Xu, Hui; An, Changqing; Hao, Ling; Yang, Xiangyong; Deng, Xinzhou; Tu, Zhenbo; Li, Xinran; Xiao, Ruijing; Zhang, Qiuping

    2016-07-01

    Leukemia represents a spectrum of hematological malignancies threatening human health. Resistance to treatments and metastasis of leukemia are the main causes of death in patients. Leukemia stem cells (LSCs) are the initiating cells of leukemia as well as the main source of drug resistance, invasion and metastasis. Consequently, eliminating LSCs is a prerequisite to eradicate leukemia. Preliminary studies in our laboratory have shown that chemokines and their related receptors play an important role in the drug resistance and metastasis of leukemic cells. In this study, we obtained high migration drug-surviving (short term) MOLT4 cells (hMDSCs-MOLT4) with treatment of doxorubicin (DOX) after Transwell assay. Then we detected stem cell-associated molecular markers on hMDSCs-MOLT4 cells and the parental MOLT4 cells by FCM, QPCR, western blotting, H&E staining and immunohisto-chemistry experimental techniques in vitro and in vivo. Moreover, we explored its impact on drug resistance and tumor formation. Then we found that compared with the parental MOLT4 cells, the mRNA expression levels of stem cell-related factors Sox2, Oct4, C-myc, Klf4, Nanog, Bmi-1, CXCR4 are increased in hMDSCs-MOLT4 cells, together with the protein expression levels of Sox2, Oct4, Klf4, Nanog, CXCR4 and CD34. Our results indicated that hMDSCs-MOLT4 cells exhibited strong drug resistance and certain cancer stem cell-like characteristics. It is the first indication that the targeting stemness factors such as Sox2, Oct4, Klf4, Nanog and CXCR4 may represent plausible options for eliminating T-ALL stem-like cells. The present findings shed light on the relationship between drug-tolerant leukemic cells and cancer stem cells. PMID:27210806

  7. Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice

    International Nuclear Information System (INIS)

    In the peripheral blood leukocytes (PBLs) from the carriers of the human T-lymphotropic virus type-1 (HTLV-1) or the patients with adult T-cell leukemia (ATL), nuclear factor kappaB (NF-κB)-mediated antiapoptotic signals are constitutively activated primarily by the HTLV-1-encoded oncoprotein Tax. Tax interacts with the I κB kinase regulatory subunit NEMO (NF-κB essential modulator) to activate NF-κB, and this interaction is maintained in part by a molecular chaperone, heat-shock protein 90 (HSP90), and its co-chaperone cell division cycle 37 (CDC37). The antibiotic geldanamycin (GA) inhibits HSP90's ATP binding for its proper interaction with client proteins. Administration of a novel water-soluble and less toxic GA derivative, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), to Tax-expressing ATL-transformed cell lines, C8166 and MT4, induced significant degradation of Tax. 17-DMAG also facilitated growth arrest and cellular apoptosis to C8166 and MT4 and other ATL cell lines, although this treatment has no apparent effects on normal PBLs. 17-DMAG also downregulated Tax-mediated intracellular signals including the activation of NF-κB, activator protein 1 or HTLV-1 long terminal repeat in Tax-transfected HEK293 cells. Oral administration of 17-DMAG to ATL model mice xenografted with lymphomatous transgenic Lck-Tax (Lck proximal promoter-driven Tax transgene) cells or HTLV-1-producing tumor cells dramatically attenuated aggressive infiltration into multiple organs, inhibited de novo viral production and improved survival period. These observations identified 17-DMAG as a promising candidate for the prevention of ATL progression

  8. Prognostic significance of cell surface phenotype in acute lymphoblastic leukemia

    OpenAIRE

    Shiek Aejaz Aziz; Susheel Kumar Sharma; Iram Sabah; M Aleem Jan

    2015-01-01

    Context: To find out the phenotypic character of lymphoblasts of acute lymphoblastic leukemia (ALL) patients in our study cohort and their possible effect on the prognosis. Aims: To investigate the phenotype in ALL in our demographic population and to prognosticate various upfront current protocols employed in our hospital. Settings and Design: The study spanned over a period of 4 years with retrospective and prospective data of January 2008 through December 2011. Materials and Methods: 159 p...

  9. Infiltration of M2 Tumor-Associated Macrophages in Oral Squamous Cell Carcinoma Correlates with Tumor Malignancy

    Energy Technology Data Exchange (ETDEWEB)

    Mori, Kazumasa [Division of Oral and Maxillofacial Surgery, Department of Diagnosis and Therapeutics, Meikai University of School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283 (Japan); Hiroi, Miki [Division of Microbiology and Immunology, Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283 (Japan); Shimada, Jun [Division of Oral and Maxillofacial Surgery, Department of Diagnosis and Therapeutics, Meikai University of School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283 (Japan); Ohmori, Yoshihiro, E-mail: ohmori@dent.meikai.ac.jp [Division of Microbiology and Immunology, Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283 (Japan)

    2011-09-28

    Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment of many solid tumors. The functional competence of TAMs varies depending on the type of tumors and their respective microenvironments. The classically activated M1 macrophages exhibit antitumor functions, whereas the alternatively activated M2 macrophages exhibit protumor functions that contribute to tumor development and progression. Although TAMs have been detected in oral squamous cell carcinoma (OSCC), little is known about their phenotype. In the present study, we performed an immunohistochemical analysis to identify TAMs in surgically resected specimens from 50 patients with OSCC and evaluated the relationship between infiltrated TAMs and the pathological grade of OSCC. Positive staining for CD163, which has been used as a marker for M2 macrophages, was observed in OSCC specimens, and the percentages of CD163{sup +} cells were significantly increased based on the pathological grade. CD163{sup +} cells were detected in the tumor stroma in grade I tumors, whereas an increase in the CD163{sup +} cells in the tumor nest was observed in higher grades of tumors. Although infiltrated CD4{sup +} and CD8{sup +} T cells were detected in all pathological grades of OSCC, no correlation between the infiltrated T cells and the CD163{sup +} TAMs was observed. These results indicate that the infiltrated TAMs in OSCC have an M2 phenotype and that the M2 macrophages may participate in the development of OSCC.

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

    Science.gov (United States)

    2015-07-31

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

  11. Alloreactive natural killer cells for the treatment of acute myeloid leukemia: from stem cell transplantation to adoptive immunotherapy

    Directory of Open Access Journals (Sweden)

    Loredana eRuggeri

    2015-10-01

    Full Text Available Natural killer cells express activating and inhibitory receptors which recognize MHC class I alleles, termed Killer cell Immunoglobulin-like Receptors (KIRs. Preclinical and clinical data from haploidentical T-cell depleted stem cell transplantation have demonstrated that alloreactive KIR-L mismatched natural killer cells play a major role as effectors against acute myeloid leukemia. Outside the transplantation setting, several reports have proven the safety and feasibility of natural killer cell infusion in acute myeloid leukemia patients and, in some cases, provided evidence that transferred NK cells are functionally alloreactive and may have a role in disease control. Aim of the present work is to briefly summarize the most recent advances in the field by moving from the first preclinical and clinical demonstration of donor NK alloreactivity in the transplantation setting to the most recent attempts of exploiting the use of alloreactive NK cell infusion as a means of adoptive immunotherapy against acute myeloid leukemia. Altogether, these data highlight the pivotal role of NK cells for the development of novel immunological approaches in the clinical management of acute myeloid leukemia.

  12. Modulatory Effects and Action Mechanisms of Tryptanthrin on Murine Myeloid Leukemia Cells

    Institute of Scientific and Technical Information of China (English)

    Hoi-Ling Chan; Hon-Yan Yip; Nai-Ki Mak; Kwok-Nam Leung

    2009-01-01

    Leukemia is the disorder of hematopoietic cell development and is characterized by an uncoupling of cell proliferation and differentiation. There is a pressing need for the development of novel tactics for leukemia therapy as conventional treatments often have severe adverse side effects. Tryptanthrin (6,12-dihydro-6,12-dioxoindolo-(2,1-b)-quinazoline) is a naturally-occurring, weakly basic alkaloid isolated from the dried roots of medicinal indigo plants (Ban-Lan-Gen). It has been reported to have various biological and pharmacological activities, including anti-microbial, anti-inflammatory, immunomodulatory and anti-tumor effects. However, its modulatory effects and action mechanisms on myeloid cells remain poorly understood. In this study, tryptanthrin was shown to suppress the proliferation of the murine myeloid leukemia WEHI-3B JCS cells in a dose- and time-dependent manner. It also significantly reduced the growth of WEHI-3B JCS cells in vivo in syngeneic BALB/c mice. However, it exhibited no significant direct cytotoxicity on normal murine peritoneal macrophages. Flow cytometric analysis showed an obvious cell cycle arrest of the tryptanthrin-treated WEHI-3B JCS cells at the G0/G1 phase. The expression of cyclin D2,D3, Cdk 2, 4 and 6 genes in WEHI-3B JCS cells was found to be down-regulated at 24 h as measured by RT-PCR. Morphological and functional studies revealed that tryptanthrin could induce differentiation in WEHI-3B JCS cells, as shown by the increases in vacuolation, cellular granularity and NBT-reducing activity in tryptanthrin-treated cells. Collectively, our findings suggest that tryptanthrin might exert its anti-tumor effect on the murine myelomonocytic leukemia WEHI-3B JCS cells by causing cell cycle arrest and by triggering cell differentiation. Cellular & Molecular Immunology. 2009;6(5):335-342.

  13. Inhibitory Effects of Omacetaxine on Leukemic Stem Cells and BCR-ABL-Induced Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia in Mice

    OpenAIRE

    Chen, Yaoyu; Hu, Yiguo; Michaels, Shawnya; Segal, David; Brown, Dennis; Li, Shaoguang

    2009-01-01

    Omacetaxine mepesuccinate (formerly homoharringtonine) is a molecule with a mechanism of action that is different from tyrosine kinase inhibitors and its activity in chronic myeloid leukemia (CML) seems to be independent of BCR-ABL mutation status. Using BCR-ABL-expressing myelogenous and lymphoid cell lines and mouse models of CML and B cell acute lymphoblastic leukemia (B-ALL) induced by wild type BCR-ABL or T315I mutant-BCR-ABL, we evaluated the inhibitory effects of omacetaxine on CML and...

  14. A transgenic mouse model of human T-cell leukemia virus type I (HTLV-1–associated diseases

    Directory of Open Access Journals (Sweden)

    Takeo eOhsugi

    2013-03-01

    Full Text Available Human T-cell leukemia virus type I (HTLV-1 is the etiological agent of adult T-cell leukemia/lymphoma (ATLL and several inflammatory diseases. Tax, the protein encoded by HTLV-1, may be responsible for the development of the diseases caused by this virus. To investigate the pathogenic role of Tax, several transgenic mouse strains expressing Tax have been developed in recent years. These mice develop various tumors including large granular lymphocytic leukemia, as well as inflammatory diseases such as arthritis. These results suggest that Tax expression alone is sufficient to cause both malignant neoplastic diseases and inflammatory diseases. However, until recently, there were no tax transgenic mice that develop T-cell leukemia and lymphoma resembling ATLL. The first successful induction of leukemia in T cells was pre–T-cell leukemia generated in transgenic mice in which a mouse lymphocyte-specific protein tyrosine kinase p56lck (lck proximal promoter was used to express the tax gene in immature T cells. Subsequently, transgenic mice were established in which the lck-distal promoter was used to express Tax in mature T cells; these mice developed mature T-cell leukemia and lymphoma that more closely resembled ATLL than did earlier mouse models.

  15. Mannosylerythritol lipid induces granulocytic differentiation and inhibits the tyrosine phosphorylation of human myelogenous leukemia cell line K562

    OpenAIRE

    Isoda, Hiroko; Nakahara, Tadaatsu

    1997-01-01

    Mannosylerythritol lipid (MEL), which induced granulocytic differentiation of human promyelocytic leukemia cell line HL60, also induced differentiation of human myelogenous leukemia cell line K562. MEL inhibited insulin-dependent cell proliferation and induced leukocyte esterase activity of K562 cells. MEL markedly increased the differentiation-associated characteristics in granulocytes, such as nitroblue tetrazolium (NBT) reducing ability, expression of Fc receptors, and phagocytic activity ...

  16. Kelainan Hemostasis pada Leukemia

    Directory of Open Access Journals (Sweden)

    Zelly Dia Rofinda

    2012-09-01

    Full Text Available AbstrakLatar belakang: Leukemia adalah penyakit keganasan pada jaringan hematopoietik yang ditandai denganpenggantian elemen sumsum tulang normal oleh sel darah abnormal atau sel leukemik. Salah satu manifestasi klinisdari leukemia adalah perdarahan yang disebabkan oleh berbagai kelainan hemostasis.Kelainan hemostasis yang dapat terjadi pada leukemia berupa trombositopenia, disfungsi trombosit,koagulasi intravaskuler diseminata, defek protein koagulasi, fibrinolisis primer dan trombosis. Patogenesis danpatofosiologi kelainan hemostasis pada leukemia tersebut terjadi dengan berbagai mekanisme.Kata kunci: leukemia, kelainan hemostasisAbstractBackground: AbstractLeukemia is a malignancy of hematopoietic tissue which is characterized bysubstituted of bone marrow element with abnormal blood cell or leukemic cell. One of clinical manifestation ofleukemia is bleeding that is caused by several hemostasis disorders.Hemostasis disorders in leukemia such asthrombocytopenia, platelet dysfunction, disseminated intravascular coagulation, coagulation protein defect, primaryfibrinolysis and thrombosis. Pathogenesis and pathophysiology of thus hemostasis disorders in leukemia occur withdifferent mechanism.Keywords: leukemia, hemostasis disorder

  17. 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.

  18. Rearrangements of the tal-1 locus as clonal markers for T cell acute lymphoblastic leukemia.

    OpenAIRE

    Jonsson, O G; Kitchens, R. L.; Baer, R J; Buchanan, G. R.; Smith, R G

    1991-01-01

    Normal and aberrant immune receptor gene assembly each produce site-specific DNA rearrangements in leukemic lymphoblasts. In either case, these rearrangements provide useful clonal markers for the leukemias in question. In the t(1;14)(p34;q11) translocation associated with T cell acute lymphoblastic leukemia (T-ALL), the breakpoints on chromosome 1 interrupt the tal-1 gene. A site-specific deletion interrupts the same gene in an additional 26% of T-ALL. Thus, nearly one-third of these leukemi...

  19. Adult T-cell leukemia/lymphoma associated with HTLV-1 infection in a Brazilian adolescent

    Directory of Open Access Journals (Sweden)

    VALLE Antonio Carlos Francesconi do

    2001-01-01

    Full Text Available We present the case of a 15-year-old patient infected with HTLV-1 who developed a cutaneous T-cell lymphoma, confirmed by histopathological and immunohistochemical examination, as well as clinically and hematologically confirmed leukemia. The patient died 3 months after initial presentation of the disease. The rarity of the disease in this age group justifies the present report.

  20. 75 FR 54496 - Diseases Associated With Exposure to Certain Herbicide Agents (Hairy Cell Leukemia and Other...

    Science.gov (United States)

    2010-09-08

    ... Federal Register (75 FR 53202), an amendment to 38 CFR 3.309 to add hairy cell leukemia and other chronic... column, second paragraph, we inadvertently provided a Web site of: ``http://vaww1.va.gov/ORPM/FY-- 2010--Published--VA--Regulations.asp'', which is corrected to read:...

  1. Modulation of monocytic leukemia cell function and survival by highgradient magnetic fields and mathematical modeling studies

    Czech Academy of Sciences Publication Activity Database

    Zablotskyy, Vitaliy A.; Syrovets, T.; Schmidt, Z.W.; Dejneka, Alexandr; Simmet, T.

    2014-01-01

    Roč. 35, č. 10 (2014), s. 3164-3171. ISSN 0142-9612 Grant ostatní: AV ČR(CZ) M100101219 Institutional support: RVO:68378271 Keywords : magnetic field * cell proliferation * leukemia * apoptosis * modeling Subject RIV: BO - Biophysics Impact factor: 8.557, year: 2014

  2. Pro-apoptotic effect of Persea americana var. Hass (avocado) on Jurkat lymphoblastic leukemia cells.

    Science.gov (United States)

    Bonilla-Porras, Angelica R; Salazar-Ospina, Andrea; Jimenez-Del-Rio, Marlene; Pereañez-Jimenez, Andres; Velez-Pardo, Carlos

    2013-11-01

    Abstract Context: Therapy for leukemia has a limited efficacy. There is a need to search for alternative anti-leukemia therapies. Persea americana Mill var. Hass (Lauraceae) is a tropical fruit (avocado) that might be used against cancer. Objective: To investigate whether P. americana induces death in Jurkat lymphoblastic leukemia cells. Materials and methods: Four ethanol extracts (0.1, 0.5, 1, 2 and 5 mg/mL) from avocado fruit (endocarp, whole seed, seed and leaves) were analyzed against Jurkat cells. Hydrogen peroxide generation by oxidation of 2',7'-dichlorodihydrofluorescein diacetate to the fluorescent compound 2',7'-dichlorfluorescein assay, acridine orange/ethidium bromide staining, flow cytometry analysis of annexin-V/7-amino-actinomycin, mitochondrial membrane potential and immunocytochemistry detection of transcription factor p53, caspase-3 and apoptosis-inducing factor (AIF) were evaluated. Results: Endocarp, seed, whole seed, and leaf (0.1 mg/mL) extracts induced significant apoptosis in Jurkat cells (p americana extracts function as a pro-apoptotic compound. Leukemic cells are eliminated through an oxidative stress mechanism. This study contributes to the understanding of the molecular mechanism of the avocado and its therapeutic action on leukemia. PMID:24188375

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

    OpenAIRE

    1983-01-01

    Fetal hematopoietic cells that express the common acute lymphoblastic leukemia antigen (CALLA) were purified from both fetal liver and fetal bone marrow by immune rosetting with sheep erythrocytes coated with rabbit anti-mouse immunoglobulin and by fluorescence-activated cell sorting. Dual fluorescence techniques disclosed that these cells were heterogenous with respect to the expression of a series of differentiation and activation antigens defined by monoclonal antibodies. Thus, whereas all...

  4. Cytotoxic and apoptotic effects of prenylflavonoid artonin B in human acute lymphoblastic leukemia cells

    Institute of Scientific and Technical Information of China (English)

    Chun-chung LEE; Chun-nan LIN; Guey-mei JOW

    2006-01-01

    Aim: To investigate the anticancer effects and molecular mechanism of artonin B on the human acute lymphoblastic leukemia CCRF-CEM cells compared with other prenylflavonoid compounds. Methods: The effects of four prenylflavonoids on the growth of CCRF-CEM and HaCa cells were studied by 3-(4,5)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Apoptosis were detected through Hoechst 33258 staining. The effect of artonin B on the cell cycle of CCRF-CEM cells were studied by propidium iodide method. The change in mitochondrial membrane potential was detected by rohdamine 123 staining. The cytochrome c release and caspase 3 activity were checked by immunoassay kits, respectively. The expression of Bcl-2 family proteins was detected by Western blot. Results: Our data revealed that artonin B strongly induced human CCRF-CEM leukemia cell death in a dose- and time-dependent manner by MTT assay, but not on normal epithelia cells (HaCa cells). Artonin B-induced cell death was considered to be apoptotic by observing the typical apoptotic morphological change by Hoechst 33258 staining. The induction of human CCRF-CEM leukemia cancer cell death was caused by an induction of apoptosis through mitochondrial membrane potential change, cytochrome c release, sub-G1 proportion increase, downregulation of Bcl-2 expression, upregulation of Bax and Bak expression and activation of caspase 3 pathways. Conclusion: These results clearly demonstrated that artonin B is able to inhibit proliferation by induction of hypoploid cells and cell apoptosis. Moreover, the anticancer effects of artonin B were related to mitochondrial pathway and caspase 3 activation in human CCRF-CEM leukemia cells.

  5. Dynamics of Telomeres and Promyelocytic Leukemia Nuclear Bodies in a Telomerase-negative Human Cell Line

    OpenAIRE

    Jegou, Thibaud; Chung, Inn; Heuvelman, Gerrit; Wachsmuth, Malte; Görisch, Sabine M.; Greulich-Bode, Karin M.; Boukamp, Petra; Lichter, Peter; Rippe, Karsten

    2009-01-01

    Telomerase-negative tumor cells maintain their telomeres via an alternative lengthening of telomeres (ALT) mechanism. This process involves the association of telomeres with promyelocytic leukemia nuclear bodies (PML-NBs). Here, the mobility of both telomeres and PML-NBs as well as their interactions were studied in human U2OS osteosarcoma cells, in which the ALT pathway is active. A U2OS cell line was constructed that had lac operator repeats stably integrated adjacent to the telomeres of ch...

  6. Proton nuclear magnetic resonance of intact friend leukemia cells: phosphorylcholine increase during differentiation

    International Nuclear Information System (INIS)

    Proton nuclear magnetic resonance of intact Friend leukemia cells was used to analyze their erythroid-like differentiation. The technique, which requires only 108 to 109 cells and approximately 2 minutes for acquisition of each spectrum, demonstrated the occurrence of many signal changes during differentiation. With cell extracts, 64 signals were assigned to 12 amino acids and 19 other intermediary metabolites, and a dramatic signal change was attributed to a fourfrease in cytoplasmic phosphorylcholines

  7. Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia

    OpenAIRE

    Somasundaram, Rajesh; Prasad, Mahadesh A. J.; Ungerbäck, Jonas; Sigvardsson, Mikael

    2015-01-01

    B-lymphocyte development in the bone marrow is controlled by the coordinated action of transcription factors creating regulatory networks ensuring activation of the B-lymphoid program and silencing of alternative cell fates. This process is tightly connected to malignant transformation because B-lineage acute lymphoblastic leukemia cells display a pronounced block in differentiation resulting in the expansion of immature progenitor cells. Over the last few years, high-resolution analysis of g...

  8. Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice

    OpenAIRE

    Asakura, Shoji; Hashimoto, Daigo; Takashima, Shuichiro; Sugiyama, Haruko; Maeda,Yoshinobu; Akashi, Koichi; Tanimoto, Mitsune; Teshima, Takanori

    2010-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is used effectively to treat a number of hematological malignancies. Its beneficial effects rely on donor-derived T cell–targeted leukemic cells, the so-called graft-versus-leukemia (GVL) effect. Induction of GVL is usually associated with concomitant development of graft-versus-host disease (GVHD), a major complication of allogeneic HSCT. The T cells that mediate GVL and GVHD are activated by alloantigen presented on host antigen-pres...

  9. Hypercalcemia associated with adult T-cell leukemia/lymphoma (ATL).

    Science.gov (United States)

    Peter, S. A.; Cervantes, J. F.

    1995-01-01

    Hypercalcemia is a frequent manifestation of human T-cell lymphotrophic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATL). Human T-cell lymphotrophic virus type I infection is endemic in the Caribbean, Japan, Melanesia, and Africa. This article presents two cases of ATL to increase awareness of the disease by primary care physicians. The management of hypercalcemia is discussed. PMID:7473848

  10. Allogeneic Hematopoietic Cell Transplantation for Patients with Mixed Phenotype Acute Leukemia.

    Science.gov (United States)

    Munker, Reinhold; Brazauskas, Ruta; Wang, Hai Lin; de Lima, Marcos; Khoury, Hanna J; Gale, Robert Peter; Maziarz, Richard T; Sandmaier, Brenda M; Weisdorf, Daniel; Saber, Wael

    2016-06-01

    Acute biphenotypic leukemias or mixed phenotype acute leukemias (MPAL) are rare and considered high risk. The optimal treatment and the role of allogeneic hematopoietic stem cell transplantation (alloHCT) are unclear. Most prior case series include only modest numbers of patients who underwent transplantation. We analyzed the outcome of 95 carefully characterized alloHCT patients with MPAL reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2012. The median age was 20 years (range, 1 to 68). Among the 95 patients, 78 were in first complete remission (CR1) and 17 were in second complete remission (CR2). Three-year overall survival (OS) of 67% (95% confidence interval [CI], 57 to 76), leukemia-free survival of 56% (95% CI, 46 to 66), relapse incidence of 29% (95% CI, 20 to 38), and nonrelapse mortality of 15% (95% CI, 9 to 23) were encouraging. OS was best in younger patients (acute myelogenous leukemia or 359 acute lymphoblastic leukemia cases. MPAL patients had more acute and a trend for more chronic graft-versus-host disease. No difference was observed between patients who underwent transplantation in CR1 versus those who underwent transplantation in CR2. AlloHCT is a promising treatment option for pediatric and adult patients with MPAL with encouraging long-term survival. PMID:26903380

  11. Prominent Lymphatic Vessel Hyperplasia with Progressive Dysfunction and Distinct Immune Cell Infiltration in Lymphedema.

    Science.gov (United States)

    Gousopoulos, Epameinondas; Proulx, Steven T; Scholl, Jeannette; Uecker, Maja; Detmar, Michael

    2016-08-01

    Lymphedema is a common complication that occurs after breast cancer treatment in up to 30% of the patients undergoing surgical lymph node excision. It is associated with tissue swelling, fibrosis, increased risk of infection, and impaired wound healing. Despite the pronounced clinical manifestations of the disease, little is known about the morphological and functional characteristics of the lymphatic vasculature during the course of lymphedema progression. We used an experimental murine tail lymphedema model where sustained fluid stasis was generated on disruption of lymphatic flow, resulting in chronic edema formation with fibrosis and adipose tissue deposition. Morphological analysis of the lymphatic vessels revealed a dramatic expansion during the course of the disease, with active proliferation of lymphatic endothelial cells at the early stages of lymphedema. The lymphatic capillaries exhibited progressively impaired tracer filling and retrograde flow near the surgery site, whereas the collecting lymphatic vessels showed a gradually decreasing contraction amplitude with unchanged contraction frequency, leading to lymphatic contraction arrest at the later stages of the disease. Lymphedema onset was associated with pronounced infiltration by immune cells, predominantly Ly6G(+) and CD4(+) cells, which have been linked to impaired lymphatic vessel function. PMID:27315777

  12. Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer.

    Directory of Open Access Journals (Sweden)

    Christina L Roland

    Full Text Available The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tumor vasculature, immune cell infiltration, and cytokine levels. Tumor vasculature and immune cell infiltration were evaluated using immunohistochemistry. Cytokine levels were evaluated using ELISA and electrochemiluminescence. We found that blocking the activation of VEGF receptor resulted in changes in intra-tumoral cytokine levels, specifically IL-1beta, IL-6 and CXCL1. Modulation of the level these cytokines is important for controlling immune cell infiltration and ultimately tumor growth. Furthermore, we demonstrate that selective inhibition of VEGF binding to VEGFR2 with r84 is more effective at controlling tumor growth and inhibiting the infiltration of suppressive immune cells (MDSC, Treg, macrophages while increasing the mature dendritic cell fraction than other anti-VEGF strategies. In addition, we found that changes in serum IL-1beta and IL-6 levels correlated with response to therapy, identifying two possible biomarkers for assessing the effectiveness of anti-VEGF therapy in breast cancer patients.

  13. Increased Infiltration of CD8+ T Cells by Dacarbazine in a Patient with Mucosal Penile Melanoma Refractory to Nivolumab

    Science.gov (United States)

    Funazumi, Masato; Arima, Yumi; Kato, Kohei; Nojima, Kohei; Tanaka, Kentaro; Miura, Keiko; Yokozeki, Hiroo

    2016-01-01

    Primary penile melanomas are rare tumors that represent less than 0.1% of all melanomas. We report a case of a 60-year-old Japanese male with a mucosal penile melanoma and describe an increased CD8+ T cell infiltration in brain after dacarbazine (DTIC) administration. After partial penectomy and left inguinal lymphadenectomy, he developed multiple lung, bone, spleen, brain and skin metastases. He was treated with interferon-β, DTIC and nivolumab. However, the metastases were not reduced in size. Immunohistochemistry showed an increase of CD8+ T cell infiltration and programmed death-ligand 1 (PD-L1) expression after the administration of DTIC, but the expression of programmed cell death protein 1 (PD-1) was negative. We speculate that DTIC exerted immunostimulatory effects, but nivolumab was ineffective due to the negative expression of PD-1 and/or an insufficient infiltration of CD8+ T cells. Although this is only one case, this case report could be the first step to discuss the development of effective therapies against melanoma to take advantage of the increased CD8+ T cell infiltration elicited by chemotherapeutic agents. It would be beneficial to pay more attention to the relationship between DTIC and immune checkpoint modulators. PMID:27489432

  14. Increased Infiltration of CD8(+) T Cells by Dacarbazine in a Patient with Mucosal Penile Melanoma Refractory to Nivolumab.

    Science.gov (United States)

    Funazumi, Masato; Namiki, Takeshi; Arima, Yumi; Kato, Kohei; Nojima, Kohei; Tanaka, Kentaro; Miura, Keiko; Yokozeki, Hiroo

    2016-08-01

    Primary penile melanomas are rare tumors that represent less than 0.1% of all melanomas. We report a case of a 60-year-old Japanese male with a mucosal penile melanoma and describe an increased CD8(+) T cell infiltration in brain after dacarbazine (DTIC) administration. After partial penectomy and left inguinal lymphadenectomy, he developed multiple lung, bone, spleen, brain and skin metastases. He was treated with interferon-β, DTIC and nivolumab. However, the metastases were not reduced in size. Immunohistochemistry showed an increase of CD8(+) T cell infiltration and programmed death-ligand 1 (PD-L1) expression after the administration of DTIC, but the expression of programmed cell death protein 1 (PD-1) was negative. We speculate that DTIC exerted immunostimulatory effects, but nivolumab was ineffective due to the negative expression of PD-1 and/or an insufficient infiltration of CD8(+) T cells. Although this is only one case, this case report could be the first step to discuss the development of effective therapies against melanoma to take advantage of the increased CD8(+) T cell infiltration elicited by chemotherapeutic agents. It would be beneficial to pay more attention to the relationship between DTIC and immune checkpoint modulators. PMID:27489432

  15. The relationship between histologic grades of invasive carcinoma of breast ducts and mast cell infiltration

    Directory of Open Access Journals (Sweden)

    Ashraf Fakhrjou

    2016-01-01

    Full Text Available Introduction: Breast carcinoma is the most prevalent tumors among women. Transformation of inflated cells in immune response leads to increase in inflammatory cells such as macrophages, mast cells (MC and fibroblasts. The aim of this study was to determine the relationship between grades of invasive carcinoma of the breast ducts and MC infiltration around tumoral cells. Methods: During the present study, 75 female patients suffering from invasive ductal carcinoma who underwent surgery or diagnostic biopsy during 2010 and 2013 in Educational-Medical centers of Tabriz University of Medical Sciences, were included in the study. Based on Bloom-Richardson grading system, 25 cases were selected from each grade. To better observe of MCs, samples were stained by Toluidine blue and MCs were counted in 10 40 × 10 fields. Results: The mean age was 47.56 ± 10.84 and the number of MCs was between 6 and 96 and their overall average was 43.01. Average count of MCs in grade 1, 2 and 3 were 15.92 ± 10.07, 45.32 ± 10.47, and 67.8 ± 20.70, respectively. There was a significant relationship between the number of MCs and increase in disease grade (P < 0.001. With increasing grade of malignancy, the number of MCs had grown. No significant relationship was observed between age and grade of disease or age and number of MC. Conclusion: According to obtained results, number of MC around tumoral cells increased significantly with an increase in the grade of disease. In order to treat in thefirst stages of the disease, recognizing primary changes in the stroma of cells could be helpful.

  16. A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis.

    Science.gov (United States)

    Bruno, Antonino; Ferlazzo, Guido; Albini, Adriana; Noonan, Douglas M

    2014-08-01

    Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This "polarization" has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as "TINKs") and tumor-associated NK (altered peripheral NK cells, which here we call "TANKs") are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology. PMID:25178695

  17. CRIF1 interacting with CDK2 regulates bone marrow microenvironment-induced G0/G1 arrest of leukemia cells.

    Directory of Open Access Journals (Sweden)

    Qian Ran

    Full Text Available BACKGROUND: To assess the level of CR6-interacting factor 1 (CRIF1, a cell cycle negative regulator, in patients with leukemia and investigate the role of CRIF1 in regulating leukemia cell cycle. METHODS: We compared the CRIF1 level in bone marrow (BM samples from healthy and acute myeloid leukemia (AML, iron deficiency anemia (IDA and AML-complete remission (AML-CR subjects. We also manipulated CRIF1 level in the Jurkat cells using lentivirus-mediated overexpression or siRNA-mediated depletion. Co-culture with the BM stromal cells (BMSCs was used to induce leukemia cell cycle arrest and mimic the BM microenvironment. RESULTS: We found significant decreases of CRIF1 mRNA and protein in the AML group. CRIF1 overexpression increased the proportion of Jurkat cells arrested in G0/G1, while depletion of endogenous CRIF1 decreased cell cycle arrest. Depletion of CRIF1 reversed BMSCs induced cell cycle arrest in leukemia cells. Co-immunoprecipitation showed a specific binding of CDK2 to CRIF1 in Jurkat cells during cell cycle arrest. Co-localization of two proteins in both nucleus and cytoplasm was also observed with immunofluorescent staining. CONCLUSION: CRIF1 may play a regulatory role in the BM microenvironment-induced leukemia cell cycle arrest possibly through interacting with CDK2 and acting as a cyclin-dependent kinase inhibitor.

  18. Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses.

    Science.gov (United States)

    Lau, Colleen M; Nish, Simone A; Yogev, Nir; Waisman, Ari; Reiner, Steven L; Reizis, Boris

    2016-03-01

    A common genetic alteration in acute myeloid leukemia is the internal tandem duplication (ITD) in FLT3, the receptor for cytokine FLT3 ligand (FLT3L). Constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. Pre-leukemic mice with the Flt3(ITD) knock-in allele manifested an expansion of classical DCs (cDCs) and plasmacytoid DCs. The expansion originated in DC progenitors, was cell intrinsic, and was further enhanced in Flt3(ITD/ITD) mice. The mutation caused the down-regulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Both canonical Batf3-dependent CD8(+) cDCs and noncanonical CD8(+) cDCs were expanded and showed specific alterations in their expression profiles. Flt3(ITD) mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T (T reg) cells. Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity without T reg cells. Thus, the FLT3-ITD mutation directly affects DC development, indirectly modulating T cell homeostasis and supporting T reg cell expansion. We hypothesize that this effect of FLT3-ITD might subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner. PMID:26903243

  19. Nilotinib and imatinib are comparably effective in reducing growth of human eosinophil leukemia cells in a newly established xenograft model.

    Directory of Open Access Journals (Sweden)

    Daniel Wicklein

    Full Text Available We developed a xenograft model of human Chronic Eosinophilic Leukemia (CEL to study disease progression and remission-induction under therapy with tyrosine kinase inhibitors using imatinib and nilotinib as examples. The FIP1L1/PDGFRA+ human CEL cell lineEOL-1 was injected intravenously into scid mice, and MR imaging and FACS analysis of mouse blood samples were performed to monitor disease development and the effects of imatinib and nilotinib. Organ infiltration was analyzed in detail by immunohistochemistry after sacrifice. All animals developed CEL and within one week of therapy, complete remissions were seen with both imatinib and nilotinib, resulting in reduced total tumor volumes by MR-imaging and almost complete disappearance of EOL-1 cells in the peripheral blood and in tissues. The new model system is feasible for the evaluation of new tyrosine kinase inhibitors and our data suggest that nilotinib may be a valuable additional targeted drug active in patients with FIP1L1/PDGFRA+ CEL.

  20. Improved anti-leukemia activities of adoptively transferred T cells expressing bispecific T-cell engager in mice.

    Science.gov (United States)

    Liu, X; Barrett, D M; Jiang, S; Fang, C; Kalos, M; Grupp, S A; June, C H; Zhao, Y

    2016-01-01

    Despite the impressive clinical efficacy of T cells engineered to express chimeric antigen receptors (CAR-Ts), the current applications of CAR-T cell therapy are limited by major treatment-related toxicity. Thus, safer yet effective alternative approaches must be developed. In this study, we compared CD19 bispecific T-cell engager (BiTE)-transferred T cells that had been transfected by RNA electroporation with CD19 CAR RNA-transferred T cells both in vitro and in an aggressive Nalm6 leukemia mouse model. BiTEs were secreted from the transferred T cells and enabled both the transferred and bystander T cells to specifically recognize CD19(+) cell lines, with increased tumor killing ability, prolonged functional persistence, increased cytokine production and potent proliferation compared with the CAR-T cells. More interestingly, in comparison with CD3/CD28 bead-stimulated T cells, T cells that were expanded by a rapid T-cell expansion protocol (REP) showed enhanced anti-tumor activities for both CAR and BiTE RNA-electroporated T cells both in vitro and in a Nalm6 mouse model (P<0.01). Furthermore, the REP T cells with BiTE RNAs showed greater efficacy in the Nalm6 leukemia model compared with REP T cells with CAR RNA (P<0.05) and resulted in complete leukemia remission. PMID:27258611

  1. Phosphatidylserine index as a marker of the procoagulant phenotype of acute myelogenous leukemia cells

    International Nuclear Information System (INIS)

    Patients with acute myelogenous leukemia (AML) are at risk for thrombotic complications. Risk to develop thrombosis is closely tied to leukemia subtype, and studies have shown an association between leukocytosis and thrombosis in AML M3. We evaluated the relative roles of cell count and the surface expression of tissue factor (TF) and phosphatidylserine (PS) in the procoagulant phenotype of AML cell lines. The TF-positive AML M3 cell lines, NB4 and HL60, and AML M2 cell line, AML14, exhibited both extrinsic tenase and prothrombinase activity in a purified system and promoted experimental thrombus formation. In contrast, the TF-negative AML cell line, HEL, exhibited only prothrombinase activity and did not affect the rate of occlusive thrombus formation. In plasma, NB4, HL60 and AML14 shortened clotting times in a cell-count, PS- and TF-dependent manner. Exposure of cultured NB4, HL60, and AML14 cells to the chemotherapeutic agent daunorubicin increased their extrinsic tenase activity and PS expression. Clot initiation time inversely correlated with logarithm of PS index, defined as the product of multiplying leukocyte count with cell surface PS exposure. We propose that leukemia cell PS index may serve as a biomarker for procoagulant activity. (paper)

  2. Spinal cord T-cell infiltration in the spared nerve injury model of neuropathic pain: a time course study

    OpenAIRE

    Clarke C.

    2012-01-01

    Background : Numerous studies have shown that immune cells infiltrate the spinal cord after peripheral nerve injury and that they play a major contribution to sensory hypersensitivity in rodents. In particular, the role of monocyte-derived cells and T lymphocytes seems to be prominent in this process. This exciting new perspective in research on neuropathic pain opens many different areas of work, including the understanding of the function of these cells and how they impact on neural functio...

  3. FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis

    OpenAIRE

    Takenaka, Miki; Seki, Naoko; Toh, Uhi; Hattori, Satoshi; KAWAHARA, AKIHIKO; Yamaguchi, Tomohiko; KOURA, KEIKO; Takahashi, Ryuji; Otsuka, Hiroko; Takahashi, Hiroki; Iwakuma, Nobutaka; Nakagawa, Shino; Fujii, Teruhiko; Sasada, Tetsuro; Yamaguchi, Rin

    2013-01-01

    The forkhead box protein 3 (FOXP3) transcription factor is highly expressed in tumor cells as well as in regulatory T cells (Tregs). It plays a tumor-enhancing role in Tregs and suppresses carcinogenesis as a potent repressor of several oncogenes. The clinical prognostic value of FOXP3 expression has not yet been elucidated. In this study, immunohistochemistry was used to investigate the prognostic significance of FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes (TILs) in br...

  4. Systemic mastocytosis in a patient with ovarian germ cell carcinoma and mast cell leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Sun, G.; Hajianpour, M.J.; Hajianpour, A.K. [Alfigen/The Genetics Institute, Pasadena, CA (United States)] [and others

    1994-09-01

    We report a 12-year-old female with a history of mixed germ cell carcinoma of the right ovary who developed a generalized skin rash after oophorectomy and chemotherapy. She also presented with periodic episodes of flushing, anemia, tachycardia, shortness of breath, high fever, hepatosplenomegaly, nausea, abdominal cramping with diarrhea, and a papuloerythematous skin rash. There was no evidence of secondary carcinoma. Skin biopsy revealed nonspecific inflammatory cells with negative staining for mast cells. Peripheral blood smear showed an increased number of mast cells, thrombocytopenia and normal white cells count. Bone marrow showed hypercellularity with 38% of the nucleated cells being mast cells. Bone marrow chromosome analysis revealed hyperdiploidy in 30% of the cells: 58-64,XX, +1, +2, +5, +6, +7, +8, +14, +16, +18, +19, +19, +20, +21, +22. She expired two months after the occurrence of systemic mastocytosis. Systemic mastocytosis has been reported in association with hematopoietic disorders and with germ cell tumors. The association between mediastinal germ cell tumors and hematological malignancies has also been observed. To our knowledge, combination of most cell leukemia, systemic mastocytosis, and ovarian germ cell carcinoma has not been observed. It is know that mutations at the locus of either proto-oncogene c-kit receptor or its ligand, mast/stem cell factor (SCF) may impair the development of three stem cell populations: hematopoietic stem cells, germ cells and melanoblasts. There have been also extensive investigations on the expression and modulation of the SCF/c-kit interaction in various malignancies. Further molecular studies in patients with germ cell tumor/hematopoietic malignancy syndrome are required to delineate underlying mechanisms.

  5. A preliminary study on epigenetic regulation of Acanthopanax senticosus in leukemia cell lines.

    Science.gov (United States)

    Wang, Qing-Yuan; Zhong, Hua; Chen, Fang-Yuan; Zhang, Min-Yue; Cai, Jia-Yi; Zhong, Ji-Hua

    2016-06-01

    Conventional chemotherapy for leukemia inevitably causes systemic toxicity. Acanthopanax senticosus, a naturally occurring herb used in traditional Chinese medicine, has been found to be a multipotent bioflavonoid with great potential in the prevention and treatment of malignant diseases. However, the mechanism underlying the action of A. senticosus in epigenetic regulation is poorly understood. In the study described here, we focused on the efficacy of A. senticosus in inducing apoptosis of leukemia cells and a possible mechanism. By evaluating the inhibition ratio and morphologic changes, we found that A. senticosus can inhibit growth and induce apoptosis of human leukemia HL-60 and HL60/ADM cells in a dose- and time-dependent manner. Furthermore, A. senticosus induced Fas ligand (FasL) expression and blocked the cell cycle in S phase. In addition, A. senticosus exhibited a potential for inhibition of histone deacetylase (HADC), which contributes to histone acetylation. It possibly resulted in the promotion of the expression of FasL. It is suggested that A. senticosus could be recognized as a new HDAC inhibitor which was able to reactivate aberrantly silenced genes. We discuss the clinical aspects of using A. senticosus for treatment of leukemia. PMID:26992299

  6. Donor Umbilical Cord Blood Transplant With or Without Ex-vivo Expanded Cord Blood Progenitor Cells in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, or Myelodysplastic Syndromes

    Science.gov (United States)

    2016-08-10

    Acute Biphenotypic Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Mixed Phenotype Acute Leukemia; Myelodysplastic Syndrome; Pancytopenia; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Secondary Acute Myeloid Leukemia

  7. Molecular diagnosis of lymphoblastic leukemia

    OpenAIRE

    Kalal Iravathy Goud; Seetha Dayakar; Prasad, S. V. S. S.; Koteshwar N Rao; Amina Shaik; S Vanjakshi

    2013-01-01

    The mixed lineage leukemia (MLL) gene at chromosome band 11q23 is commonly involved in reciprocal translocations that is detected in acute leukemia. The MLL gene, coomonly known as mixed lineage leukemia or myeloid lymphoid leukemia, has been independently identified and cloned from the 11q23 breakpoint of acute leukemia. We describe a patient with acute lymphoblastic leukemia whose cells had shown reciprocal translocation between short arm (p21) of chromosome 2 and long arm (q23) of chromoso...

  8. Performance Factors and Sulfur Tolerance of Metal Supported Solid Oxide Fuel Cells with Nanostructured Ni:GDC Infiltrated Anodes

    DEFF Research Database (Denmark)

    Nielsen, Jimmi; Sudireddy, Bhaskar Reddy; Hagen, Anke; Persson, Åsa Helen

    2016-01-01

    Two metal supported solid oxide fuel cells (active area 16 cm2) with nanostructured Ni:GDC infiltrated anodes, possessing different anode and support microstructures were studied in respect to sulfur tolerance at an operating temperature of 650°C. The studied MS-SOFCs are based on ferretic stainl...

  9. Performance Factors and Sulfur Tolerance of Metal Supported Solid Oxide Fuel Cells with Nanostructured Ni:GDC Infiltrated Anodes

    DEFF Research Database (Denmark)

    Nielsen, Jimmi; Sudireddy, Bhaskar Reddy; Hagen, Anke; Persson, Åsa Helen

    2015-01-01

    Two metal supported solid oxide fuel cells (active area 16 cm2) with nanostructured Ni:GDC infiltrated anodes, but different anode and support microstructures were studied in respect to sulfur tolerance at the aimed operating temperature of 650ºC. The studied MS-SOFCs are based on ferretic stainl...

  10. Characterization of a pediatric T-cell acute lymphoblastic leukemia patient with simultaneous LYL1 and LMO2 rearrangements

    OpenAIRE

    Homminga, Irene; Vuerhard, Maartje J.; Langerak, Anton W; Buijs-Gladdines, Jessica; Pieters, Rob; Meijerink, Jules P. P.

    2012-01-01

    Translocation of the LYL1 oncogene are rare in T-cell acute lymphoblastic leukemia, whereas the homologous TAL1 gene is rearranged in approximately 20% of patients. Previous gene-expression studies have identified an immature T-cell acute lymphoblastic leukemia subgroup with high LYL1 expression in the absence of chromosomal aberrations. Molecular characterization of a t(7;19)(q34;p13) in a pediatric T-cell acute lymphoblastic leukemia patient led to the identification of a translocation betw...

  11. Usefulness of liver infiltrating CD86-positive mononuclear cells for diagnosis of autoimmune hepatitis

    Institute of Scientific and Technical Information of China (English)

    Kazutaka Kurokohchi; Shigeki Kuriyama; Tsutomu Masaki; Takashi Himoto; Akihiro Deguchi; Seiji Nakai; Asahiro Morishita; Hirohito Yoneyama; Yasuhiko Kimura; Seishiro Watanabe

    2006-01-01

    AIM: Although the pathogenic mechanism underlying autoimmune hepatitis (AIH) remains unclear, the immune system is thought to be critical for the progression of the disease. Cellular immune responses may be linked to the hepatocellular damage in AIH. Recently, much attention has been focused on the critical functions of costimulatory molecules expressed on mononuclear cells in the generation of effective T cell-mediated immune responses. Analysis of costimulatory molecule expressed on mononuclear cells from the patients with AIH may give us insight into the pathogenic mechanism of hepatocellular damage in AIH.METHODS: Peripheral blood mononuclear cells (PBMC)were taken from the patients with AIH (34 cases) and healthy controls (25 cases). Liver infiltrating mononuclear cells (LIMCs) were taken from the patients with AIH (18 cases), the patient with chronic hepatitis C (CH-C) (13 cases) and the patients with fatty liver (2 cases).Using flow cytometry, the cells were analyzed for the expression of costimulatory molecules, such as CD80,CD86, and CD152 (CTLA-4). The results were compared with clinical data such as the level of gammaglobulin,histological grade, presence or absence of corticosteroids administration and the response to corticosteroids.RESULTS: The levels of CD80+, CD86+ and CD152+PBMC were significantly reduced in the patients with AIH as compared with healthy controls. By contrast,those cells were significantly higher in LTMC than in PBMC of the patients with AIH. Especially, the level of CD86+ LIMC showed a marked increase irrespective of the degree of disease activity in the patients with ATH,although CD86+ cells were rarely present in PBMC. The levels of CD86+ cells were present in significantly higher frequency in patients with AIH than in the patients with CH-C. Furthermore, the patients with AIH with high levels of CD86+ LIMC showed good responses to corticosteroids, whereas 2 cases of AIH with low levels of CD86+ LIMC did not respond well

  12. T cell-prolymphocytic leukemia detected in a patient of breast cancer at the time of recurrence: a case report

    OpenAIRE

    Singhal, Manish; Raina, Vinod; GUPTA Ritu; Das, Prasenjit

    2010-01-01

    Introduction Therapy related second malignancy of the hematological system is small but real risk after adjuvant chemotherapy for breast cancer. It includes acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS); however T-cell prolymphocytic leukemia (T-PLL) has not been described earlier in relation to breast cancer and its therapy. T-PLL is a rare chronic T-cell lymphoproliferative disease with a mature post-thymic T-cell immunophenotype and aggressive clinical course. Case presen...

  13. Apoptosis of infiltrating T cells in the central nervous system of mice infected with Theiler's murine encephalomyelitis virus

    International Nuclear Information System (INIS)

    Theiler murine encephalomyelitis virus (TMEV), DA strain, induces in susceptible strain of mice a biphasic disease consisting of early acute disease followed by late chronic demyelinating disease. Both phases of the disease are associated with inflammatory infiltrates of the central nervous system (CNS). Late chronic demyelinating disease induced by TMEV serves as an excellent model to study human demyelinating disease, multiple sclerosis. During early acute disease, the virus is partially cleared from the CNS by CD3+ T cells. These T cells express Fas, FasL, negligible levels of Bcl-2 proteins and undergo activation-induced cell death as determined by TUNEL assay leading to resolution of the inflammatory response. In contrast, during late chronic demyelinating disease, and despite dense perivascular and leptomeningeal infiltrates, only very few cells undergo apoptosis. Mononuclear cells infiltrating the CNS express Bcl-2. It appears that the lack of apoptosis of T cells during late chronic demyelinating disease leads to the accumulation of these cells in the CNS. These cells may play a role in the pathogenesis of the demyelinating disease

  14. ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival.

    Science.gov (United States)

    Zhong, Wenbin; Yi, Qing; Xu, Bing; Li, Shiqian; Wang, Tong; Liu, Fupei; Zhu, Biying; Hoffmann, Peter R; Ji, Guangju; Lei, Pingsheng; Li, Guoping; Li, Jiwei; Li, Jian; Olkkonen, Vesa M; Yan, Daoguang

    2016-01-01

    Metabolic pathways are reprogrammed in cancer to support cell survival. Here, we report that T-cell acute lymphoblastic leukemia (T-ALL) cells are characterized by increased oxidative phosphorylation and robust ATP production. We demonstrate that ORP4L is expressed in T-ALL but not normal T-cells and its abundance is proportional to cellular ATP. ORP4L acts as an adaptor/scaffold assembling CD3ɛ, Gαq/11 and PLCβ3 into a complex that activates PLCβ3. PLCβ3 catalyzes IP3 production in T-ALL as opposed to PLCγ1 in normal T-cells. Up-regulation of ORP4L thus results in a switch in the enzyme responsible for IP3-induced endoplasmic reticulum Ca(2+) release and oxidative phosphorylation. ORP4L knockdown results in suboptimal bioenergetics, cell death and abrogation of T-ALL engraftment in vivo. In summary, we uncovered a signalling pathway operating specifically in T-ALL cells in which ORP4L mediates G protein-coupled ligand-induced PLCβ3 activation, resulting in an increase of mitochondrial respiration for cell survival. Targeting ORP4L might represent a promising approach for T-ALL treatment. PMID:27581363

  15. Inhibition of tryptase and chymase induced nucleated cell infiltration by proteinase inhibitors

    Institute of Scientific and Technical Information of China (English)

    Shao-heng HE; Han-qiu CHEN; Jian ZHENG

    2004-01-01

    AIM: To investigate the ability of proteinase inhibitors to modulate nucleated cell infiltration into the peritoneum of mice induced by tryptase and chymase. METHODS: Human lung tryptase and skin chymase were purified by a similar procedure involving high salt extraction, heparin agarose affinity chromatography followed by S-200 Sephacryl gel filtration chromatography. The actions of proteinase inhibitors on tryptase and chymase induced nucleated cell accumulation were examined with a mouse peritoneum model. RESULTS: A selective chymase inhibitor Z-Ile-GluPro-Phe-CO2Me (ZIGPPF) was able to inhibit approximately 90% neutrophil, 73% eosinophil, 87% lymphocyte and 60% macrophage accumulation induced by chymase at 16 h following injection. Soy bean trypsin inhibitor (SBTI), chymostatin, and α1-antitrypsin showed slightly less potency than ZIGPPF in inhibition of the actions of chymase. While all tryptase inhibitors tested were able to inhibit neutrophil, eosinophil, and macrophage accumulation provoked by tryptase at 16 h following injection, only leupeptin, APC366, and aprotinin were capable of inhibiting tryptase induced lymphocyte accumulation. The inhibitiors of tryptase tested were also able to inhibit tryptase induced neutrophil and eosinophil accumulation at 6 h following injection. When being injected alone, all inhibitors of chymase and tryptase at the concentrations tested by themselves had no significant effect on the accumulation of nucleated cells in the peritoneum of mice at both 6 h and 16 h. CONCLUSION: Proteinase inhibitors significantly inhibited tryptase and chymase-induced nucleated cell accumulation in vivo, and therefore they are likely to be developed as a novel class of anti-inflammatory drugs.

  16. Sensitization of K562 Leukemia Cells to Doxorubicin by the Viscum album Extract.

    Science.gov (United States)

    Srdic-Rajic, Tatjana; Tisma-Miletic, Nevena; Cavic, Milena; Kanjer, Ksenija; Savikin, Katarina; Galun, Danijel; Konic-Ristic, Aleksandra; Zoranovic, Tamara

    2016-03-01

    Toxicity of conventional chemotherapeutics highlights the requirement for complementary or alternative medicines that would reduce side effects and improve their anticancer effectiveness. European mistletoe (Viscum album) has long been used as a complementary and alternative medicine supporting cancer therapy. The aim of this study was to investigate synergistic antitumor action of V. album extract and doxorubicin during co-treatment of chemoresistant chronic myelogenic leukemia K562 cells. Combined treatment of leukemia cells led to inhibitory synergism at sub-apoptotic doxorubicin concentrations and multifold reduction of cytotoxic effects in healthy control cells. Prolonged co-treatment was associated with reduced G2/M accumulation and increased expression of early and late apoptotic markers. Our data indicate that V. album extract increases antileukemic effectiveness of doxorubicin against resistant K562 cells by preventing G2/M arrest and inducing apoptosis. PMID:26692465

  17. DNA Microarray Assay Helps to Identify Functional Genes Specific for Leukemia Stem Cells

    Directory of Open Access Journals (Sweden)

    Haojian Zhang

    2013-01-01

    Full Text Available Chronic myeloid leukemia (CML is a myeloproliferative disease derived from an abnormal hematopoietic stem cell (HSC and is consistently associated with the formation of Philadelphia (Ph chromosome. Tyrosine kinase inhibitors (TKIs are highly effective in treating chronic phase CML but do not eliminate leukemia stem cells (LSCs, which are believed to be related to disease relapse. Therefore, one major challenge in the current CML research is to understand the biology of LSCs and to identify the molecular difference between LSCs and its normal stem cell counterparts. Comparing the gene expression profiles between LSCs and normal HSCs by DNA microarray assay is a systematic and unbiased approach to address this issue. In this paper, we present a DNA microarray dataset for CML LSCs and normal HSCs to show that the microarray assay will benefit the current and future studies of the biology of CML stem cells.

  18. Comparison of infiltrated ceramic fiber paper and mica base compressive seals for planar solid oxide fuel cells

    Energy Technology Data Exchange (ETDEWEB)

    Le, Shiru; Sun, Kening; Shao, Yanbin; An, Maozhong; Fu, Qiang; Zhu, Xiaodong [Department of Applied Chemistry, Harbin Institute of Technology, No. 92 of West Dazhi Street, P.O. Box 211, Harbin 150001 (China); Zhang, Naiqing [Department of Applied Chemistry, Harbin Institute of Technology, No. 92 of West Dazhi Street, P.O. Box 211, Harbin 150001 (China); The Research Station on Material Science and Engineering for Postoral Fellows, No. 2 Yikang Street, Harbin 150001 (China)

    2007-06-01

    Solid oxide fuel cells using non-glass sealants have become increasingly common. In this paper, fumed silica infiltrated ceramic fiber paper with pre-compression was compared with plain and pre-compressed at 10 MPa hybrid mica as compressive seals. Leakage tests were measured under a 0.1-1.0 MPa compressive load with the pressure gradient varying from 2 to 15 kPa. The results demonstrated that the leakage rate of infiltrated fiber paper was 0.04 sccm cm{sup -1} for a 10 kPa gradient, under 1.0 MPa compressive load, while for mica it was 0.60 and 0.63 sccm cm{sup -1} which indicated that the infiltrated ceramic fiber paper showed a much lower leakage than mica. Long-term thermal cycling tests demonstrated that although the leakage of fumed silica infiltrated fiber paper was slightly higher than that of hybrid mica, it remained stable after 20 thermal cycles and no interlayer was needed. The mass loss of the fiber paper was 1.7 x 10{sup -2} mg cm{sup -2} h{sup -1} in a hydrogen environment at 1073 K for 200 h. The leakage of infiltrated fiber paper remained about 0.06 sccm cm{sup -1} after reduction. (author)

  19. Inhibition of MerTK increases chemosensitivity and decreases oncogenic potential in T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Brandao, L N; Winges, A; Christoph, S; Sather, S; Migdall-Wilson, J; Schlegel, J; McGranahan, A; Gao, D; Liang, X; Deryckere, D; Graham, D K

    2013-01-01

    Pediatric leukemia survival rates have improved dramatically over the past decades. However, current treatment protocols are still largely ineffective in cases of relapsed leukemia and are associated with a significant rate of chronic health conditions. Thus, there is a continued need for new therapeutic options. Here, we show that mer receptor tyrosine kinase (MerTK) was abnormally expressed in approximately one half of pediatric T-cell leukemia patient samples and T-cell acute lymphoblastic leukemia (T-ALL) cell lines. Stimulation of MerTK by the ligand Gas6 led to activation of the prosurvival proteins Erk 1/2 and Stat5, and MerTK-dependent activation of the STAT pathway in leukemia represents a novel finding. Furthermore, inhibition of MerTK expression increased the sensitivity of T-ALL cells to treatment with chemotherapeutic agents and decreased the oncogenic potential of the Jurkat T-ALL cell line in a methylcellulose colony-forming assay. Lastly, inhibition of MerTK expression significantly increased median survival in a xenograft mouse model of leukemia (30.5 days vs 60 days, P<0.0001). These results suggest that inhibition of MerTK is a promising therapeutic strategy for the treatment of leukemia and may allow for dose reduction of currently used chemotherapeutics resulting in decreased rates of therapy-associated toxicities. PMID:23353780

  20. Inhibition of MerTK increases chemosensitivity and decreases oncogenic potential in T-cell acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Pediatric leukemia survival rates have improved dramatically over the past decades. However, current treatment protocols are still largely ineffective in cases of relapsed leukemia and are associated with a significant rate of chronic health conditions. Thus, there is a continued need for new therapeutic options. Here, we show that mer receptor tyrosine kinase (MerTK) was abnormally expressed in approximately one half of pediatric T-cell leukemia patient samples and T-cell acute lymphoblastic leukemia (T-ALL) cell lines. Stimulation of MerTK by the ligand Gas6 led to activation of the prosurvival proteins Erk 1/2 and Stat5, and MerTK-dependent activation of the STAT pathway in leukemia represents a novel finding. Furthermore, inhibition of MerTK expression increased the sensitivity of T-ALL cells to treatment with chemotherapeutic agents and decreased the oncogenic potential of the Jurkat T-ALL cell line in a methylcellulose colony-forming assay. Lastly, inhibition of MerTK expression significantly increased median survival in a xenograft mouse model of leukemia (30.5 days vs 60 days, P<0.0001). These results suggest that inhibition of MerTK is a promising therapeutic strategy for the treatment of leukemia and may allow for dose reduction of currently used chemotherapeutics resulting in decreased rates of therapy-associated toxicities

  1. Polydatin-induced cell apoptosis and cell cycle arrest are potentiated by Janus kinase 2 inhibition in leukemia cells.

    Science.gov (United States)

    Cao, Wei-Jie; Wu, Ke; Wang, Chong; Wan, Ding-Ming

    2016-04-01

    Polydatin (PD), a natural precursor of resveratrol, has a variety of biological activities, including anti‑tumor effects. However, the underlying molecular mechanisms of the anti-cancer activity of PD has not been fully elucidated. The present study demonstrated that PD significantly inhibited the proliferation of the MOLT-4 leukemia cell line in a dose‑ and time-dependent manner by using Cell Counting Kit‑8 assay. PD also dose-dependently increased the apoptotic rate and caused cell cycle arrest in S phase in MOLT‑4 cells, as revealed by flow cytometry. In addition, PD dose-dependently decreased the mitochondrial membrane potential and led to the generation of reactive oxygen species in MOLT-4 cells. Western blot analysis revealed that the expression of anti‑apoptotic protein B-cell lymphoma 2 (Bcl-2) was decreased, whereas that of pro‑apoptotic protein Bcl‑2‑associated X was increased by PD. Furthermore, the expression of two cell cycle regulatory proteins, cyclin D1 and cyclin B1, was suppressed by PD. Of note, the pro‑apoptotic and cell cycle‑inhibitory effects of PD were potentiated by Janus kinase 2 (JAK2) inhibition. In conclusion, the results of the present study strongly suggested that PD is a promising therapeutic compound for the treatment of leukemia, particularly in combination with JAK inhibitors. PMID:26934953

  2. Immunoglobulin D Multiple Myeloma, Plasma Cell Leukemia and Chronic Myelogenous Leukemia in a Single Patient Treated Simultaneously with Lenalidomide, Bortezomib, Dexamethasone and Imatinib

    OpenAIRE

    Naveed Ali; Pickens, Peter V.; Auerbach, Herbert E.

    2016-01-01

    Multiple myeloma (MM) is a neoplastic lymphoproliferative disorder characterized by uncontrolled monoclonal plasma cell proliferation. Among different isotypes of MM, immunoglobulin D (IgD) MM is very rare, representing only 1 to 2% of all isotypes. Chronic myelogenous leukemia (CML) is a neoplastic myeloproliferative disorder of pluripotent hematopoietic stem cell, which is characterized by the uncontrolled proliferation of myeloid cells. An 88-year-old male was diagnosed simultaneously with...

  3. Clinical significance of tumor-infiltrating immune cells focusing on BTLA and Cbl-b in patients with gallbladder cancer.

    Science.gov (United States)

    Oguro, Seiji; Ino, Yoshinori; Shimada, Kazuaki; Hatanaka, Yutaka; Matsuno, Yoshihiro; Esaki, Minoru; Nara, Satoshi; Kishi, Yoji; Kosuge, Tomoo; Hiraoka, Nobuyoshi

    2015-12-01

    The host immune system plays a significant role in tumor control, although most cancers escape immune surveillance through a variety of mechanisms. The aim of the present study was to evaluate the clinicopathological significance of a novel co-inhibitory receptor, B and T lymphocyte attenuator (BTLA), the anergy cell marker Casitas-B-lineage lymphoma protein-b (Cbl-b), and clinical implications of tumor-infiltrating immune cells in gallbladder cancer (GBC) tissues. We investigated 211 cases of GBC, 21 cases of chronic cholecystitis (CC), and 11 cases of xanthogranulomatous cholecystitis (XGC) using immunohistochemistry to detect tissue-infiltrating immune cells and their expression of BTLA and Cbl-b, and carried out correlation and survival analyses. The density of infiltrating T cells was significantly higher in CC and XGC than in GBC. The density ratio of BTLA(+) cells to CD8(+) T cells (BTLA/CD8) and that of Cbl-b(+) cells to CD8(+) T cells (Cbl-b/CD8) were significantly higher in GBC than in CC and XGC. The FOXP3/CD4, BTLA/CD8, and Cbl-b/CD8 ratios were significantly correlated with each other, and also with malignant phenotypes. Survival analyses revealed that a lower density of tumor-infiltrating CD8(+) cells, and higher Foxp3/CD4, BTLA/CD8, and Cbl-b/CD8 ratios were significantly associated with shorter overall survival and disease-free survival in GBC patients. Multivariate analyses showed that M factor, perineural invasion, BTLA/CD8, and Cbl-b/CD8 were closely associated with shorter overall survival. These findings suggest that higher ratios of BTLA/CD8 and Cbl-b/CD8 are independent indicators of unfavorable outcome in GBC patients, and that upregulation of BTLA in cancer tissues is involved in inhibition of antitumor immunity. PMID:26395180

  4. Adipocytes Cause Leukemia Cell Resistance to L-Asparaginase via Release of Glutamine

    OpenAIRE

    Ehsanipour, Ehsan A.; SHENG, Xia; Behan, James W.; Wang, Xingchao; Butturini, Anna; Avramis, Vassilios I; Mittelman, Steven D.

    2013-01-01

    Obesity is a significant risk factor for cancer. A link between obesity and a childhood cancer has been identified: obese children diagnosed with high-risk acute lymphoblastic leukemia (ALL) had a 50% greater risk of relapse than their lean counterparts. L-asparaginase (ASNase) is a first-line therapy for ALL that breaks down asparagine and glutamine, exploiting the fact that ALL cells are more dependent on these amino acids than other cells. In the present study, we investigated whether adip...

  5. DNA Damage, Cell Cycle Arrest, and Apoptosis Induction Caused by Lead in Human Leukemia Cells.

    Science.gov (United States)

    Yedjou, Clement G; Tchounwou, Hervey M; Tchounwou, Paul B

    2016-01-01

    In recent years, the industrial use of lead has been significantly reduced from paints and ceramic products, caulking, and pipe solder. Despite this progress, lead exposure continues to be a significant public health concern. The main goal of this research was to determine the in vitro mechanisms of lead nitrate [Pb(NO₃)₂] to induce DNA damage, apoptosis, and cell cycle arrest in human leukemia (HL-60) cells. To reach our goal, HL-60 cells were treated with different concentrations of Pb(NO₃)₂ for 24 h. Live cells and necrotic death cells were measured by the propidium idiode (PI) assay using the cellometer vision. Cell apoptosis was measured by the flow cytometry and DNA laddering. Cell cycle analysis was evaluated by the flow cytometry. The result of the PI demonstrated a significant (p rupture by Pb(NO₃)₂ compared to the control. Data generated from the comet assay indicated a concentration-dependent increase in DNA damage, showing a significant increase (p < 0.05) in comet tail-length and percentages of DNA cleavage. Data generated from the flow cytometry assessment indicated that Pb(NO₃)₂ exposure significantly (p < 0.05) increased the proportion of caspase-3 positive cells (apoptotic cells) compared to the control. The flow cytometry assessment also indicated Pb(NO₃)₂ exposure caused cell cycle arrest at the G₀/G₁ checkpoint. The result of DNA laddering assay showed presence of DNA smear in the agarose gel with little presence of DNA fragments in the treated cells compared to the control. In summary, Pb(NO₃)₂ inhibits HL-60 cells proliferation by not only inducing DNA damage and cell cycle arrest at the G₀/G₁ checkpoint but also triggering the apoptosis through caspase-3 activation and nucleosomal DNA fragmentation accompanied by secondary necrosis. We believe that our study provides a new insight into the mechanisms of Pb(NO₃)₂ exposure and its associated adverse health effects. PMID:26703663

  6. Novel quinazolinone MJ-29 triggers endoplasmic reticulum stress and intrinsic apoptosis in murine leukemia WEHI-3 cells and inhibits leukemic mice.

    Directory of Open Access Journals (Sweden)

    Chi-Cheng Lu

    Full Text Available The present study was to explore the biological responses of the newly compound, MJ-29 in murine myelomonocytic leukemia WEHI-3 cells in vitro and in vivo fates. We focused on the in vitro effects of MJ-29 on ER stress and mitochondria-dependent apoptotic death in WEHI-3 cells, and to hypothesize that MJ-29 might fully impair the orthotopic leukemic mice. Our results indicated that a concentration-dependent decrease of cell viability was shown in MJ-29-treated cells. DNA content was examined utilizing flow cytometry, whereas apoptotic populations were determined using annexin V/PI, DAPI staining and TUNEL assay. Increasing vital factors of mitochondrial dysfunction by MJ-29 were further investigated. Thus, MJ-29-provaked apoptosis of WEHI-3 cells is mediated through the intrinsic pathway. Importantly, intracellular Ca(2+ release and ER stress-associated signaling also contributed to MJ-29-triggered cell apoptosis. We found that MJ-29 stimulated the protein levels of calpain 1, CHOP and p-eIF2α pathways in WEHI-3 cells. In in vivo experiments, intraperitoneal administration of MJ-29 significantly improved the total survival rate, enhanced body weight and attenuated enlarged spleen and liver tissues in leukemic mice. The infiltration of immature myeloblastic cells into splenic red pulp was reduced in MJ-29-treated leukemic mice. Moreover, MJ-29 increased the differentiations of T and B cells but decreased that of macrophages and monocytes. Additionally, MJ-29-stimulated immune responses might be involved in anti-leukemic activity in vivo. Based on these observations, MJ-29 suppresses WEHI-3 cells in vitro and in vivo, and it is proposed that this potent and selective agent could be a new chemotherapeutic candidate for anti-leukemia in the future.

  7. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    International Nuclear Information System (INIS)

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response

  8. Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Okabe, Seiichi, E-mail: okabe@tokyo-med.ac.jp; Tauchi, Tetsuzo; Tanaka, Yuko; Ohyashiki, Kazuma

    2013-06-07

    Highlights: •Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells okabe et al. •Imatinib or nilotinib resistance was involved Src family kinase. •The BCR-ABL point mutation (E334V) was highly resistant to imatinib or nilotinib. •Ponatinib was a powerful strategy against imatinib or nilotinib resistant Ph-positive cells. -- Abstract: Because a substantial number of patients with chronic myeloid leukemia acquire resistance to ABL tyrosine kinase inhibitors (TKIs), their management remains a challenge. Ponatinib, also known as AP24534, is an oral multi-targeted TKI. Ponatinib is currently being investigated in a pivotal phase 2 clinical trial. In the present study, we analyzed the molecular and functional consequences of ponatinib against imatinib- or nilotinib-resistant (R) K562 and Ba/F3 cells. The proliferation of imatinib- or nilotinib-resistant K562 cells did not decrease after treatment with imatinib or nilotinib. Src family kinase Lyn was activated. Point mutation Ba/F3 cells (E334 V) were also highly resistant to imatinib and nilotinib. Treatment with ponatinib for 72 h inhibited the growth of imatinib- and nilotinib-resistant cells. The phosphorylation of BCR-ABL, Lyn, and Crk-L was reduced. This study demonstrates that ponatinib has an anti-leukemia effect by reducing ABL and Lyn kinase activity and this information may be of therapeutic relevance.

  9. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Waters, Katrina M. [Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Sontag, Ryan L. [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Weber, Thomas J., E-mail: Thomas.Weber@pnl.gov [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States)

    2013-04-15

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response.

  10. Loss of oncogenic miR-155 in tumor cells promotes tumor growth by enhancing C/EBP-β-mediated MDSC infiltration.

    Science.gov (United States)

    Kim, Sinae; Song, Jin Hoi; Kim, Seokho; Qu, Peng; Martin, Betty K; Sehareen, Waheed S; Haines, Diana C; Lin, Pengnian C; Sharan, Shyam K; Chang, Suhwan

    2016-03-01

    The oncogenic role of microRNA-155 (miR-155) in leukemia is well established but its role in other cancers, especially breast cancer, is gradually emerging. In this study we examined the effect of mir-155 loss in a well-characterized spontaneous breast cancer mouse model where Brca1 and Trp53 are deleted by K14-Cre. miR-155 is known to be up-regulated in BRCA1-deficient tumors. Surprisingly, complete loss of miR-155 (miR-155ko/ko) did not alter the tumor free survival of the mutant mice. However, we found increased infiltration of myeloid derived suppressor cells (MDSCs) in miR-155 deficient tumors. In addition, cytokine/chemokine array analysis revealed altered level of cytokines that are implicated in the recruitment of MDSCs. Mechanistically, we identified C/EBP-β, a known miR-155 target, to regulate the expression of these cytokines in the miR-155-deficient cells. Furthermore, using an allograft model, we showed that inhibition of miR-155 in cancer cells suppressed in vivo growth, which was restored by the loss of miR-155 in the microenvironment. Taken together, we have uncovered a novel tumor suppressive function of miR-155 in the tumor microenvironment, which is also dependent on miR-155 expression in the tumor cells. Because of the oncogenic as well as tumor suppressive roles of miR-155, our findings warrant caution against a systemic inhibition of miR-155 for anticancer therapy. PMID:26848978

  11. Prognostic impact of tumor infiltrating CD8+ T cells in association with cell proliferation in ovarian cancer patients - a study of the OVCAD consortium

    International Nuclear Information System (INIS)

    Epithelial ovarian cancer is one of the most lethal gynecologic malignancies. Clinicopathological factors do not permit precise prognosis and cannot provide guidance to specific treatments. In this study we assessed tumor infiltrating CD8+ T cells in association with Ki67 proliferation index and evaluated their prognostic impact in EOC samples. CD8+ cells and Ki67 proliferation index were immunohistochemically determined on tissue microarrays including 203 primary epithelial ovarian tumors. Additionally, CD8 gene expression was assessed with RT-qPCR. Correlations were analyzed using Pearson’s correlation coefficients, ANOVA or T-test, or Fischer’s exact tests. Prognostic impact was evaluated using the Kaplan-Meier method and Cox regression model. The density of CD8+ infiltrating lymphocytes did not correlate with tumor cell proliferation. Epithelial ovarian cancer patients with no Ki67+ cells in the tumor had a more than three times higher risk to die compared to the population with Ki67+ cells in the tumor (Hazard ratio (HR) = 3.34, 95%CI 1.59-7.04). High CD8+ cell infiltration was associated with improved overall survival (HR = 0.82, 95%CI 0.73-0.92). The density of tumor infiltrating lymphocytes is independent of tumor cell proliferation. Ovarian cancer patients with Ki67- tumors showed a significantly reduced overall survival, presumably due to no or poor response to platinum-based chemotherapy. Moreover, the association of high densities of tumor infiltrating cytotoxic T lymphocytes with a better overall survival was confirmed

  12. Fabrication and characterization of protonic-ceramic fuel cells and electrolysis cells utilizing infiltrated lanthanum nickelate electrodes

    Science.gov (United States)

    Babiniec, Sean M.

    High-temperature protonic ceramics (HTPCs) have gained interest as fuel cell and electrolysis cell electrolytes, as well as hydrogen separation membranes. The transport of hydrogen as opposed to oxygen results in several benefits and applications, including higher fuel efficiency, dehydrogenation of fuel streams, and hydrogen-based chemical synthesis. However, limited work has been done in the development of air/steam electrodes for these devices. This work presents the characterization of lanthanum nickelate, La 2NiO4+delta (LN), as a potential air/steam electrode material for use with BaCe0.2Zr0.7Y0.1O3-delta (BCZY27) HTPC electrolytes fabricated by the solid-state reactive sintering technique. Two types of devices were made; a symmetric cell used for electrode characterization, and a full fuel cell/electrolysis cell used for device performance characterization. The symmetric cell consists of a 1 mm thick BCZY27 substrate with identical air/steam electrodes on both sides. Air/steam electrodes were made by infiltrating ˜ 50 nm lanthanum nickelate nanoparticles into a BCZY27 porous backbone. The fuel cell/electrolysis cell consists of a 1mm thick Ni/BCZY27 anode support, a 25 mum thick BCZY27 electrolyte, and a 50 mum thick porous BCZY27 backbone infiltrated with lanthanum nickelate. Through symmetric cell testing, it was found that the electrode polarization resistance decreases with increasing oxygen content, indicating good oxygen reduction reaction characteristics. A minimum polarization resistance was found as 2.58 Ohm-cm2 in 3% humidied oxygen at 700 °C. Full cell testing revealed a peak power density of 27 mW-cm-2 at 700 °C. Hydrogen flux measurements were also taken in the both galvanic/post-galvanic and electrolytic operation. Galvanic/post-galvanic fluxes exhibit a very high faradaic efficiency. However, electrolytic hydrogen fluxes were much lower than the calculated hydrogen faradaic flux, indicating a different charge carrier other than protons is

  13. Monocytoid leukemia cell line CTV-1: morphological, immunological and isoenzymatic characteristics.

    Science.gov (United States)

    Drexler, H G; Gaedicke, G; Maeda, S; Chen, P M; Minowada, J

    1986-01-01

    The human leukemia cell line CTV-1 was established from a case of acute monoblastic leukemia (AMoL). We analyzed the phenotypic marker profile of the CTV-1 cells in their original, untreated state and during induction of differentiation with the phorbolester 12-0-tetradecanoylphorbol 13-acetate (TPA). TPA led to morphological changes with signs of differentiation. Cell proliferation decreased in a dose-dependent fashion during exposure to TPA. In the surface marker analysis using a panel of 45 monoclonal antibodies (MoAbs) and several polyclonal antisera, CTV-1 cells were negative for markers of the T- and B-cell lineages, and were positive for several, but not all, myelomonocytic markers. Although the cells were reactive with the MoAb Leu-7 which identifies natural killer (NK) T-cells, no NK activity was detected. In the isoenzyme analysis of the four enzymes carboxylic esterase, acid phosphatase, hexosaminidase and lactate dehydrogenase (LDH) performed by isoelectric focusing on polyacrylamide gels, CTV-1 cells displayed isoenzyme profiles of immature myeloid cells. The overall marker profile of CTV-1 cells demonstrated cells of monocytoid origin arrested at a very early stage of differentiation, possibly close to the stage of precursor cells. As compared to other myelomonocytic cell lines, CTV-1 cells showed unusual morphological, immunological, functional and biochemical features and appeared to be relatively insensitive to treatment with TPA, although some alterations of the phenotype could be induced. PMID:3458274

  14. Susceptibility of human primary neuronal cells to Xenotropic Murine Leukemia Virus-related (XMRV virus infection

    Directory of Open Access Journals (Sweden)

    Girisetty Mohan

    2011-09-01

    Full Text Available Abstract Background Xenotropic Murine Leukemia Virus-related (XMRV virus is a recently identified mouse gammaretrovirus that has the ability to infect certain human cells. In this study, we investigated the susceptibility of primary neuronal cell types to infection with XMRV. Findings We observed that the human primary progenitors, progenitor-derived neurons, and progenitor-derived astrocytes supported XMRV multiplication. Interestingly, both progenitors and progenitor-derived neurons were more susceptible compared with progenitor-derived astrocytes. In addition, XMRV-infected Jurkat cells were able to transmit infection to neuronal cells. Conclusions These data suggest that neuronal cells are susceptible for XMRV infection.

  15. The Role of Tumor-Infiltrating Lymphocytes in Development, Progression, and Prognosis of Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Bremnes, Roy M; Busund, Lill-Tove; Kilvær, Thomas L; Andersen, Sigve; Richardsen, Elin; Paulsen, Erna Elise; Hald, Sigurd; Khanehkenari, Mehrdad Rakaee; Cooper, Wendy A; Kao, Steven C; Dønnem, Tom

    2016-06-01

    A malignant tumor is not merely an accumulation of neoplastic cells, but constitutes a microenvironment containing endothelial cells, fibroblasts, structural components, and infiltrating immune cells that impact tumor development, invasion, metastasis, and outcome. Hence, the evolution of cancers reflects intricate cellular and molecular interactions between tumor cells and constituents of the tumor microenvironment. Recent studies have shed new light on this complex interaction between tumor and host immune cells and the resulting immune response. The composition of the immune microenvironment differs across patients as well as in cancers of the same type, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, and macrophages. The type, density, location, and organization of immune cells within solid tumors define the immune contexture, which has proved to be a major determinant of tumor characteristics and patient outcome. Lung cancer consists mostly of non-small cell lung cancer (85%); it is our most deadly malignant disease, with the 5-year survival rate being merely 15%. This review focuses on the immune contexture; the tumor-suppressing roles of tumor-infiltrating lymphocytes; and the relevance of this immune contexture for cancer diagnostics, prognostication, and treatment allocation, with an emphasis on non-small cell lung cancer. PMID:26845192

  16. IFN-γ and indoleamine 2,3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity

    OpenAIRE

    Lu, Ying; Giver, Cynthia R.; Sharma, Akshay; Li, Jian Ming; Darlak, Katarzyna A.; Owens, Lauren M.; Roback, John D.; Galipeau, Jacques; Waller, Edmund K.

    2012-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) can eradicate chemorefractory leukemia through the graft-versus-leukemia (GVL) activity of donor T cells. However, the clinical success of allo-HSCT is limited by the graft-versus-host disease (GVHD) activity of donor T cells. We have reported previously that donor bone marrow precursors of plasmacytoid dendritic cells (pre-pDCs) can activate donor T cells toward T-helper 1 immune polarization in murine allogeneic HSCT. To optimize the...

  17. Three-dimensional cellulose sponge: Fabrication, characterization, biomimetic mineralization, and in vitro cell infiltration.

    Science.gov (United States)

    Joshi, Mahesh Kumar; Pant, Hem Raj; Tiwari, Arjun Prasad; Maharjan, Bikendra; Liao, Nina; Kim, Han Joo; Park, Chan Hee; Kim, Cheol Sang

    2016-01-20

    In this study, cellulose based scaffolds were produced by electrospinning of cellulose acetate (CA) solution followed by its saponification with NaOH/ethanol system for 24h. The resulting nonwoven cellulose mat was treated with sodium borohydride (SB) solution. In situ hydrolysis of SB solution into the pores of the membrane produced hydrogen gas resulting a three-dimensional (3D) cellulose sponge. SEM images demonstrated an open porous and loosely packed fibrous mesh compared to the tightly packed single-layered structure of the conventional electrospun membrane. 3D cellulose sponge showed admirable ability to nucleate bioactive calcium phosphate (Ca-P) crystals in simulated body fluid (SBF) solution. SEM-EDX and X-ray diffraction studies revealed that the minerals deposited on the nanofibers have the nonstoichiometric composition similar to that of hydroxyapatite, the mineralized component of the bone. 3D cellulose sponge exhibited the better cell infiltration, spreading and proliferation compared to 2D cellulose mat. Therefore, a facile fabrication of 3D cellulose sponge with improved mineralization represents an innovative strategy for the bone tissue engineering applications. PMID:26572341

  18. Cronkhite-Canada syndrome polyps infiltrated with IgG4-positive plasma cells.

    Science.gov (United States)

    Fan, Ru-Ying; Wang, Xiao-Wei; Xue, Li-Jun; An, Ran; Sheng, Jian-Qiu

    2016-08-16

    Cronkhite-Canada syndrome (CCS) is a rare but serious protein-losing enteropathy, but little is known about the mechanism. Further more, misdiagnosis is common due to non-familiarity of its clinical manifestation. A 40-year-old male patient was admitted to our hospital because of diarrhea and hypogeusia associated with weight loss for 4 mo. On physical examination, skin pigmentation, dystrophic nail changes and alopecia were noted. He had no alike family history. Laboratory results revealed low levels of serum albumin (30.1 g/L, range: 35.0-55.0 g/L), serum potassium (2.61 mmol/L, range: 3.5-5.5 mmol/L) and blood glucose (2.6 mmol/L, range: 3.9-6.1 mmol/L). The erythrocyte sedimentation rate was elevated to 17 mm/h (range: 0-15 mm/h). X-ray of chest and mandible was normal. The endoscopic examination showed multiple sessile polyps in the stomach, small bowel and colorectum. Histopathologic examination of biopsies obtained from those polyps showed hyperplastic change, cystic dilatation and distortion of glands with inflammatory infiltration, eosinophilic predominance and stromal edema. Immune staining for IgG4 plasma cells was positive in polyps of stomach and colon. The patient was diagnosed of CCS and treated with steroid, he had a good response to steroid. Both histologic findings and treatment response to steroid suggested an autoimmune mechanism underling CCS. PMID:27574615

  19. Fucoidan Suppresses the Growth of Human Acute Promyelocytic Leukemia Cells In Vitro and In Vivo.

    Science.gov (United States)

    Atashrazm, Farzaneh; Lowenthal, Ray M; Woods, Gregory M; Holloway, Adele F; Karpiniec, Samuel S; Dickinson, Joanne L

    2016-03-01

    Fucoidan, a natural component of seaweeds, is reported to have immunomodulatory and anti-tumor effects. The mechanisms underpinning these activities remain poorly understood. In this study, the cytotoxicity and anti-tumor activities of fucoidan were investigated in acute myeloid leukemia (AML) cells. The human AML cell lines NB4, KG1a, HL60, and K562 were treated with fucoidan and cell cycle, cell proliferation, and expression of apoptotic pathways molecules were analyzed. Fucoidan suppressed the proliferation and induced apoptosis through the intrinsic and extrinsic pathways in the acute promyelocytic leukemia (APL) cell lines NB4 and HL60, but not in KG1a and K562 cells. In NB4 cells, apoptosis was caspase-dependent as it was significantly attenuated by pre-treatment with a pan-caspase inhibitor. P21/WAF1/CIP1 was significantly up-regulated leading to cell cycle arrest. Fucoidan decreased the activation of ERK1/2 and down-regulated the activation of AKT through hypo-phosphorylation of Thr(308) residue but not Ser(473). In vivo, a xenograft model using the NB4 cells was employed. Mice were fed with fucoidan and tumor growth was measured following inoculation with NB4 cells. Subsequently, splenic natural killer (NK) cell cytotoxic activity was also examined. Oral doses of fucoidan significantly delayed tumor growth in the xenograft model and increased cytolytic activity of NK cells. Taken together, these data suggest that the selective inhibitory effect of fucoidan on APL cells and its protective effect against APL development in mice warrant further investigation of fucoidan as a useful agent in treatment of certain types of leukemia. PMID:26241708

  20. Underground Adaptation to a Hostile Environment: Acute Myeloid Leukemia vs. Natural Killer Cells

    Science.gov (United States)

    Dulphy, Nicolas; Chrétien, Anne-Sophie; Khaznadar, Zena; Fauriat, Cyril; Nanbakhsh, Arash; Caignard, Anne; Chouaib, Salem; Olive, Daniel; Toubert, Antoine

    2016-01-01

    Acute myeloid leukemia (AML) is a heterogeneous group of malignancies which incidence increases with age. The disease affects the differentiation of hematopoietic stem or precursor cells in the bone marrow and can be related to abnormal cytogenetic and/or specific mutational patterns. AML blasts can be sensitive to natural killer (NK) cell antitumor response. However, NK cells are frequently defective in AML patients leading to tumor escape. NK cell defects affect not only the expression of the activating NK receptors, including the natural cytotoxicity receptors, the NK group 2, member D, and the DNAX accessory molecule-1, but also cytotoxicity and IFN-γ release. Such perturbations in NK cell physiology could be related to the adaptation of the AML to the immune pressure and more generally to patient’s clinical features. Various mechanisms are potentially involved in the inhibition of NK-cell functions in AML, including defects in the normal lymphopoiesis, reduced expression of activating receptors through cell-to-cell contacts, and production of immunosuppressive soluble agents by leukemic blasts. Therefore, the continuous cross-talk between AML and NK cells participates to the leukemia immune escape and eventually to patient’s relapse. Methods to restore or stimulate NK cells seem to be attractive strategies to treat patients once the complete remission is achieved. Moreover, our capacity in stimulating the NK cell functions could lead to the development of preemptive strategies to eliminate leukemia-initiating cells before the emergence of the disease in elderly individuals presenting preleukemic mutations in hematopoietic stem cells. PMID:27014273

  1. How Is Acute Myeloid Leukemia Classified?

    Science.gov (United States)

    ... also form the basis for treating these leukemias. Markers on the leukemia cells If the leukemia cells ... no signs or symptoms of the disease. A molecular complete remission means there is no evidence of ...

  2. Bruceine D induces apoptosis in human chronic myeloid leukemia K562 cells via mitochondrial pathway

    Science.gov (United States)

    Zhang, Jian-Ye; Lin, Min-Ting; Tung, Ho-Yi; Tang, Si-Li; Yi, Tao; Zhang, Ya-Zhou; Tang, Yi-Na; Zhao, Zhong-Zhen; Chen, Hu-Biao

    2016-01-01

    Chronic myeloid leukemia (CML), an acquired malignant myeloproliferative disorder of hematopoietic stem cells, is one of the three most common forms of leukemia. In this study, we investigated the effects of bruceine D, which have been isolated from Brucea javanica (L.) Merr. on human chronic myeloid leukemia K562 cells. MTT assay was used to evaluate cell growth inhibition. Flow cytometry was performed to analyze mitochondrial membrane potential (ΔΨm). Western blot was applied to detect expression of cytochrome c, caspases-9, -3, PARP and other proteins. Bruceine D exhibited potent cytotoxicity to K562 cells with IC50 of 6.37 ± 0.39 μM. It led to loss of ΔΨm, release of cytochrome c, activation of caspases-9, -3 and cleavage of PARP, which suggested that bruceine D induced apoptosis of K562 cells through mitochondrial pathway. In addition, bruceine D inhibited the phosphorylation of AKT and ERK. It’s indicative that the potent anticancer activity of bruceine D be related to MAPK and PI3K pathways.

  3. Hairy Cell Leukemia Presenting with Isolated Skeletal Involvement Successfully Treated by Radiation Therapy and Cladribine: A Case Report and Review of the Literature

    Science.gov (United States)

    Yonal-Hindilerden, Ipek; Hindilerden, Fehmi; Bulut-Dereli, Sanem; Yıldız, Eren; Dogan, Ibrahim Oner; Nalcaci, Meliha

    2015-01-01

    We describe an unusual case of hairy cell leukemia (HCL) in a 55-year-old male presenting with isolated skeletal disease as the initial manifestation without abnormal peripheral blood counts, bone marrow involvement, or splenomegaly. To the best of our knowledge, there have been only two previous reports of a similar case. The patient presented with pain in the right femur. Anteroposterior radiographs of both femurs revealed mixed lytic-sclerotic lesions. PET scan showed multiple metastatic lesions on axial skeleton, pelvis, and both femurs. Histopathological examination of the bone biopsy revealed an infiltrate of HCL. Localized radiation therapy to both proximal femurs and subsequently 4 weeks later, a 7-day course of 0.1 mg/kg/day cladribine provided complete remission with relief of symptoms and resolution of bone lesions. We addressed the manifestations and management of HCL patients with skeletal involvement. PMID:26788382

  4. Hairy Cell Leukemia Presenting with Isolated Skeletal Involvement Successfully Treated by Radiation Therapy and Cladribine: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Ipek Yonal-Hindilerden

    2015-01-01

    Full Text Available We describe an unusual case of hairy cell leukemia (HCL in a 55-year-old male presenting with isolated skeletal disease as the initial manifestation without abnormal peripheral blood counts, bone marrow involvement, or splenomegaly. To the best of our knowledge, there have been only two previous reports of a similar case. The patient presented with pain in the right femur. Anteroposterior radiographs of both femurs revealed mixed lytic-sclerotic lesions. PET scan showed multiple metastatic lesions on axial skeleton, pelvis, and both femurs. Histopathological examination of the bone biopsy revealed an infiltrate of HCL. Localized radiation therapy to both proximal femurs and subsequently 4 weeks later, a 7-day course of 0.1 mg/kg/day cladribine provided complete remission with relief of symptoms and resolution of bone lesions. We addressed the manifestations and management of HCL patients with skeletal involvement.

  5. Targeting interleukin-2 to the bone marrow stroma for therapy of acute myeloid leukemia relapsing after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Schliemann, Christoph; Gutbrodt, Katrin L; Kerkhoff, Andrea; Pohlen, Michele; Wiebe, Stefanie; Silling, Gerda; Angenendt, Linus; Kessler, Torsten; Mesters, Rolf M; Giovannoni, Leonardo; Schäfers, Michael; Altvater, Bianca; Rossig, Claudia; Grünewald, Inga; Wardelmann, Eva; Köhler, Gabriele; Neri, Dario; Stelljes, Matthias; Berdel, Wolfgang E

    2015-05-01

    The antibody-based delivery of IL2 to extracellular targets expressed in the easily accessible tumor-associated vasculature has shown potent antileukemic activity in xenograft and immunocompetent murine models of acute myelogenous leukemia (AML), especially in combination with cytarabine. Here, we report our experience with 4 patients with relapsed AML after allogeneic hematopoietic stem cell transplantation (allo-HSCT), who were treated with the immunocytokine F16-IL2, in combination with low-dose cytarabine. One patient with disseminated extramedullary AML lesions achieved a complete metabolic response identified by PET/CT, which lasted 3 months. Two of 3 patients with bone marrow relapse achieved a blast reduction with transient molecular negativity. One of the 2 patients enjoyed a short complete remission before AML relapse occurred 2 months after the first infusion of F16-IL2. In line with a site-directed delivery of the cytokine, F16-IL2 led to an extensive infiltration of immune effector cells in the bone marrow. Grade 2 fevers were the only nonhematologic side effects in 2 patients. Grade 3 cytokine-release syndrome developed in the other 2 patients but was manageable in both cases with glucocorticoids. The concept of specifically targeting IL2 to the leukemia-associated stroma deserves further evaluation in clinical trials, especially in patients who relapse after allo-HSCT. PMID:25672398

  6. [Genetic information from tumor-infiltrating B lymphocytes as a driver tool ("GPS") for anti-tumor T cell CARs].

    Science.gov (United States)

    Kotlan, Beatrix; Csuka, Orsolya; Tóth, László; Farkas, Emil; Plótár, Vanda; Horváth, Szabolcs; Éles, Klára; Olasz, Judit; Tóth, József; Kásler, Miklós; Liszkay, Gabriella

    2016-03-01

    The rapidly growing field of gene therapy techniques to modify T cells with chimeric antigen receptors (CARs) for cancer care solutions, reached considerable achievements. However, there is an urgent need of reliable, well tolerable tumor-associated antigen specific antibodies. Tumor-infiltrating B (TIL-B) cell originated single chain Fv (scFv) gene regions could be selected with tumor specificity. DNA sequences of these antibody variable regions were subjects to get engineered into new CAR constructs. Our novel strategy harnesses tumor-infiltrating B cells' unique capacity to reveal highly tumor-associated disialylated glycosphingolipids (GD3 gangliosides). We used these human antibody fragments for generating GD3 ganglioside specific CAR gene constructs for potential usage in solid tumors. PMID:26934353

  7. Dimethyl sulfoxide inactivates the anticancer effect of cisplatin against human myelogenous leukemia cell lines in in vitro assays

    OpenAIRE

    Rahul Raghavan; Sanith Cheriyamundath; Joseph Madassery

    2015-01-01

    Objectives: To investigate the effect of DMSO on cisplatin induced cytotoxicity (invitro) against K562 (Human mylogenous leukemia) cell line and to study the cisplatin-DMSO adduct formation using UV-spectrophotometer. Materials and methods: Effect of DMSO on the cytotoxicity of cisplatin was studied in K562 (Chronic mylogenous leukemia) cell line by MTT assay. Cisplatin-DMSO adduct formation was studied by continuously monitoring the increase in absorption peaks for 30 minutes using UV-s...

  8. The increased susceptibility of hematopoietic stem cells to Friend leukemia virus in the repopulating period

    International Nuclear Information System (INIS)

    The present study considers two fundamental problems of leukemia and stem cells: (1) whether the target cells for malignant transformation of Friend leukemia virus (FV) are the pluripotential stem cells; (2) whether the susceptibility of the target cell is changeable depending on the proliferating state of the cell. In the experiments, inbred 8- to 12-week-old C3H/He and BC3Fl hybrid mice were used. As target cells for FV, two candidate cell populations should be considered. These are the pluripotential stem cells expressed as CFUs and the committed stem cells expressed as erythropoietin-responsive cells (ERC). According to our preliminary experiments on the recovery patterns of CFUs or ERC, after a single 150 rads X-irradiation (X) or administration of 215 mg/kg of cyclophosphamide (CY), it was clear that the repopulation of CFUs was quite different from that of ERC. The target cells for FV-induced transformation are the stem cells expressed as CFUs and the susceptibility of these increases under conditions of active repopulation after X-irradiation and cyclophosphamide administration. After the irradiation especially, this effect is dose-dependent for doses over 25 rads at 2 weeks after irradiation. (Auth.)

  9. Immunoglobulin D multiple myeloma, plasma cell leukemia and chronic myelogenous leukemia in a single patient treated simultaneously with lenalidomide, bortezomib, dexamethasone and imatinib

    Directory of Open Access Journals (Sweden)

    Naveed Ali

    2016-03-01

    Full Text Available Multiple myeloma (MM is a neoplastic lymphoproliferative disorder characterized by uncontrolled monoclonal plasma cell proliferation. Among different isotypes of MM, immunoglobulin D (IgD MM is very rare, representing only 1 to 2% of all isotypes. Chronic myelogenous leukemia (CML is a neoplastic myeloproliferative disorder of pluripotent hematopoietic stem cell, which is characterized by the uncontrolled proliferation of myeloid cells. An 88-year-old male was diagnosed simultaneously with IgD kappa MM and CML. A distinctive feature in this patient was the progression to plasma cell leukemia without any symptomatic myeloma stage. He was treated simultaneously with lenalidomide, bortezomib and imatinib. Synchronous occurrence of these rare hematological malignancies in a single patient is an exceedingly rare event. Multiple hypotheses to explain co-occurrence of CML and MM have been proposed; however, the exact etiological molecular pathophysiology remains elusive.

  10. Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia

    Science.gov (United States)

    Kukreja, Manisha; Wang, Tao; Giralt, Sergio A.; Szer, Jeffrey; Arora, Mukta; Woolfrey, Ann E.; Cervantes, Francisco; Champlin, Richard E.; Gale, Robert Peter; Halter, Joerg; Keating, Armand; Marks, David I.; McCarthy, Philip L.; Olavarria, Eduardo; Stadtmauer, Edward A.; Abecasis, Manuel; Gupta, Vikas; Khoury, H. Jean; George, Biju; Hale, Gregory A.; Liesveld, Jane L.; Rizzieri, David A.; Antin, Joseph H.; Bolwell, Brian J.; Carabasi, Matthew H.; Copelan, Edward; Ilhan, Osman; Litzow, Mark R.; Schouten, Harold C.; Zander, Axel R.; Horowitz, Mary M.; Maziarz, Richard T.

    2008-01-01

    Imatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM+) and 900 subjects who did not receive IM before HCT (IM−) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM+ and IM− groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT. PMID:18664621

  11. Aleukemic Leukemia Cutis Manifesting with Disseminated Nodular Eruptions and a Plaque Preceding Acute Monocytic Leukemia: A Case Report

    Science.gov (United States)

    Yonal, Ipek; Hindilerden, Fehmi; Coskun, Raif; Dogan, Oner Ibrahim; Nalcaci, Meliha

    2011-01-01

    Aleukemic leukemia cutis (ALC), a discrete tumor of leukemic cells involving the skin, may be the first manifestation of acute myeloid leukemia, preceding the onset in marrow and blood by months and years. ALC is often difficult to diagnose and is associated with a dismal prognosis. A 63-year-old male presented with nodular swellings on the face, a plaque extending over the right shoulder and multiple enlarged cervical lymph nodes. The skin biopsy of the plaque lesion showed a diffuse neoplastic infiltration extending from the dermis to subcutaneous tissue with diffuse positivity for myeloperoxidase and focal positivity for CD34 on immunohistochemical staining. The diagnosis was leukemia cutis. One month later, acute monocytic leukemia (FAB AML-M5b) was diagnosed. The patient died on the seventh month of diagnosis. PMID:22187541

  12. Two-dimensional analysis of metabolically and cell surface radiolabeled proteins of some human lymphoid and myeloid leukemia cell lines. II

    International Nuclear Information System (INIS)

    Cell surface glycoproteins, radiolabelled by the sodium metaperiodate/tritiated borohydride technique, and cell phosphoproteins, metabolically radiolabelled with 32P-orthophosphate were analyzed by two-dimensional electrophoretic analysis in some myeloid and lymphoid leukemia cell lines. Some markedly expressed major glycoproteins were predominant in some of the cell lines (such as 95k and 100k glycoproteins with marked charge heterogeneity in non-T, non-B acute lymphoblastic leukemia cell lines NALM 6 and NALM 16), but markedly quantitatively reduced in other examined cell lines, such as lymphoblastoid cell line UHKT 34/2. 32P-orthophosphate radiolabelled phosphoprotein two-dimensional patterns of the examined lymphoid leukemia cell lines were essentially similar, with some minor differences, in examined lymphoid and myeloid leukemia cell lines, such as marked expression of a series of large phosphoproteins in the molecular weight range 80-100k in lymphoid cell lines and almost complete absence of these phosphoproteins on the examined myeloid leukemia cell lines. Another configuration of acidic phosphoproteins (30-35k) exhibited individual cell line variability and differences between both individual myeloid leukemia cell lines and between the lymphoid and myeloid cell lines examined. (author) 2 figs., 15 refs

  13. Ocular adnexal marginal zone B cell lymphoma infiltrated by IgG4-positive plasma cells

    OpenAIRE

    KUBOTA, TOSHINOBU; Moritani, Suzuko; Yoshino, Tadashi; Nagai, Hirokazu; Terasaki, Hiroko

    2010-01-01

    Aims To report the clinicopathological characteristics of patients with ocular adnexal marginal zone B cell lymphoma (MZBL) with IgG4-positive plasma cells. Methods 114 biopsy samples of ocular adnexal MZBLs were analysed. MZBLs with IgG4-positive plasma cells were included when the IgG4:IgG ratio was >40% (IgG4-related group). The serum levels of each subclass of immunoglobulins and soluble interleukin-2 receptor in the IgG4-related group were compared with those in 61 consecutive patients h...

  14. Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft-versus-leukemia effects across MHC barriers in full chimeras

    OpenAIRE

    Ghosh, Arnab; Koestner, Wolfgang; Hapke, Martin; Schlaphoff, Verena; Länger, Florian; Baumann, Rolf; Koenecke, Christian; Cornberg, Markus; Welte, Karl; Blazar, Bruce R; Sauer, Martin G.

    2009-01-01

    Antigen-presenting cells (APCs) of host origin drive graft-versus-leukemia (GVL) effects but can also trigger life-threatening graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) across major histocompatibility complex (MHC) barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APCs in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro, generated and expanded T cel...

  15. Artesunate induces ROS-mediated apoptosis in doxorubicin-resistant T leukemia cells.

    Directory of Open Access Journals (Sweden)

    Thomas Efferth

    Full Text Available BACKGROUND: A major obstacle for successful cancer treatment often is the development of drug resistance in cancer cells during chemotherapy. Therefore, there is an urgent need for novel drugs with improved efficacy against tumor cells and with less toxicity on normal cells. Artesunate (ART, a powerful anti-malarial herbal compound, has been shown to inhibit growth of various tumor cell lines in vitro and of xenografted Kaposi's sarcoma in mice in vivo. However, the molecular mechanisms by which ART exerts its cytotoxicity have not been elucidated. The ART-class of anti-malarial compounds is attractive due to their activity against multidrug-resistant Plasmodium falciparum and Plasmodium vivax strains. Another salient feature of these compounds is the lack of severe side effects in malaria patients. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we used T-cell leukemias as a model system to study the molecular mechanisms of ART-induced apoptosis. The most typical anticancer drugs are DNA intercalators such as Doxorubicin. To investigate drug sensitivity and resistance, we chose a Doxorubicin-resistant leukemia cell line and investigated the killing effect of ART on these cells. We show that ART induces apoptosis in leukemic T cells mainly through the mitochondrial pathway via generation of reactive oxygen species (ROS, a mechanism different from Doxorubicin. This is confirmed by the fact that the antioxidant N-Acetyle-Cysteine (NAC could completely block ROS generation and, consequently, inhibited ART-induced apoptosis. Therefore, ART can overcome the Doxorubicin-resistance and induce the Doxorubicin-resistant leukemia cells to undergo apoptosis. We also show that ART can synergize with Doxorubicin to enhance apoptotic cell death in leukemic T cells. This synergistic effect can be largely explained by the fact that ART and Doxorubicin use different killing mechanisms. CONCLUSIONS: Our studies raise the possibility to develop ART in

  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. Diversity and Complexity of Ceramide Generation After Exposure of Jurkat Leukemia Cells to Irradiation

    International Nuclear Information System (INIS)

    Purpose: To define which intracellular pools of sphingomyelin and ceramide are involved in the triggering of apoptosis of Jurkat leukemia cells in response to γ-ray exposure. Methods and Materials: We examined the kinetics of ceramide generation at the whole-cell level and in different subcellular compartments (plasma membrane rafts, mitochondria, and endoplasmic reticulum) after irradiation with photons. Ceramide was measured by high-performance liquid chromatography or after pulse labeling experiments, and the presence of sphingomyelinase within mitochondria was assessed by electron microscopy. Results: Irradiation of Jurkat leukemia cells resulted in the sequential triggering of sphingomyelin hydrolysis, followed by de novo synthesis that led to a late ceramide response (from 24 h) correlated with the triggering of apoptosis. At the subcellular level, pulse-label experiments, using [3H]-palmitate as a precursor, strengthened the involvement of the radiation-induced sphingomyelin breakdown and revealed a very early peak (15 min) of ceramide in plasma membrane rafts. A second peak in mitochondria was measured 4 h after irradiation, resulting from an increase of the sphingomyelin content relating to the targeting of acid sphingomyelinase toward this organelle. Conclusion: These data confirm that ceramide is a major determinant in the triggering of radiation-induced apoptosis and highlight the complexity of the sequential compartment-specific ceramide-mediated response of Jurkat leukemia cells to γ-rays

  18. Understanding Leukemia

    Science.gov (United States)

    ... a second cancer, including melanoma, sarcoma, colorectal cancer, lung cancer, basal cell cancer, squamous cell skin cancer or myeloma. {{ See your primary care doctor to keep up with other healthcare needs. Understanding Leukemia I page 21 {{ Talk with family and friends about how ...

  19. Control of T cell infiltration and tumor rejection by regulatory T cells, basophils and macrophages

    OpenAIRE

    Sektioglu, Ibrahim Murathan

    2015-01-01

    Most solid tumors are intrinsically resistant to immune rejection due to immunosuppressive mechanisms operative within the tumor microenvironment. Cancer patients frequently harbor elevated numbers of regulatory T cells (Tregs), which inhibit efficient anti-tumor T cell responses. We employed different mouse models for Treg depletion in order to study the mechanisms that control tumor rejection. Depletion of about 99% Tregs in Foxp3DTR knock-in mice resulted in complete rejection of transplan...

  20. Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine

    Directory of Open Access Journals (Sweden)

    Vittorio Simeon

    2015-07-01

    Full Text Available Primary plasma cell leukemia (pPCL is a rare and aggressive variant of multiple myeloma (MM which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL.

  1. Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine.

    Science.gov (United States)

    Simeon, Vittorio; Todoerti, Katia; La Rocca, Francesco; Caivano, Antonella; Trino, Stefania; Lionetti, Marta; Agnelli, Luca; De Luca, Luciana; Laurenzana, Ilaria; Neri, Antonino; Musto, Pellegrino

    2015-01-01

    Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL). PMID:26263974

  2. Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine

    Science.gov (United States)

    Simeon, Vittorio; Todoerti, Katia; La Rocca, Francesco; Caivano, Antonella; Trino, Stefania; Lionetti, Marta; Agnelli, Luca; De Luca, Luciana; Laurenzana, Ilaria; Neri, Antonino; Musto, Pellegrino

    2015-01-01

    Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL). PMID:26263974

  3. Structure-activity relationship of lysophosphatidylcholines in HL-60 human leukemia cells

    Institute of Scientific and Technical Information of China (English)

    Eun-hee LEE; Mi-ran YUN; Wei-hong WANG; Jee H JUNG; Dong-soon IM

    2004-01-01

    AIM: To explore the structure-activity relationship of lysophosphatidylcholine (LPC) and lysolipid molecules from a marine sponge and ladybirds. METHODS: We tested three synthetic LPCs and four natural lysolipids on Ca2+mobilization in HL-60 human leukemia cells. RESULTS: We observed lysolipid-mediated Ca2+ mobilization. The activity was the same in both ester- and ether-linked lysolipids, and introduction of a double bond or methoxy group on the alkyl chain did not significantly modulate the activity. However, replacement of trimethylammonium moiety in the choline structure with ammonium moiety reduced the activity. Furthermore, change of the alkyl chain length influenced the Ca2+ response. CONCLUSION: LPC-induced Ca2+ mobilization might be dependent on the length of alkyl chain and the presence of choline moiety in HL-60 leukemia cells.

  4. Crystal structures of inhibitor complexes of human T-cell leukemia virus (HTLV-1) protease

    Energy Technology Data Exchange (ETDEWEB)

    Satoh, Tadashi; Li, Mi; Nguyen, Jeffrey-Tri; Kiso, Yoshiaki; Gustchina, Alla; Wlodawer, Alexander (NCI); (Kyoto)

    2010-09-28

    Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with several serious diseases, such as adult T-cell leukemia and tropical spastic paraparesis/myelopathy. For a number of years, the protease (PR) encoded by HTLV-1 has been a target for designing antiviral drugs, but that effort was hampered by limited available structural information. We report a high-resolution crystal structure of HTLV-1 PR complexed with a statine-containing inhibitor, a significant improvement over the previously available moderate-resolution structure. We also report crystal structures of the complexes of HTLV-1 PR with five different inhibitors that are more compact and more potent. A detailed study of structure-activity relationships was performed to interpret in detail the influence of the polar and hydrophobic interactions between the inhibitors and the protease.

  5. Crystal Structures of Inhibitir Complexes of Human T-Cell Leukemia Virus (HTLV-1) Protease

    Energy Technology Data Exchange (ETDEWEB)

    Satoh, Tadashi; Li, Mi; Nguyen, Jeffrey-Tri; Kiso, Yoshiaki; Gustchina, Alla; Wlodawer, Alexander (NCI); (Kyoto)

    2010-09-17

    Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with several serious diseases, such as adult T-cell leukemia and tropical spastic paraparesis/myelopathy. For a number of years, the protease (PR) encoded by HTLV-1 has been a target for designing antiviral drugs, but that effort was hampered by limited available structural information. We report a high-resolution crystal structure of HTLV-1 PR complexed with a statine-containing inhibitor, a significant improvement over the previously available moderate-resolution structure. We also report crystal structures of the complexes of HTLV-1 PR with five different inhibitors that are more compact and more potent. A detailed study of structure-activity relationships was performed to interpret in detail the influence of the polar and hydrophobic interactions between the inhibitors and the protease.

  6. Infectious complications of human T cell leukemia/lymphoma virus type I infection.

    Science.gov (United States)

    Marsh, B J

    1996-07-01

    Infection with human T cell leukemia/lymphoma virus type I (HTLV-I) has been etiologically associated with two diseases: adult T cell leukemia and HTLV-I-associated myelopathy/tropical spastic paraparesis. Increasing evidence suggests that HTLV-I infection may be associated with immunosuppression and, as a consequence, affect the risk and expression of several other infectious diseases, of which the best studied are strongyloidiasis, tuberculosis, and leprosy. In strongyloidiasis, coinfection with HTLV-I appears to result in a higher rate of chronic carriage, an increased parasite load, and a risk of more severe infection. In tuberculosis, a decrease in delayed-type hypersensitivity to Mycobacterium tuberculosis has been established, but whether this decrease is clinically significant has yet to be determined. In leprosy, an increased risk of disease is suggested, but the published studies are all too poorly controlled to draw definite conclusions. PMID:8816143

  7. Transformation of bone marrow stem-cells and radiation-induced myeloid leukemia in mice

    International Nuclear Information System (INIS)

    After a single whole-body X-irradiation of 300R to male RFM/MsNrs strain mice, the occurrence of myeloid leukemia initiated since four months and ceased at eleven months after irradiation. The cumulative incidence reached 24.5%. A time course study on the kinetics of pluripotential stem-cells (CFU-S) and granuloid committed stem-cells (CFU-C) in the marrow after 300R was also performed. The repopulation of CFU-S was accomplished within one month whereas that of CFU-C needed 210 days after irradiation. The incidence of leukemia was very rare after the complete repopulation of CFU-C. Simultaneously, collected spleen cells from the irradiated mice without overt leukemia were transplanted into 300-600R irradiated recipients of another sex. Three months thereafter, recipients were sacrificed to detect leukemic changes and the origin of leukemic cells by chromosome analysis. The results revealed that leukemic cell transformation of donor cells began 18 days after irradiation and on an average, 37.1% of the irradiated mice carried potentially leukemic cells for seven months after exposure, whereas none of the unirradiated mice carried leukemic cells at 7 months after irradiation. To investigate host factor(s) contributing to the proliferation of leukemic cells, the suppression of cellular immunity after 300R was measured by GVH mortality assay. However, the recovery of cellular immunity was observed until three months after irradiation and the role of cellular immunity to proliferation of leukemic cells after three months was negligible. (author)

  8. 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.

  9. Chromosomal translocation involving the beta T cell receptor gene in acute leukemia

    OpenAIRE

    1988-01-01

    DNA spanning a t(7;19) chromosomal translocation breakpoint was isolated from the human T cell line SUP-T7 established from an acute lymphoblastic leukemia. Nucleotide sequence analysis showed that the point of crossover on chromosome 7 occurred immediately adjacent to joining segment J beta 1.1 within the TCR-beta gene, suggesting that this translocation resulted from an error in TCR gene rearrangement. On chromosome 19, the translocation occurred within a previously uncharacterized transcri...

  10. Protein stabilization explains the gag requirement for transformation of lymphoid cells by Abelson murine leukemia virus

    OpenAIRE

    Prywes, R; Hoag, J; Rosenberg, N; Baltimore, D

    1985-01-01

    The single protein encoded by Abelson murine leukemia virus is a fusion of sequence from the retroviral gag genes with the v-abl sequence. Deletion of most of the gag region from the transforming protein results in a virus capable of transforming fibroblasts but no longer capable of transforming lymphoid cells. Smaller deletions in gag reveal that p15 gag sequences are responsible for this effect, whereas deletion of p12 sequences had no effect on lymphoid transformation. In transformed fibro...

  11. Molecular classification and pharmacogenetics of primary plasma cell leukemia: an initial approach toward precision medicine

    OpenAIRE

    Vittorio Simeon; Katia Todoerti; Francesco La Rocca; Antonella Caivano; Stefania Trino; Marta Lionetti; Luca Agnelli; Luciana De Luca; Ilaria Laurenzana; Antonino Neri; Pellegrino Musto

    2015-01-01

    Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, ...

  12. Identification of Interconnected Markers for T-Cell Acute Lymphoblastic Leukemia

    OpenAIRE

    Emine Guven Maiorov; Ozlem Keskin; Ozden Hatirnaz Ng; Ugur Ozbek; Attila Gursoy

    2013-01-01

    Hindawi Publishing Corporation BioMed Research International Volume 2013, Article ID 210253, 20 pages http://dx.doi.org/10.1155/2013/210253 Research Article Identification of Interconnected Markers for T-Cell Acute Lymphoblastic Leukemia Emine Guven Maiorov,1 Ozlem Keskin,1 Ozden Hatirnaz Ng,2 Ugur Ozbek,2 and Attila Gursoy1 1 Center for Computational Biology and Bioinformatics and College of Engineering, Koc¸ University, Rumelifeneri Yolu, Sariyer, 34450 Istanbu...

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

    OpenAIRE

    Tucker DL; Rule SA

    2015-01-01

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

  14. Autologous Stem Cell Transplantation in Patients with Acute Myeloid Leukemia: a Single-Centre Experience

    Directory of Open Access Journals (Sweden)

    Kakucs Enikő

    2013-04-01

    Full Text Available Introduction: Autologous haemopoietic stem cell transplantation (SCT is an important treatment modality for patients with acute myeloid leukemia with low and intermediate risk disease. It has served advantages over allogenic transplantation, because it does not need a matched donor, there is no graft versus host disease, there are less complications and a faster immune reconstitution than in the allo-setting. The disadvantage is the lack of the graft versus leukaemia effect.

  15. Cross Talk between Expression of the Human T-Cell Leukemia Virus Type 1 Tax Transactivator and the Oncogenic bHLH Transcription Factor TAL1▿ †

    OpenAIRE

    Terme, Jean-Michel; Wencker, Melanie; Favre-Bonvin, Arnaud; Bex, Françoise; Gazzolo, Louis; Duc Dodon, Madeleine; Jalinot, Pierre

    2008-01-01

    The human T-cell leukemia virus type 1 (HTLV-1) Tax transactivator is known to induce or repress various cellular genes, several of them encoding transcription factors. As Tax is known to deregulate various basic bHLH factors, we looked more specifically at its effect on TAL1 (T-cell acute lymphoblastic leukemia 1), also known as SCL (stem cell leukemia). Indeed, TAL1 is deregulated in a high percentage of T-cell acute lymphoblastic leukemia cells, and its oncogenic properties are well-establ...

  16. High expression of the CC chemokine TARC in Reed-Sternberg cells : A possible explanation for the characteristic T-cell infiltrate in Hodgkin's lymphoma

    NARCIS (Netherlands)

    van den Berg, A.; Visser, L; Poppema, S

    1999-01-01

    Hodgkin's lymphoma is characterized by the combination of Reed-Sternberg (R-S) cells and a prominent inflammatory cell infiltrate. One of the intriguing questions regarding this disease is what is causing the influx of T lymphocytes into the involved tissues. We applied the serial analysis of gene e

  17. Effect of Epigallocatechin-3-gallate (EGCG on cell proliferation inhibition and apoptosis induction in lymphoblastic leukemia cell line

    Directory of Open Access Journals (Sweden)

    Ghasemi-Pirbaluti Masome

    2015-04-01

    Full Text Available Introduction: Acute lymphoblastic leukemia (ALL is one of the malignant proliferations of lymphoid cells in the early stages of differentiation and accounts for ¾ of all cases of childhood leukemia. Available treatment cannot completely treat this disease. Epigallocatechin-3-gallate (EGCG is a polyphenolic compounds in the green tea that has demonstrated to have anticancer and antimitotic properties. The purpose of the present study was the evaluation of the effect of EGCG on the proliferation inhibition and apoptosis induction in a lymphoblastic leukemia cell line. Methods: Jurkat cell line was cultured in standard condition and in different concentrations of EGCG (0-100 micromolar for 24, 48 and 72 hours. Cell viability was measured by MTS assay. Apoptosis induction was assessed by annexin V-FITC and flow cytometry analysis. Results: The MTS assay revealed that EGCG has decreased cell viability with a time and dose dependent manner. The level of cell apoptosis in all used concentrations of EGCG (50, 70 and 100 μm was higher than control group (71%, 40% and 31% respectively vs. 8% and reached to significant level at 100 μm concentration. Conclusion: The study indicated that EGCG is effective on proliferation inhibition and apoptotic induction in Jurkat lymphoblastic cell line. Therefore, the study of the mechanism of apoptosis induction could be a step of progress toward target therapy which might be considered in the future studies.

  18. 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.

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

    Science.gov (United States)

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

    2016-04-01

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

  20. Natural Product Vibsanin A Induces Differentiation of Myeloid Leukemia Cells through PKC Activation.

    Science.gov (United States)

    Yu, Zu-Yin; Xiao, He; Wang, Li-Mei; Shen, Xing; Jing, Yu; Wang, Lin; Sun, Wen-Feng; Zhang, Yan-Feng; Cui, Yu; Shan, Ya-Jun; Zhou, Wen-Bing; Xing, Shuang; Xiong, Guo-Lin; Liu, Xiao-Lan; Dong, Bo; Feng, Jian-Nan; Wang, Li-Sheng; Luo, Qing-Liang; Zhao, Qin-Shi; Cong, Yu-Wen

    2016-05-01

    All-trans retinoic acid (ATRA)-based cell differentiation therapy has been successful in treating acute promyelocytic leukemia, a unique subtype of acute myeloid leukemia (AML). However, other subtypes of AML display resistance to ATRA-based treatment. In this study, we screened natural, plant-derived vibsane-type diterpenoids for their ability to induce differentiation of myeloid leukemia cells, discovering that vibsanin A potently induced differentiation of AML cell lines and primary blasts. The differentiation-inducing activity of vibsanin A was mediated through direct interaction with and activation of protein kinase C (PKC). Consistent with these findings, pharmacological blockade of PKC activity suppressed vibsanin A-induced differentiation. Mechanistically, vibsanin A-mediated activation of PKC led to induction of the ERK pathway and decreased c-Myc expression. In mouse xenograft models of AML, vibsanin A administration prolonged host survival and inhibited PKC-mediated inflammatory responses correlated with promotion of skin tumors in mice. Collectively, our results offer a preclinical proof of concept for vibsanin A as a myeloid differentiation-inducing compound, with potential application as an antileukemic agent. Cancer Res; 76(9); 2698-709. ©2016 AACR. PMID:26984756

  1. DNA Damage, Cell Cycle Arrest, and Apoptosis Induction Caused by Lead in Human Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Clement G. Yedjou

    2015-12-01

    Full Text Available In recent years, the industrial use of lead has been significantly reduced from paints and ceramic products, caulking, and pipe solder. Despite this progress, lead exposure continues to be a significant public health concern. The main goal of this research was to determine the in vitro mechanisms of lead nitrate [Pb(NO32] to induce DNA damage, apoptosis, and cell cycle arrest in human leukemia (HL-60 cells. To reach our goal, HL-60 cells were treated with different concentrations of Pb(NO32 for 24 h. Live cells and necrotic death cells were measured by the propidium idiode (PI assay using the cellometer vision. Cell apoptosis was measured by the flow cytometry and DNA laddering. Cell cycle analysis was evaluated by the flow cytometry. The result of the PI demonstrated a significant (p < 0.05 increase of necrotic cell death in Pb(NO32-treated cells, indicative of membrane rupture by Pb(NO32 compared to the control. Data generated from the comet assay indicated a concentration-dependent increase in DNA damage, showing a significant increase (p < 0.05 in comet tail-length and percentages of DNA cleavage. Data generated from the flow cytometry assessment indicated that Pb(NO32 exposure significantly (p < 0.05 increased the proportion of caspase-3 positive cells (apoptotic cells compared to the control. The flow cytometry assessment also indicated Pb(NO32 exposure caused cell cycle arrest at the G0/G1 checkpoint. The result of DNA laddering assay showed presence of DNA smear in the agarose gel with little presence of DNA fragments in the treated cells compared to the control. In summary, Pb(NO32 inhibits HL-60 cells proliferation by not only inducing DNA damage and cell cycle arrest at the G0/G1 checkpoint but also triggering the apoptosis through caspase-3 activation and nucleosomal DNA fragmentation accompanied by secondary necrosis. We believe that our study provides a new insight into the mechanisms of Pb(NO32 exposure and its associated adverse

  2. Human T-cell leukemia virus types I and II exhibit different DNase I protection patterns

    International Nuclear Information System (INIS)

    Human T-cell leukemia virus types I (HTLV-I) and II (HTLV-II) are human retroviruses which normally infect T-lymphoid cells. HTLV-I infection is associated with adult T-cell leukemia-lymphoma, and HTLV-II is associated with an indolent form of hairy-cell leukemia. To identify potential transcriptional regulatory elements of these two related human retroviruses, the authors performed DNase I footprinting of both the HTLV-I and HTLV-II long terminal repeats (LTRs) by using extracts prepared from uninfected T cells, HTLV-I and HTLV-II transformed T cells, and HeLa cells. Five regions of the HTLV-I LTR and three regions of the HTLV-II LTR showed protection by DNase I footprinting. All three of the 21-base-pair repeats previously shown to be important in HTLV transcriptional regulation were protected in the HTLV-I LTR, whereas only one of these repeats was protected in the HTLV-II LTR. Several regions exhibited altered protection in extracts prepared from lymphoid cells as compared with HeLa cells, but there were minimal differences in the protection patterns between HTLV-infected and uninfected lymphoid extracts. A number of HTLV-I and HTLV-II LTR fragments which contained regions showing protection in DNase I footprinting were able to function as inducible enhancer elements in transient CAT gene expression assays in the presence of the HTLV-II tat protein. The alterations in the pattern of the cellular proteins which bind to the HTLV-I and HTLV-II LTRs may in part be responsible for differences in the transcriptional regulation of these two related viruses

  3. G2/M Cell Cycle Arrest and Tumor Selective Apoptosis of Acute Leukemia Cells by a Promising Benzophenone Thiosemicarbazone Compound

    OpenAIRE

    Cabrera, Maia; Gomez, Natalia; Remes Lenicov, Federico; Echeverría, Emiliana; Shayo, Carina; Moglioni, Albertina; Fernández, Natalia; Davio, Carlos

    2015-01-01

    Anti-mitotic therapies have been considered a hallmark in strategies against abnormally proliferating cells. Focusing on the extensively studied family of thiosemicarbazone (TSC) compounds, we have previously identified 4,4’-dimethoxybenzophenone thiosemicarbazone (T44Bf) as a promising pharmacological compound in a panel of human leukemia cell lines (HL60, U937, KG1a and Jurkat). Present findings indicate that T44Bf-mediated antiproliferative effects are associated with a reversible chronic ...

  4. Blinatumomab: Bridging the Gap in Adult Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Folan, Stephanie A; Rexwinkle, Amber; Autry, Jane; Bryan, Jeffrey C

    2016-08-01

    Adult patients with acute lymphoblastic leukemia who relapse after frontline therapy have extremely poor outcomes despite advances in chemotherapy and hematopoietic stem cell transplantation. Blinatumomab is a first-in-class bispecific T-cell engager that links T cells to tumor cells leading to T-cell activation and tumor cell lysis. In December 2014, the Food and Drug Administration approved blinatumomab for treatment of relapsed or refractory Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia. In a phase II trial, blinatumomab produced response rates of 43%, and 40% of patients achieving a complete remission proceeded to hematopoietic stem cell transplantation. Early use of blinatumomab was complicated with adverse effects, including cytokine release syndrome and neurotoxicity. Management strategies, including dexamethasone premedication and 2-step dose escalation during the first cycle of blinatumomab, have decreased the incidence and severity of these adverse effects. Blinatumomab currently is being studied for other B-cell malignancies and has the potential to benefit many patients with CD19+ malignancies in the future. PMID:27521320

  5. Relationship between triterpenoid anticancer drug resistance, autophagy, and caspase-1 in adult T-cell leukemia

    Science.gov (United States)

    Nakanishi, Tsukasa; Morita, Kentaro; Tsukada, Junichi; Kanazawa, Tamotsu

    2016-01-01

    We previously reported that the inflammasome inhibitor cucurbitacin D (CuD) induces apoptosis in human leukemia cell lines. Here, we investigated the effects of CuD and a B-cell lymphoma extra-large (Bcl-xL) inhibitor on autophagy in peripheral blood lymphocytes (PBL) isolated from adult T-cell leukemia (ATL) patients. CuD induced PBL cell death in patients but not in healthy donors. This effect was not significantly inhibited by treatment with rapamycin or 3-methyladenine (3-MA). The Bcl-xL inhibitor Z36 induced death in primary cells from ATL patients including that induced by CuD treatment, effects that were partly inhibited by 3-MA. Similarly, cell death induced by the steroid prednisolone was enhanced in the presence of Z36. A western blot analysis revealed that Z36 also promoted CuD-induced poly(ADP ribose) polymerase cleavage. Interestingly, the effects of CuD and Z36 were attenuated in primary ATL patient cells obtained upon recurrence after umbilical cord blood transplantation, as compared to those obtained before chemotherapy. Furthermore, cells from this patient expressed a high level of caspase-1, and treatment with caspase-1 inhibitor-enhanced CuD-induced cell death. Taken together, these results suggest that rescue from resistance to steroid drugs can enhance chemotherapy, and that caspase-1 is a good marker for drug resistance in ATL patients. PMID:27190722

  6. Extramedullary Involvement of Mast Cell Leukemia Detected by 18F-FDG PET/CT.

    Science.gov (United States)

    Fu, Zhanli; Zhang, Jin; Liu, Meng; Li, Ziao; Li, Qian

    2016-07-01

    Mast cell leukemia (MCL) is a very rare subtype of systemic mastocytosis, characterized by the leukemic expansion of immature mast cells. We present a case of MCL with extramedullary involvement of cervical lymph node and lung demonstrated by the initial F-FDG PET/CT scan. After a transient complete remission by induction chemotherapy and allogeneic hematopoietic stem cell transplantation, the follow-up PET/CT showed extensive extramedullary relapse involving multiple lymph nodes and small bowel. F-FDG PET/CT may be a useful tool to comprehensively stage and follow-up MCL. PMID:26975014

  7. Rationale for targeting the pre-B-cell receptor signaling pathway in acute lymphoblastic leukemia.

    Science.gov (United States)

    Müschen, Markus

    2015-06-11

    Inhibitors of B-cell receptor (BCR) and pre-BCR signaling were successfully introduced into patient care for various subtypes of mature B-cell lymphoma (e.g., ibrutinib, idelalisib). Acute lymphoblastic leukemia (ALL) typically originates from pre-B cells that critically depend on survival signals emanating from a functional pre-BCR. However, whether patients with ALL benefit from treatment with (pre-) BCR inhibitors has not been explored. Recent data suggest that the pre-BCR functions as tumor suppressor in the majority of cases of human ALL. However, a distinct subset of human ALL is selectively sensitive to pre-BCR antagonists. PMID:25878119

  8. Concurrent thymoma, thymic carcinoma, and T lymphoblastic leukemia/lymphoma in an anterior mediastinal mass.

    Science.gov (United States)

    Ito, Junko; Yoshida, Akihiko; Maeshima, Akiko Miyagi; Nakagawa, Kazuo; Watanabe, Shun-ichi; Kobayashi, Yukio; Fukuhara, Suguru; Tsuta, Koji

    2015-09-01

    We report a case of a 62-year-old man with concurrent thymoma, thymic carcinoma, and T lymphoblastic leukemia/lymphoma. Computed tomography revealed a 5.5-cm anterior mediastinal mass, and surgical resection was performed. Histologically, the mass showed concurrent thymoma (type AB), thymic carcinoma, and T lymphoblastic leukemia/lymphoma. Lymphoma cells infiltrated in the left lung, pulmonary hilar lymph nodes, and involved bone marrow. The patient underwent chemotherapy for T lymphoblastic leukemia/lymphoma and achieved remission. One year after surgery, he remains free of both thymoma and thymic carcinoma, and T lymphoblastic leukemia/lymphoma remains complete remission under maintenance therapy. Thymoma and T lymphoblastic leukemia/lymphoma can combine in the same mass, although this is quite rare. At the time of the diagnosis of thymoma, additional attention should be directed toward lymphocytes in the background. PMID:26150396

  9. Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells

    Institute of Scientific and Technical Information of China (English)

    Xing-Xiang Peng; Amit K. Tiwari; Hsiang-Chun Wu; Zhe-Sheng Chen

    2012-01-01

    Imatinib,a breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) tyrosine kinase inhibitor (TKI),has revolutionized the treatment of chronic myelogenous leukemia (CML).However,development of multidrug resistance(MDR) limits the use of imatinib.In the present study,we aimed to investigate the mechanisms of cellular resistance to imatinib in CML.Therefore,we established an imatinib-resistant human CML cell line (K562-imatinib) through a stepwise selection process.While characterizing the phenotype of these cells,we found that K562-imatinib cells were 124.6-fold more resistant to imatinib than parental K562 cells.In addition,these cells were cross-resistant to second- and third-generation BCR-ABL TKIs.Western blot analysis and reverse transcription-polymerase chain reaction(RT-PCR) demonstrated that P-glycoprotein (P-gp) and MDR1 mRNA levels were increased in K562-imatinib cells.In addition,accumulation of [14C]6-mercaptopurine (6-MP) was decreased,whereas the ATP-dependent efflux of [14C] 6-MP and [3H]methotrexate transport were increased in K562-imatinib cells.These data suggest that the overexpression of P-gp may play a crucial role in acquired resistance to imatinib in CML K562-imatinib cells.

  10. Identification of dendritic cells, B cell and T cell subsets in Tasmanian devil lymphoid tissue; evidence for poor immune cell infiltration into devil facial tumors.

    Science.gov (United States)

    Howson, Lauren J; Morris, Katrina M; Kobayashi, Takumi; Tovar, Cesar; Kreiss, Alexandre; Papenfuss, Anthony T; Corcoran, Lynn; Belov, Katherine; Woods, Gregory M

    2014-05-01

    The Tasmanian devil is under threat of extinction due to the transmissible devil facial tumor disease (DFTD). This fatal tumor is an allograft that does not induce an immune response, raising questions about the activity of Tasmanian devil immune cells. T and B cell analysis has been limited by a lack of antibodies, hence the need to produce such reagents. Amino acid sequence analysis revealed that CD4, CD8, IgM, and IgG were closely related to other marsupials. Monoclonal antibodies were produced against CD4, CD8, IgM, and IgG by generating bacterial fusion proteins. These, and commercial antibodies against CD1a and CD83, identified T cells, B cells and dendritic cells by immunohistochemistry. CD4(+) and CD8(+) T cells were identified in pouch young thymus, adult lymph nodes, spleen, bronchus- and gut-associated lymphoid tissue. Their anatomical distribution was characteristic of mammalian lymphoid tissues with more CD4(+) than CD8(+) cells in lymph nodes and splenic white pulp. IgM(+) and IgG(+) B cells were identified in adult lymph nodes, spleen, bronchus-associated lymphoid tissue and gut-associated lymphoid tissue, with more IgM(+) than IgG(+) cells. Dendritic cells were identified in lymph node, spleen and skin. This distribution is consistent with eutherian mammals and other marsupials, indicating they have the immune cell subsets for an anti-tumor immunity. Devil facial tumor disease tumors contained more CD8(+) than CD4(+) cells, but in low numbers. There were also low numbers of CD1a(+) and MHC class II(+) cells, but no CD83(+) IgM(+) or IgG(+) B cells, consistent with poor immune cell infiltration. PMID:24664954

  11. Infiltration of IL-17-Producing T Cells and Treg Cells in a Mouse Model of Smoke-Induced Emphysema.

    Science.gov (United States)

    Duan, Min-Chao; Zhang, Jian-Quan; Liang, Yue; Liu, Guang-Nan; Xiao, Jin; Tang, Hai-Juan; Liang, Yi

    2016-08-01

    Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible chronic inflammatory disease associated with the accumulation of activated T cells. To date, there is little information concerning the intrinsic association among Th17, Tc17, and regulatory T (Treg) cells in COPD. The objective of this study was to investigate the variation of lungs CD4(+)Foxp3(+) Treg cells and IL-17-producing CD4 and CD8 (Th17 and Tc17) lymphocytes in mice with cigarette-induced emphysema. Groups of mice were exposed to cigarette smoke or room air. At weeks 12 and 24, mice were sacrificed to observe histological changes by HE stain. The frequencies of Th17 (CD4(+)IL-17(+)T), Tc17 (CD8(+)IL-17(+)T), and Treg (CD4(+)Foxp3(+)T) cells in lungs from these mice were analyzed by flow cytometry. The mRNA levels of orphan nuclear receptor ROR γt and Foxp3 were performed by real-time quantitative polymerase chain reaction. The protein levels of interleukin-17 (IL-17), IL-6, IL-10, and transforming growth factor-beta (TGF-β1) were measured by enzyme-linked immunosorbent assay. Cigarette smoke caused substantial enlargement of the air spaces accompanied by the destruction of the normal alveolar architecture and led to emphysema. The frequencies of Th17 and Tc17 cells, as well as the expressions of IL-6, IL-17, TGF-β1, and ROR γt were greater in the lungs of cigarette smoke (CS)-exposed mice, particularly in the 24-week CS-exposed mice. The frequencies of Treg cells and the expressions of IL-10 and Foxp3 were lower in CS-exposed mice compared to control group. More important, the frequencies of Tregs were negatively correlated with Th17 cells and with Tc17 cells. Interestingly, a significant portion of the cells that infiltrate the lungs was skewed towards a Tc17 phenotype. Our findings suggest the contribution of Th17, Tc17, and Treg cells in the pathogenesis of COPD. Rebalance of these cells will be helpful for developing and refining the new immunological therapies for COPD

  12. Acute myeloid leukemia of donor origin after allogeneic stem cell transplantation from a sibling who harbors germline XPD and XRCC3 homozygous polymorphisms

    Directory of Open Access Journals (Sweden)

    da Silva Dayse A

    2011-09-01

    Full Text Available Abstract A 54-year-old woman was diagnosed with infiltrative ductal breast carcinoma. Two years after treatment, the patient developed an acute myeloid leukemia (AML which harbored del(11q23 in 8% of the blast cells. The patient was submitted for allogeneic stem cell transplantation (aSCT from her HLA-compatible sister. Ten months after transplantation, she relapsed with an AML with basophilic maturation characterized by CD45low CD33high, CD117+, CD13-/+, HLA Drhigh, CD123high, and CD203c+ blast cells lacking expression of CD7, CD10, CD34, CD15, CD14, CD56, CD36, CD64, and cytoplasmic tryptase. Karyotype analysis showed the emergence of a new clone with t(2;14 and FISH analysis indicated the presence of MLL gene rearrangement consistent with del(11q23. Interestingly, AML blast cell DNA tested with microsatellite markers showed the same pattern as the donor's, suggesting that this AML emerged from donor cells. Additionally, polymorphisms of the XPA, XPD, XRCC1, XRCC3 and RAD51 DNA repair genes revealed three unfavorable alleles with low DNA repair capacity. In summary, we report the first case of AML involving XPD and XRCC3 polymorphisms from donor origin following allogeneic stem cell transplantation and highlight the potential need for careful analysis of DNA repair gene polymorphisms in selecting candidate donors prior to allogeneic stem cell transplantation.

  13. Impact of graft versus host disease on outcome of allogeneic peripherial blood stem cell transplantation for leukemia

    Institute of Scientific and Technical Information of China (English)

    黎美章

    2014-01-01

    Objective To analyze the impact of the occurrence and severity of acute and chronic graft versus host disease(GVHD)on the long-term outcome of allogeneic peripheral blood stem cell transplantation(allo-PBSCT)for leukemia.Methods A total of 231 patients with leukemia,who underwent allo-HSCT in Changhai Hospital from Jan1st,2001 to Dec 31th,2011,were retrospectively analyzed.The overall survival(OS),disease-free survival

  14. The effect of aqueous cinnamon extract on the apoptotic process in acute myeloid leukemia HL-60 cells

    OpenAIRE

    Vahideh Assadollahi; Kazem Parivar; Nasim Hayati Roudbari; Ali Reza Khalatbary; Masoumeh Motamedi; Behrouz Ezatpour; Gholam Reza Dashti

    2013-01-01

    Background: Acute promyelocytic leukemia (APL) is an acute leukemia diagnosed by translocation of chromosomes 15 and 17 [T (15,17)] and aggregation of neoplastic promyelocytes which are incapable of being converted into mature cells. Today, many tend to use medicinal herbs in studies and clinical applications for treatment of cancers. Cinnamon with scientific name "cinnamomumzelanicum" is a shrub of Laurales order, lauraceae family with cinnamomum genus. It is a medicinal shrub with anti-prol...

  15. Identification of galectin-1 as a novel mediator for chemoresistance in chronic myeloid leukemia cells.

    Science.gov (United States)

    Luo, Wu; Song, Li; Chen, Xi-Lei; Zeng, Xiang-Feng; Wu, Jian-Zhang; Zhu, Cai-Rong; Huang, Tao; Tan, Xiang-Peng; Lin, Xiao-Mian; Yang, Qi; Wang, Ji-Zhong; Li, Xiao-Kun; Wu, Xiao-Ping

    2016-05-01

    Multidrug resistance protein-1 (MDR1) has been proven to be associated with the development of chemoresistance to imatinib (Glivec, STI571) which displays high efficacy in treatment of BCR-ABL-positive chronic myelogenous leukemia (CML). However, the possible mechanisms of MDR1 modulation in the process of the resistance development remain to be defined. Herein, galectin-1 was identified as a candidate modulator of MDR1 by proteomic analysis of a model system of leukemia cell lines with a gradual increase of MDR1 expression and drug resistance. Coincidently, alteration of galectin-1 expression triggers the change of MDR1 expression as well as the resistance to the cytotoxic drugs, suggesting that augment of MDR1 expression engages in galectin-1-mediated chemoresistance. Moreover, we provided the first data showing that NF-κB translocation induced by P38 MAPK activation was responsible for the modulation effect of galectin-1 on MDR1 in the chronic myelogenous leukemia cells. Galectin-1 might be considered as a novel target for combined modality therapy for enhancing the efficacy of CML treatment with imatinib. PMID:27050374

  16. Kinetics of indium-111-labeled leukemic cells in patients with acute non-lymphocytic leukemia

    International Nuclear Information System (INIS)

    The kinetics of autologous leukemic cells labeled with In-111 oxine were studied in 5 patients with acute myeloblastic leukemia (AML) and one patient with acute premyelocytic leukemia (APL), and kinetics of OKM1 monoclonal antibody-treated leukemic cells were studied in one patient with acute monoblastic leukemia (AMoL). Recoveries of 33.7 +- 23.3%(range, 22.0 to 48.1%) were achieved at 10min after injection of In-111 oxine labeled leukemic cells in AML and APL patients. However, in a patient with AMoL recovery of 12.3% was only achieved at 10min after injection of OKM1-treated leukemic cells. Clearance of the activity from blood was rapid up to one in all patients. The clearance curve of the activity in 5 AML patients showed a hump or a plateau from one to 5hr after injection of labeled leukemic cells. In APL patient and AMoL patient, however, this hump or plateau was not noted. In AML and APL patients the activity over the spleen was higher than that of over the liver at from 30min to 3hr after and showed a plateau or gradual rising thereafter. In a patient with AMoL, the hepatic activity was higher than the splenic activity at 30min after, but thereafter the latter became higher than the former. Liver activity curves showed transient fall at 3hr after and then gradual uprising in all patients. In a patient with APL, high activity was noted over the kidneys. This rose to a maximum after 3hr and then decreased rapidly. Since In-111 oxine stays firmly attached to the cells in spite of the possibility of radiation damage in a long-term survey, it seems an ideal label for studying leukemic cell kinetics

  17. 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

  18. A mouse model for inducible overexpression of Prdm14 results in rapid-onset and highly penetrant T-cell acute lymphoblastic leukemia (T-ALL

    Directory of Open Access Journals (Sweden)

    Brandi L. Carofino

    2013-11-01

    PRDM14 functions in embryonic stem cell (ESC maintenance to promote the expression of pluripotency-associated genes while suppressing differentiation genes. Expression of PRDM14 is tightly regulated and typically limited to ESCs and primordial germ cells; however, aberrant expression is associated with tumor initiation in a wide variety of human cancers, including breast cancer and leukemia. Here, we describe the generation of a Cre-recombinase-inducible mouse model for the spatial and temporal control of Prdm14 misexpression [ROSA26 floxed-stop Prdm14 (R26PR]. When R26PR is mated to either of two Cre lines, Mx1-cre or MMTV-cre, mice develop early-onset T-cell acute lymphoblastic leukemia (T-ALL with median overall survival of 41 and 64 days for R26PR;Mx1-cre and R26PR;MMTV-cre, respectively. T-ALL is characterized by the accumulation of immature single-positive CD8 cells and their widespread infiltration. Leukemia is preceded by a dramatic expansion of cells resembling hematopoietic stem cells and lymphoid-committed progenitors prior to disease onset, accompanied by a blockage in B-cell differentiation at the early pro-B stage. Rapid-onset PRDM14-induced T-ALL requires factors that are present in stem and progenitor cells: R26PR;dLck-cre animals, which express Prdm14 starting at the double-positive stage of thymocyte development, do not develop disease. PRDM14-induced leukemic cells contain high levels of activated NOTCH1 and downstream NOTCH1 targets, including MYC and HES1, and are sensitive to pharmacological inhibition of NOTCH1 with the γ-secretase inhibitor DAPT. Greater than 50% of human T-ALLs harbor activating mutations in NOTCH1; thus, our model carries clinically relevant molecular aberrations. The penetrance, short latency and involvement of the NOTCH1 pathway will make this hematopoietic R26PR mouse model ideal for future studies on disease initiation, relapse and novel therapeutic drug combinations. Furthermore, breeding R26PR to additional Cre

  19. Control of Both Myeloid Cell Infiltration and Angiogenesis by CCR1 Promotes Liver Cancer Metastasis Development in Mice

    Directory of Open Access Journals (Sweden)

    Mathieu Paul Rodero

    2013-06-01

    Full Text Available Expression of the CC chemokine receptor 1 (CCR1 by tumor cells has been associated with protumoral activity; however, its role in nontumoral cells during tumor development remains elusive. Here, we investigated the role of CCR1 deletion on stromal and hematopoietic cells in a liver metastasis tumor model. Metastasis development was strongly impaired in CCR1-deficient mice compared to control mice and was associated with reduced liver monocyte infiltration. To decipher the role of myeloid cells, sublethally irradiated mice were reconstituted with CCR1-deficient bone marrow (BM and showed better survival rates than the control reconstituted mice. These results point toward the involvement of CCR1 myeloid cell infiltration in the promotion of tumor burden. In addition, survival rates were extended in CCR1-deficient mice receiving either control or CCR1-deficient BM, indicating that host CCR1 expression on nonhematopoietic cells also supports tumor growth. Finally, we found defective tumor-induced neoangiogenesis (in vitro and in vivo in CCR1-deficient mice. Overall, our results indicate that CCR1 expression by both hematopoietic and nonhematopoietic cells favors tumor aggressiveness. We propose CCR1 as a potential therapeutical target for liver metastasis therapy.

  20. Advance in hematopoietic stem cells transplantation for leukemia

    Institute of Scientific and Technical Information of China (English)

    HUANG Xiao-jun

    2008-01-01

    @@ During the past 50 years, intensive studies into the characteristics of hematopoietic stem cell transplantation immunology and the emergence of new immunosuppressant and anti-infective drugs have significantly improved the clinical result of hematopoietic stem cell transplantation (HSCT).

  1. G2/M Cell Cycle Arrest and Tumor Selective Apoptosis of Acute Leukemia Cells by a Promising Benzophenone Thiosemicarbazone Compound.

    Science.gov (United States)

    Cabrera, Maia; Gomez, Natalia; Remes Lenicov, Federico; Echeverría, Emiliana; Shayo, Carina; Moglioni, Albertina; Fernández, Natalia; Davio, Carlos

    2015-01-01

    Anti-mitotic therapies have been considered a hallmark in strategies against abnormally proliferating cells. Focusing on the extensively studied family of thiosemicarbazone (TSC) compounds, we have previously identified 4,4'-dimethoxybenzophenone thiosemicarbazone (T44Bf) as a promising pharmacological compound in a panel of human leukemia cell lines (HL60, U937, KG1a and Jurkat). Present findings indicate that T44Bf-mediated antiproliferative effects are associated with a reversible chronic mitotic arrest caused by defects in chromosome alignment, followed by induced programmed cell death. Furthermore, T44Bf selectively induces apoptosis in leukemia cell lines when compared to normal peripheral blood mononuclear cells. The underlying mechanism of action involves the activation of the mitochondria signaling pathway, with loss of mitochondrial membrane potential and sustained phosphorylation of anti-apoptotic protein Bcl-xL as well as increased Bcl-2 (enhanced phosphorylated fraction) and pro-apoptotic protein Bad levels. In addition, ERK signaling pathway activation was found to be a requisite for T44Bf apoptotic activity. Our findings further describe a novel activity for a benzophenone thiosemicarbazone and propose T44Bf as a promising anti-mitotic prototype to develop chemotherapeutic agents to treat acute leukemia malignancies. PMID:26360247

  2. G2/M Cell Cycle Arrest and Tumor Selective Apoptosis of Acute Leukemia Cells by a Promising Benzophenone Thiosemicarbazone Compound.

    Directory of Open Access Journals (Sweden)

    Maia Cabrera

    Full Text Available Anti-mitotic therapies have been considered a hallmark in strategies against abnormally proliferating cells. Focusing on the extensively studied family of thiosemicarbazone (TSC compounds, we have previously identified 4,4'-dimethoxybenzophenone thiosemicarbazone (T44Bf as a promising pharmacological compound in a panel of human leukemia cell lines (HL60, U937, KG1a and Jurkat. Present findings indicate that T44Bf-mediated antiproliferative effects are associated with a reversible chronic mitotic arrest caused by defects in chromosome alignment, followed by induced programmed cell death. Furthermore, T44Bf selectively induces apoptosis in leukemia cell lines when compared to normal peripheral blood mononuclear cells. The underlying mechanism of action involves the activation of the mitochondria signaling pathway, with loss of mitochondrial membrane potential and sustained phosphorylation of anti-apoptotic protein Bcl-xL as well as increased Bcl-2 (enhanced phosphorylated fraction and pro-apoptotic protein Bad levels. In addition, ERK signaling pathway activation was found to be a requisite for T44Bf apoptotic activity. Our findings further describe a novel activity for a benzophenone thiosemicarbazone and propose T44Bf as a promising anti-mitotic prototype to develop chemotherapeutic agents to treat acute leukemia malignancies.

  3. Development of donor cell leukemia following peripheral blood stem cell transplantation for severe aplastic anemia: A case report

    Science.gov (United States)

    MA, HONGBING; LIU, TING

    2016-01-01

    Donor cell leukemia (DCL) is a rare complication of hematopoietic stem cell transplantation (HSCT) which occurs in ~5% of all leukemic relapses. In the English literature, >60 cases of DCL have been reported, however, only two cases of DCL following HSCT for the treatment of severe aplastic anemia (SAA) have been described to date. In the present study, the case of a 25 year-old male patient diagnosed with SAA, who underwent a peripheral blood stem cell transplantation (PBSCT) using cells obtained from a sibling with an identical human leukocyte antigen, is presented. The patient developed acute myeloid leukemia with an (8;21)(q22;q22) translocation and an extra copy of the chromosome 8 in donor cells 2.5 years following PBSCT, which was preceded by the development of Graves' disease 1 year following PBSCT. The leukemia achieved complete remission following 1 cycle of priming therapy, 2 cycles of consolidation chemotherapy with daunorubicin and cytarabine and maintenance therapy with interleukin-2 (IL-2). At present, the patient has discontinued IL-2 therapy, and the DCL has been in molecular remission for >3 years. The present case indicates that chemotherapy and IL-2 maintenance therapy are an effective treatment for DCL; hyperthyroidism was relieved following treatment, although hypothyroidism subsequently developed. PMID:27313707

  4. Characterization of T cell receptors of Th1 cells infiltrating inflamed skin of a novel murine model of palladium-induced metal allergy.

    Directory of Open Access Journals (Sweden)

    Hiroshi Kobayashi

    Full Text Available Metal allergy is categorized as a delayed-type hypersensitivity reaction, and is characterized by the recruitment of lymphocytes into sites of allergic inflammation. Because of the unavailability of suitable animal models for metal allergy, the role of T cells in the pathogenesis of metal allergy has not been explored. Thus, we developed a novel mouse model for metal allergy associated with infiltration of T cells by multiple injections of palladium (Pd plus lipopolysaccharide into the footpad. Using this model, we characterized footpad-infiltrating T cells in terms of phenotypic markers, T cell receptor (TCR repertoires and cytokine expression. CD3+ CD4+ T cells accumulated in the allergic footpads 7 days after Pd challenge. The expression levels of CD25, interleukin-2, interferon-γ and tumor necrosis factor, but not interleukin-4 and interleukin-5, increased in the footpads after challenge, suggesting CD4+ T helper 1 (Th1 cells locally expanded in response to Pd. Infiltrated T cells in the footpads frequently expressed AV18-1 and BV8-2 T cell receptor (TCR chains compared with T cells in the lymph nodes and exhibited oligoclonality. T-cell clones identified from Pd-allergic mouse footpads shared identical CDR3 sequences containing AV18-1 and BV8-2. These results suggest that TCR AV18-1 and BV8-2 play dominant and critical parts in the antigen specificity of Pd-specific Th1 cells.

  5. Regulation of vitamin D receptor expression by retinoic acid receptor alpha in acute myeloid leukemia cells.

    Science.gov (United States)

    Marchwicka, Aleksandra; Cebrat, Małgorzata; Łaszkiewicz, Agnieszka; Śnieżewski, Łukasz; Brown, Geoffrey; Marcinkowska, Ewa

    2016-05-01

    Acute myeloid leukemia (AML) is the predominant acute leukemia among adults, characterized by an accumulation of malignant immature myeloid precursors. A very promising way to treat AML is differentiation therapy using either all-trans-retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3 (1,25D), or the use of both these differentiation-inducing agents. However, the effect of combination treatment varies in different AML cell lines, and this is due to ATRA either down- or up-regulating transcription of vitamin D receptor (VDR) in the cells examined. The mechanism of transcriptional regulation of VDR in response to ATRA has not been fully elucidated. Here, we show that the retinoic acid receptor α (RARα) is responsible for regulating VDR transcription in AML cells. We have shown that a VDR transcriptional variant, originating in exon 1a, is regulated by RARα agonists in AML cells. Moreover, in cells with a high basal level of RARα protein, the VDR gene is transcriptionally repressed as long as RARα agonist is absent. In these cells down-regulation of the level of RARα leads to increased expression of VDR. We consider that our findings provide a mechanistic background to explain the different outcomes from treating AML cell lines with a combination of ATRA and 1,25D. PMID:26969398

  6. Analysis of Gene Expression in the K562-n High Tumorigenitic Human Leukemia Cell Line

    Institute of Scientific and Technical Information of China (English)

    Shuqing Lü; Xiaoping Xu; Fang Xia; JianMin Wang

    2005-01-01

    OBJECTIVE The human leukemia K562-n cell line displays much higher tumorigenic actively in nude mice compared with its parental K562 cell line. The molecular mechanism of the differences in tumorigenicity between K562-n and K562 in nude mice was examined.METHODS The differences in gene expression between K562 and K562-n cells were analyzed by using cDNA microarrays.RESULTS Among the12,800 genes examined, there was a significant difference in expression of 139 genes between K562-n and K562 cells.Eighty-five of these genes have been registered in the GeneBank and 54are unknown. The genes accessible from the GeneBank include:1)oncogenes and tumor-supressor genes; 2) genes related to transcription regulation, the cell cycle and apoptosis; 3) genes related to the cytoskeleton and cytokinetics; 4) genes related to metabolism and transport; 5) genes related to immune function. There were also some differently expressed genes with mixed functions.CONCLUSION There are many genes differentially expressed between K562-n and K562 cells .The high tumorigenicity of the human leukemia K562-n cell line in nude mice might be related to its specific geneexpression profile.

  7. CELLULAR AND MOLECULAR BASIS OF HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE SUCCESSFUL TREATMENT OF HIGH RISK LEUKEMIAS.

    Directory of Open Access Journals (Sweden)

    FRANCO eLOCATELLI

    2013-02-01

    Full Text Available Natural Killer (NK cells are involved in innate immune responses and play a major role in tumor surveillance and in defence against viruses. Human NK cells recognize HLA-class I molecules via surface receptors (KIR and NKG2A delivering signals that inhibit NK cell function and kill HLA-class I-deficient target cells, a frequent event in tumors or virus-infected cells. NK cell triggering is mediated by activating receptors that recognize ligands expressed primarily on tumors or virus-infected cells. NK cells play also a key role in the cure of high-risk leukemias. Thus, donor-derived alloreactive NK cells are fundamental effectors in adult acute myeloid leukemia (AML and in pediatric acute lymphoblastic leukemia (ALL patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT. Alloreactive NK cells mediate killing of leukemia cells and patient’s DC, thus preventing respectively leukemic relapses and graft-versus-host responses. FACS analysis of KIRs expressed by NK cells allows to define the size of the alloreactive NK subset and the selection of the best potential donor. Recently, it has been shown that also the expression of activating KIRs, in particular the (C2-specific KIR2DS1, may contribute to donor NK alloreactivity. It has also been established a correlation between the size of the alloreactive NK cell population and the clinical outcome. Notably, the alloreactive NK cells derived from donor’s HSC are generated and persist in patients over time. The high survival rates of patients undergoing haploidentical HSCT highlight an important new reality in the setting of allograft performed to cure otherwise fatal leukemias. Novel approaches are in progress to further improve the clinical outcome based on the infusion of donor alloreactive NK cells either as a component of the transplanted cell population or as in vitro expanded NK cells.

  8. Graft-infiltrating cells expressing a CD200 transgene prolong allogeneic skin graft survival in association with local increases in Foxp3(+)Treg and mast cells.

    Science.gov (United States)

    Gorczynski, Reginald M; Chen, Zhiqi; Khatri, Ismat; Yu, Kai

    2011-12-01

    Expression of the molecule CD200 has been reported to increase allograft survival by suppression of inflammation and acquired immunity. In previous studies we have shown that increased skin and cardiac allograft survival in transgenic mice over-expressing CD200 (CD200(tg)) occurs in association with increased intra-graft expression of mRNAs for genes associated with altered T cell subset differentiation. We investigated changes in graft-infiltrating cells, Treg and mast cells in skin grafts post transplantation into control or CD200(tg) mice, using focused gene array and real-time PCR to assess altered gene expression, and FACS, immunohistology and MLC to determine numbers/function of those cells. Graft-infiltrating cells isolated from CD200(tg) recipients suppressed induction of CTL from control lymph node cells in vitro, and contained increased numbers of infiltrating, non-degranulating, mast cells and Foxp3(+)Treg. Mast cells were also evident in graft tissue of control animals, but there these cells showed evidence for degranulation, and fewer Foxp3(+)Treg were present than was the case of CD200(tg) mice. The infusion of a competitive inhibitor of CD200:CD200R interactions, CD200(tr), at high concentrations (50μg/mouse iv) caused rapid rejection of grafts in CD200(tg) mice, mast cell degranulation within graft tissue, and a decrease in Treg infiltrates. These effects were attenuated by simultaneous infusion of the mast cell stabilizer, sodium cromoglycate. We conclude that CD200 expression contributes to graft prolongation through local suppression of mast cell degranulation, attraction/expansion of Treg, and attenuation of T cell effector activation. PMID:21801836

  9. Application of infiltrated LSCM-GDC oxide anode in direct carbon/coal fuel cells.

    Science.gov (United States)

    Yue, Xiangling; Arenillas, Ana; Irvine, John T S

    2016-08-15

    Hybrid direct carbon/coal fuel cells (HDCFCs) utilise an anode based upon a molten carbonate salt with an oxide conducting solid electrolyte for direct carbon/coal conversion. They can be fuelled by a wide range of carbon sources, and offer higher potential chemical to electrical energy conversion efficiency and have the potential to decrease CO2 emissions compared to coal-fired power plants. In this study, the application of (La, Sr)(Cr, Mn)O3 (LSCM) and (Gd, Ce)O2 (GDC) oxide anodes was explored in a HDCFC system running with two different carbon fuels, an organic xerogel and a raw bituminous coal. The electrochemical performance of the HDCFC based on a 1-2 mm thick 8 mol% yttria stabilised zirconia (YSZ) electrolyte and the GDC-LSCM anode fabricated by wet impregnation procedures was characterized and discussed. The infiltrated oxide anode showed a significantly higher performance than the conventional Ni-YSZ anode, without suffering from impurity formation under HDCFC operation conditions. Total polarisation resistance (Rp) reached 0.8-0.9 Ω cm(2) from DCFC with an oxide anode on xerogel and bituminous coal at 750 °C, with open circuit voltage (OCV) values in the range 1.1-1.2 V on both carbon forms. These indicated the potential application of LSCM-GDC oxide anode in HDCFCs. The chemical compatibility of LSCM/GDC with carbon/carbonate investigation revealed the emergence of an A2BO4 type oxide in place of an ABO3 perovskite structure in the LSCM in a reducing environment, due to Li attack as a result of intimate contact between the LSCM and Li2CO3, with GDC being stable under identical conditions. Such reaction between LSCM and Li2CO3 was not observed on a LSCM-YSZ pellet treated with Li-K carbonate in 5% H2/Ar at 700 °C, nor on a GDC-LSCM anode after HDCFC operation. The HDCFC durability tests of GDC-LSCM oxide on a xerogel and on raw bituminous coal were performed under potentiostatic operation at 0.7 V at 750 °C. The degradation mechanisms were

  10. Inhibiting effect of CaMK Ⅱ N up-regulation on leukemia cells growth and its mechanism

    Institute of Scientific and Technical Information of China (English)

    侯军

    2014-01-01

    Objective To investigate the inhibitory effects of CaMKⅡN on acute myeloid leukemia cell line HL-60to explore a novel therapeutic target of leukemia.Methods Human CaMKⅡN gene expression vector pcDNA3.1/hCaMKⅡN or empty vector pcDNA3.1/myc-His(-)B was transfected into HL-60 cells by Lipofectamine2000.Human CaMKⅡN proteins of transfected cells were detected by Westem blot.Cell proliferation affected by human CaMKⅡN was determined by MTT.Colonyforming assay was performed by soft agar

  11. An oligomer complementary to c-myb-encoded mRNA inhibits proliferation of human myeloid leukemia cell lines.

    OpenAIRE

    Anfossi, G; Gewirtz, A M; Calabretta, B

    1989-01-01

    To study the role of the protooncogene c-myb in regulating myeloid leukemia cell proliferation and differentiation, we exposed cells of the human leukemia lines HL-60, ML-3, KG-1, and KG-1a to an oligodeoxynucleotide complementary to an 18-base-pair (bp) sequence of c-myb-encoded mRNA. This treatment resulted in a significant decrease in cell proliferation in all of the lines, which was most marked in HL-60 cells. After 5 days in culture, in several separate experiments with different oligome...

  12. Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function.

    Science.gov (United States)

    Wang, Weihuan; Zimmerman, Grant; Huang, Xiaoran; Yu, Shuiliang; Myers, Jay; Wang, Yiwei; Moreton, Stephen; Nthale, Joseph; Awadallah, Amad; Beck, Rose; Xin, Wei; Wald, David; Huang, Alex Y; Zhou, Lan

    2016-03-15

    More than half of T-cell acute lymphoblastic leukemia (T-ALL) patients harbor gain-of-function mutations in the intracellular domain of Notch1. Diffuse infiltration of the bone marrow commonly occurs in T-ALL and relapsed B-cell acute lymphoblastic leukemia patients, and is associated with worse prognosis. However, the mechanism of leukemia outgrowth in the marrow and the resulting biologic impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular and molecular abnormalities in leukemia marrow stroma responsible for the suppression of normal hematopoiesis using a T-ALL mouse model and human T-ALL xenografts. We found that actively proliferating leukemia cells inhibited normal hematopoietic stem and progenitor cell (HSPC) proliferation and homing to the perivascular region. In addition, leukemia development was accompanied by the suppression of the endosteum-lining osteoblast population. We further demonstrated that aberrant Notch activation in the stroma plays an important role in negatively regulating the expression of CXLC12 on osteoblasts and their differentiation. Notch blockade reversed attenuated HSPC cycling, leukemia-associated abnormal blood lineage distribution, and thrombocytopenia as well as recovered osteoblast and HSPC abundance and improved the hematopoietic-supportive functions of osteoblasts. Finally, we confirmed that reduced osteoblast frequency and enhanced Notch signaling were also features of the marrow stroma of human ALL tissues. Collectively, our findings suggest that therapeutically targeting the leukemia-infiltrated hematopoietic niche may restore HSPC homeostasis and improve the outcome of ALL patients. PMID:26801976

  13. Serum soluble IL-2 receptor as a reliable and noninvasive marker of disease activity in patients with hairy cell leukemia

    International Nuclear Information System (INIS)

    Hairy cell leukemia is a chronic lymphoproliferative disorder of B-cell lineage. Malignant cells express the interleukin-2 receptor (IL-2R) which is released in vitro as well as in vivo. The sera of patients with hairy cell leukemia contain elevated levels of this soluble receptor (sIL-2R). Sere of 24 patients with hairy cell leukemia were tested for sIL-2R. In 9 patients treated with 2-chloro-deoxyadenosine an improved clinical status was associated with decreasing serum sIL-2R. The maximal rate of decrease of sIL-2R level was observed within the second and the third week after the therapy initiation. Patients with disease progression had an increase in serum sIL-2R level. Our results suggest that serial can be used as a reliable, noninvasive means to assess the disease activity and its response to therapy. (author)

  14. Approaches for cytogenetic and molecular analyses of small flow-sorted cell populations from childhood leukemia bone marrow samples

    DEFF Research Database (Denmark)

    Obro, Nina Friesgaard; Madsen, Hans Ole; Ryder, Lars Peter; Andersen, Mette Klarskov; Schmiegelow, Kjeld; Marquart, Hanne Vibeke

    defined cell populations with subsequent analyses of leukemia-associated cytogenetic and molecular marker. The approaches described here optimize the use of the same tube of unfixed, antibody-stained BM cells for flow-sorting of small cell populations and subsequent exploratory FISH and PCR-based analyses....

  15. Genes of cell-cell interactions, chemotherapy detoxification and apoptosis are induced during chemotherapy of acute myeloid leukemia

    International Nuclear Information System (INIS)

    The molecular changes in vivo in acute myeloid leukemia cells early after start of conventional genotoxic chemotherapy are incompletely understood, and it is not known if early molecular modulations reflect clinical response. The gene expression was examined by whole genome 44 k oligo microarrays and 12 k cDNA microarrays in peripheral blood leukocytes collected from seven leukemia patients before treatment, 2–4 h and 18–24 h after start of chemotherapy and validated by real-time quantitative PCR. Statistically significantly upregulated genes were classified using gene ontology (GO) terms. Parallel samples were examined by flow cytometry for apoptosis by annexin V-binding and the expression of selected proteins were confirmed by immunoblotting. Significant differential modulation of 151 genes were found at 4 h after start of induction therapy with cytarabine and anthracycline, including significant overexpression of 31 genes associated with p53 regulation. Within 4 h of chemotherapy the BCL2/BAX and BCL2/PUMA ratio were attenuated in proapoptotic direction. FLT3 mutations indicated that non-responders (5/7 patients, 8 versus 49 months survival) are characterized by a unique gene response profile before and at 4 h. At 18–24 h after chemotherapy, the gene expression of p53 target genes was attenuated, while genes involved in chemoresistance, cytarabine detoxification, chemokine networks and T cell receptor were prominent. No signs of apoptosis were observed in the collected cells, suggesting the treated patients as a physiological source of pre-apoptotic cells. Pre-apoptotic gene expression can be monitored within hours after start of chemotherapy in patients with acute myeloid leukemia, and may be useful in future determination of therapy responders. The low number of patients and the heterogeneity of acute myeloid leukemia limited the identification of gene expression predictive of therapy response. Therapy-induced gene expression reflects the complex

  16. A Review of Nelarabine in the Treatment of T-cell Lymphoblastic Leukemia/Lymphoma

    OpenAIRE

    Hernandez-Ilizaliturri, Francisco J.; Czuczman, Myron S.

    2009-01-01

    Patients with relapsed/refractory T-cell acute lymphocytic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) have a dismal prognosis. Prior to the development of novel purine analogs, salvage chemotherapy was of limited efficacy. Nelarabine, and more recently, clofarabine and forodesine have demonstrated significant anti-tumor activity in relapsed/refractory T-ALL and T-LBL. As a single agent, nelarabine induces response rates in between 33% to 50% of adult or pediatric patients with...

  17. MYCN is a novel oncogenic target in pediatric T-cell Acute Lymphoblastic Leukemia

    OpenAIRE

    Astolfi, Annalisa; Vendemini, Francesca; Urbini, Milena; Melchionda, Fraia; Masetti, Riccardo; Franzoni, Monica; Libri, Virginia; Serravalle, Salvatore; Togni, Marco; Paone, Giuseppina; Montemurro, Luca; Bressanin, Daniela; Chiarini, Francesca; Martelli, Alberto M.; Tonelli, Roberto

    2013-01-01

    MYCN is an oncogene frequently overexpressed in pediatric solid tumors whereas few evidences suggest his involvement in the pathogenesis of haematologic malignancies. Here we show that MYCN is overexpressed in a relevant proportion (40 to 50%) of adult and pediatric T-cell acute lymphoblastic leukemias (T-ALL). Focusing on pediatric T-ALL, MYCN-expressing samples were found almost exclusively in the TAL1-positive subgroup. Moreover, TAL1 knockdown in T-ALL cell lines resulted in a reduction o...

  18. A third tal-1 promoter is specifically used in human T cell leukemias

    OpenAIRE

    1992-01-01

    A common feature of T cell acute lymphoblastic leukemias (T-ALLs) is the presence of structural alteration of the 5' part of the tal-1 locus, localized on chromosomal band 1p32. These alterations consist of either a t(1;14)(p32;q11) chromosomal translocation (3% of T-ALLs) or tald submicroscopic deletion (12-25% additional T-ALLs). We have characterized a case of T-ALL with t(1;14)(p32;q11) in which, unlike the majority of t(1;14), the recombination with the T cell receptor delta elements aff...

  19. Precursor T-Cell acute lymphoblastic leukemia/lymphoma with rare presentation in the urinary bladder

    Directory of Open Access Journals (Sweden)

    Alexander Pham

    2011-10-01

    Full Text Available We present the 16th reported case of Acute Lymphoblastic Leukemia (ALL with involvement in the bladder. Our patient was a 22 yearold man with T-cell ALL with a mediastinal mass. He received hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone (HyperCVAD with mediastinal radiation. Prior to starting maintenance, he relapsed in the bladder and marrow. He received a nelarabine- based induction regimen and achieved remission. This was followed by an unrelated 11/12 HLA-matched myeloablative allogeneic stem cell transplant. He is in complete remission for the past 409 days.

  20. 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

    2016-01-01

    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. PMID:27151989

  1. Armed and accurate: engineering cytotoxic T cells for eradication of leukemia

    Directory of Open Access Journals (Sweden)

    Radic Marko

    2012-02-01

    Full Text Available Abstract Translational medicine depends on a rapid and efficient exchange of results between the bench and the bedside. A recent example from the field of cancer immunotherapy highlights the essential nature of this exchange. Methods have been developed to convert a patient's cytotoxic T cells into efficient and specific killers of cancer cells in patients with leukemia. By using recombinant DNA techniques, a lentiviral vector was constructed to express chimeric antigen receptors in cytotoxic T cells from patients with advanced chronic lymphocytic leukemia. The purpose of the chimeric receptors was to direct the cytotoxic T cell activity against cells causing the cancer. The effect of infusing the engineered T cells back into the cancer patients was tested in a Phase I trial at the University of Pennsylvania, and the initial results were described in two articles from the research team of Dr. Carl June. The remarkable success of this trial should energize further applications of biotechnology in the development of new cancer immunotherapies.

  2. Molecular analysis of the apoptotic effects of BPA in acute myeloid leukemia cells

    Directory of Open Access Journals (Sweden)

    Del Pozzo Giovanna

    2009-06-01

    Full Text Available Abstract Background: BPA (bisphenol A or 2,2-bis(4-hydroxy-phenolpropane is present in the manufacture of polycarbonate plastic and epoxy resins, which can be used in impact-resistant safety equipment and baby bottles, as protective coatings inside metal food containers, and as composites and sealants in dentistry. Recently, attention has focused on the estrogen-like and carcinogenic adverse effects of BPA. Thus, it is necessary to investigate the cytotoxicity and apoptosis-inducing activity of this compound. Methods: Cell cycle, apoptosis and differentiation analyses; western blots. Results: BPA is able to induce cell cycle arrest and apoptosis in three different acute myeloid leukemias. Although some granulocytic differentiation concomitantly occurred in NB4 cells upon BPA treatment, the major action was the induction of apoptosis. BPA mediated apoptosis was caspase dependent and occurred by activation of extrinsic and intrinsic cell death pathways modulating both FAS and TRAIL and by inducing BAD phosphorylation in NB4 cells. Finally, also non genomic actions such as the early decrease of both ERK and AKT phosphorylation were induced by BPA thus indicating that a complex intersection of regulations occur for the apoptotic action of BPA. Conclusion: BPA is able to induce apoptosis in leukemia cells via caspase activation and involvement of both intrinsic and extrinsic pathways of apoptosis.

  3. T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer's disease-like cerebral amyloidosis.

    Science.gov (United States)

    Ferretti, M T; Merlini, M; Späni, C; Gericke, C; Schweizer, N; Enzmann, G; Engelhardt, B; Kulic, L; Suter, T; Nitsch, R M

    2016-05-01

    Cerebral beta-amyloidosis, one of the pathological hallmarks of Alzheimer's disease (AD), elicits a well-characterised, microglia-mediated local innate immune response. In contrast, it is not clear whether cells of the adaptive immune system, in particular T-cells, react to cerebral amyloidosis in AD. Even though parenchymal T-cells have been described in post-mortem brains of AD patients, it is not known whether infiltrating T-cells are specifically recruited to the extracellular deposits of beta-amyloid, and whether they are locally activated into proliferating, effector cells upon interaction with antigen-presenting cells (APCs). To address these issues we have analysed by confocal microscopy and flow-cytometry the localisation and activation status of both T-cells and APCs in transgenic (tg) mice models of AD-like cerebral amyloidosis. Increased numbers of infiltrating T-cells were found in amyloid-burdened brain regions of tg mice, with concomitant up-regulation of endothelial adhesion molecules ICAM-1 and VCAM-1, compared to non-tg littermates. The infiltrating T-cells in tg brains did not co-localise with amyloid plaques, produced less interferon-gamma than those in controls and did not proliferate locally. Bona-fide dendritic cells were virtually absent from the brain parenchyma of both non-tg and tg mice, and APCs from tg brains showed an immature phenotype, with accumulation of MHC-II in intracellular compartments. These results indicate that cerebral amyloidosis promotes T-cell infiltration but interferes with local antigen presentation and T-cell activation. The inability of the brain immune surveillance to orchestrate a protective immune response to amyloid-beta peptide might contribute to the accumulation of amyloid in the progression of the disease. PMID:26872418

  4. Evaluation of dendritic cells loaded with apoptotic cancer cells or expressing tumour mRNA as potential cancer vaccines against leukemia

    International Nuclear Information System (INIS)

    Leukemia is a clonal disorder characterized by uncontrolled proliferation of haematopoietic cells, and represents the most common form of cancer in children. Advances in therapy for childhood leukemia have relied increasingly on the use of high-dose chemotherapy often combined with stem-cell transplantation. Despite a high success rate and intensification of therapy, children still suffer from relapse and progressive disease resistant to further therapy. Thus, novel forms of therapy are required. This study focuses on dendritic cell (DC) vaccination of childhood leukemia and evaluates the in vitro efficacy of different strategies for antigen loading of professional antigen-presenting cells. We have compared DCs either loaded with apoptotic leukemia cells or transfected with mRNA from the same leukemia cell line, Jurkat E6, for their capacity to induce specific CD4+ and CD8+ T-cell responses. Monocyte-derived DCs from healthy donors were loaded with tumor antigen, matured and co-cultured with autologous T cells. After one week, T-cell responses against antigen-loaded DCs were measured by enzyme-linked immunosorbent spot (ELISPOT) assay. DCs loaded with apoptotic Jurkat E6 cells or transfected with Jurkat E6-cell mRNA were both able to elicit specific T-cell responses in vitro. IFNγ-secreting T cells were observed in both the CD4+ and CD8+ subsets. The results indicate that loading of DCs with apoptotic leukemia cells or transfection with tumour mRNA represent promising strategies for development of cancer vaccines for treatment of childhood leukemia

  5. Mechanisms that uncouple growth and differentiation in myeloid leukemia cells: restoration of requirement for normal growth-inducing protein without restoring induction of differentiation-inducing protein.

    OpenAIRE

    Lotem, J; Sachs, L

    1982-01-01

    There are different macrophage- and granulocyte-inducing (MGI) proteins. Normal myeloid precursors are induced to multiply by one form (MGI-1) and to differentiate by another form (MGI-2). There are clones of myeloid leukemia cells that no longer require MGI-1 for growth but can still be induced to differentiate by MGI-2. After induction of differentiation in these leukemia cells by adding MCI-2 or inducing endogenous production of MGI-2 by lipopolysaccharide, the differentiating leukemia cel...

  6. Comparison of outcomes after unrelated cord blood and unmanipulated haploidentical stem cell transplantation in adults with acute leukemia

    DEFF Research Database (Denmark)

    Ruggeri, A; Labopin, M; Sanz, G;

    2015-01-01

    Outcomes after unmanipulated haploidentical stem cell transplantation (Haplo) and after unrelated cord blood transplantation (UCBT) are encouraging and have become alternative options to treat patients with high-risk acute leukemia without human leukocyte antigen (HLA) matched donor. We compared...... differences on main outcomes after unmanipulated Haplo and UCBT, and both approaches are valid for acute leukemia patients lacking a HLA matched donor. Both strategies expand the donor pool for patients in need....... outcomes after UCBT and Haplo in adults with de novo acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Median follow-up was 24 months. Analysis was performed separately for patients with AML, n=918 (Haplo=360, UCBT=558) and ALL, n=528 (Haplo=158 and UCBT=370). UCBT was associated with...

  7. Correlation between CD4, CD8 cell infiltration in gastric mucosa, Helicobacter pylori infection and symptoms in patients with chronic gastritis

    OpenAIRE

    Lu, Ai-ping; Zhang, Sheng-Sheng; Zha, Qing-Lin; Ju, Da-Hong; Wu, Hao; Jia, Hong-Wei; Xiao, Cheng; Li, Shao; Hui JIAN

    2005-01-01

    AIM: To evaluate the correlation between CD4, CD8 cell infiltration in gastric mucosa, Helicobacter pylori (H pylori) infection and symptoms or the assemblage of symptoms in cases with chronic gastritis.

  8. Ganoderma lucidum Polysaccharides Induce Macrophage-Like Differentiation in Human Leukemia THP-1 Cells via Caspase and p53 Activation

    Directory of Open Access Journals (Sweden)

    Jia-Wei Hsu

    2011-01-01

    Full Text Available Differentiation therapy by induction of tumor cells is an important method in the treatment of hematological cancers such as leukemia. Tumor cell differentiation ends cancer cells' immortality, thus stopping cell growth and proliferation. In our previous study, we found that fucose-containing polysaccharide fraction F3 extracted from Ganoderma lucidum can bring about cytokine secretion and cell death in human leukemia THP-1 cells. This prompted us to further investigate on how F3 induces the differentiation in human leukemia cells. We integrated time-course microarray analysis and network modeling to study the F3-induced effects on THP-1 cells. In addition, we determined the differentiation effect using Liu's staining, nitroblue tetrazolium (NBT reduction assay, flow cytometer, western blotting and Q-PCR. We also examined the modulation and regulation by F3 during the differentiation process. Dynamic gene expression profiles showed that cell differentiation was induced in F3-treated THP-1 cells. Furthermore, F3-treated THP-1 cells exhibited enhanced macrophage differentiation, as demonstrated by changes in cell adherence, cell cycle arrest, NBT reduction and expression of differentiation markers including CD11b, CD14, CD68, matrix metalloproteinase-9 and myeloperoxidase. In addition, caspase cleavage and p53 activation were found to be significantly enhanced in F3-treated THP-1 cells. We unraveled the role of caspases and p53 in F3-induced THP-1 cells differentiation into macrophages. Our results provide a molecular explanation for the differentiation effect of F3 on human leukemia THP-1 cells and offer a prospect for a potential leukemia differentiation therapy.

  9. Levofloxacin in Preventing Infection in Young Patients With Acute Leukemia Receiving Chemotherapy or Undergoing Stem Cell Transplantation

    Science.gov (United States)

    2016-04-08

    Acute Leukemias of Ambiguous Lineage; Bacterial Infection; Diarrhea; Fungal Infection; Musculoskeletal Complications; Neutropenia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  10. Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Michele Tanturli

    Full Text Available We previously demonstrated that severe hypoxia inhibits growth of Chronic Myeloid Leukemia (CML cells and selects stem cells where BCR/Abl(protein is suppressed, although mRNA is not, so that hypoxia-selected stem cells, while remaining leukemic, are independent of BCR/Abl signaling and thereby refractory to Imatinib-mesylate. The main target of this study was to address the effects of the proteasome inhibitor Bortezomib (BZ on the maintenance of stem or progenitor cells in hypoxic primary cultures (LC1, by determining the capacity of LC1 cells to repopulate normoxic secondary cultures (LC2 and the kinetics of this repopulation. Unselected K562 cells from day-2 hypoxic LC1 repopulated LC2 with rapid, progenitor-type kinetics; this repopulation was suppressed by BZ addition to LC1 at time 0, but completely resistant to day-1 BZ, indicating that progenitors require some time to adapt to stand hypoxia. K562 cells selected in hypoxic day-7 LC1 repopulated LC2 with stem-type kinetics, which was largely resistant to BZ added at either time 0 or day 1, indicating that hypoxia-selectable stem cells are BZ-resistant per se, i.e. before their selection. Furthermore, these cells were completely resistant to day-6 BZ, i.e. after selection. On the other hand, hypoxia-selected stem cells from CD34-positive cells of blast-crisis CML patients appeared completely resistant to either time-0 or day-1 BZ. To exploit in vitro the capacity of CML cells to adapt to hypoxia enabled to detect a subset of BZ-resistant leukemia stem cells, a finding of particular relevance in light of the fact that our experimental system mimics the physiologically hypoxic environment of bone marrow niches where leukemia stem cells most likely home and sustain minimal residual disease in vivo. This suggests the use of BZ as an enhanced strategy to control CML. in particular to prevent relapse of disease, to be considered with caution and to need further deepening.

  11. What Is Childhood Leukemia?

    Science.gov (United States)

    ... red blood cells, or platelets. Hybrid or mixed lineage leukemia: In these rare leukemias, the cells have ... from too many white blood cells in the lungs), and an enlarged spleen and lymph nodes. Last Medical Review: ... Information Cancer Basics Cancer Prevention & Detection Signs & Symptoms ...

  12. UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Benyoucef, Aissa; Palii, Carmen G; Wang, Chaochen; Porter, Christopher J; Chu, Alphonse; Dai, Fengtao; Tremblay, Véronique; Rakopoulos, Patricia; Singh, Kulwant; Huang, Suming; Pflumio, Francoise; Hébert, Josée; Couture, Jean-Francois; Perkins, Theodore J; Ge, Kai; Dilworth, F Jeffrey; Brand, Marjorie

    2016-03-01

    T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures, and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and, as such, T-ALL treatments are uniformly applied across subtypes, leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL by which a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in the dosage and activity of the histone 3 Lys27 (H3K27) demethylase UTX/KDM6A. Specifically, we identify UTX as a coactivator of TAL1 and show that it acts as a major regulator of the TAL1 leukemic gene expression program. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a pro-oncogenic cofactor essential for leukemia maintenance in TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we propose a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that efficiently kills TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients. PMID:26944678

  13. Chromosome arm-specific long telomeres: a new clonal event in primary chronic myelogenous leukemia cells.

    Science.gov (United States)

    Samassekou, Oumar; Li, Huiyu; Hébert, Josée; Ntwari, Aimé; Wang, Haixia; Cliché, Catherine Grenier; Bouchard, Eric; Huang, Shiang; Yan, Ju

    2011-06-01

    Previous studies demonstrated that critically shortened telomere lengths correlate with the chromosome instability in carcinogenesis. However, little has been noticed regarding the correlation of long telomeres at specific chromosomes with malignant disorders. We studied relative telomere lengths (RTLs) for individual chromosomes using the quantitative fluorescence in situ hybridization technique in a cohort of 32 patients with chronic myeloid leukemia (CML) and 32 normal samples. We found that telomeres at some specific chromosome arms remain well maintained or even lengthened in a high frequency (27/32) of leukemia cases. In particular, 10 chromosome arms, 4q, 5p, 7q, 11p, 13p, 13q, 14p, 15p, 18p, and Xp, with long telomeres were consistently identified in different samples, and six of them (4q, 5p, 13p, 13q, 14p, and Xp) with relatively long telomeres were also observed in normal samples, but they appeared in lower occurrence rate and shorter RTL than in CML samples. Our results strongly indicate the presence of a special leukemia cell population, or a clone, originated from a common progenitor that is characterized with chromosome arm-specific long telomeres. We suggest that relatively long telomeres located at key chromosomes could be preferentially maintained or further elongated during the early stage of malignant transformation. PMID:21677878

  14. Chromosome Arm-Specific Long Telomeres: A New Clonal Event in Primary Chronic Myelogenous Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Oumar Samassekou

    2011-06-01

    Full Text Available Previous studies demonstrated that critically shortened telomere lengths correlate with the chromosome instability in carcinogenesis. However, little has been noticed regarding the correlation of long telomeres at specific chromosomes with malignant disorders. We studied relative telomere lengths (RTLs for individual chromosomes using the quantitative fluorescence in situ hybridization technique in a cohort of 32 patients with chronic myeloid leukemia (CML and 32 normal samples. We found that telomeres at some specific chromosome arms remain well maintained or even lengthened in a high frequency (27/32 of leukemia cases. In particular, 10 chromosome arms, 4q, 5p, 7q, 11p, 13p, 13q, 14p, 15p, 18p, and Xp, with long telomeres were consistently identified in different samples, and six of them (4q, 5p, 13p, 13q, 14p, and Xp with relatively long telomeres were also observed in normal samples, but they appeared in lower occurrence rate and shorter RTL than in CML samples. Our results strongly indicate the presence of a special leukemia cell population, or a clone, originated from a common progenitor that is characterized with chromosome arm-specific long telomeres. We suggest that relatively long telomeres located at key chromosomes could be preferentially maintained or further elongated during the early stage of malignant transformation.

  15. A new symmetric solid oxide fuel cell with a samaria-doped ceria framework and a silver-infiltrated electrocatalyst

    Science.gov (United States)

    Lin, Ye; Su, Chao; Huang, Cheng; Kim, Ju Sik; Kwak, Chan; Shao, Zongping

    2012-01-01

    A new symmetric SOFC with an SDC framework and a silver-infiltrated electrocatalyst is presented for the first time in this paper. A three-electrode polarization test shows that the Ag-SDC has a low area specific resistance of 1.07 Ω cm2 at 600 °C, a low activation energy of 85 kJ mol-1 and high exchange current densities of 428.2 and 129.0 mA cm-2 at 750 and 650 °C, respectively, when it is used as an oxygen reduction electrode. It also exhibits low polarization resistance in a humidified hydrogen atmosphere. A symmetric single cell is used in real fuel cell conditions to deliver peak power densities of 200 and 84 mW cm-2 at 750 and 650 °C, respectively, when humidified hydrogen is used as a fuel and ambient air is used as the cathode atmosphere. The cell still reaches a peak power density of 81 mW cm-2 at 750 °C when operating on CO. O2-TPO analysis demonstrates that the Ag-SDC electrode has even better coking resistance than the pure SDC scaffold. The results indicate that Ag-SDC|SDC|Ag-SDC symmetric cells with an infiltrated silver electrocatalyst are a promising new type of fuel cell for use with both hydrogen fuel and carbon-containing fuels.

  16. Fludarabine Phosphate and Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Has Responded to Treatment With Imatinib Mesylate, Dasatinib, or Nilotinib

    Science.gov (United States)

    2015-07-20

    Adult Acute Lymphoblastic Leukemia in Remission; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia

  17. Scorpion venom component III inhibits cell proliferation by modulating NF-κB activation in human leukemia cells

    OpenAIRE

    SONG, XIANGFENG; Zhang, Guojun; SUN, AIPING; Guo, Jiqiang; TIAN, ZHONGWEI; Wang, Hui; Liu, Yufeng

    2012-01-01

    Scorpion venom contains various groups of compounds that exhibit anticancer activity against a variety of malignancies through a poorly understood mechanism. While the aberrant activation of nuclear factor κB (NF-κB) has been linked with hematopoietic malignancies, we hypothesized that scorpion venom mediates its effects by modulating the NF-κB signaling pathway. In the present study, we examined the effects of scorpion venom component III (SVCIII) on the human leukemia cell lines THP-1 and J...

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

    OpenAIRE

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

    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 report...

  19. NRS2002 assesses nutritional status of leukemia patients undergoing hematopoietic stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    Peng Liu; Zhao-Feng Zhang; Jing-Jing Cai; Bo-Shi Wang; Xia Yan

    2012-01-01

    Objective:To discuss whether nutritional risk screening 2002 (NRS2002) is appropriate for nutritional risk screening for leukemia patients before and after hematopoietic stem cell transplantation (HSCT),and whether there are risk differences in other conditions,such as age,gender and matching degree; to find the methods and indicators of nutritional risk screening for these patients before and after HSCT,in order to give timely intervention to guarantee the successful completion of the entire transplantation process.Methods:Nutritional risk of 99 leukemia patients was screened with NRS2002 before and after HSCT.The x2 test was applied to compare the risk differences between groups such as age,gender and matching degree,while the differences of other enumeration data,such as recent (1-3 months) weight loss,reduced food intake within one week and BMI,were compared by continuity correction.Results:Of the 99 leukemia patients,22 cases (22.2%) had nutritional risk before HSCT,while all patients had nutritional risk after HSCT; there is no significant difference in nutritional risk between male and female,and patients of less than 30 years old,not-full matched,recent (1-3 months) weight loss,reduced food intake within a week or BMI <18.5 were more likely to have nutritional risk; and 77 cases (77.8%) had weight loss,among which 49 patients (63.6%) had more than 5% weight loss within one month.Conclusions:This study showed that leukemia patients should receive the nutritional risk screening conventionally before and after HSCT,and NRS2002 was only appropriate for nutritional risk screening before HSCT.More attention should be paid to the patients less than 30 years old or not-full matched.Weight change was one of the important nutritional indicators for patients after HSCT.

  20. Factors that contribute to long-term survival in patients with leukemia not in remission at allogeneic hematopoietic cell transplantation

    Directory of Open Access Journals (Sweden)

    Okamura Hiroshi

    2011-04-01

    Full Text Available Abstract Background There has been insufficient examination of the factors affecting long-term survival of more than 5 years in patients with leukemia that is not in remission at transplantation. Method We retrospectively analyzed leukemia not in remission at allogeneic hematopoietic cell transplantation (allo-HCT performed at our institution between January 1999 and July 2009. Forty-two patients with a median age of 39 years received intensified conditioning (n = 9, standard (n = 12 or reduced-intensity conditioning (n = 21 for allo-HCT. Fourteen patients received individual chemotherapy for cytoreduction during the three weeks prior to reduced-intensity conditioning. Diagnoses comprised acute leukemia (n = 29, chronic myeloid leukemia-accelerated phase (n = 2, myelodysplastic syndrome/acute myeloid leukemia (MDS/AML (n = 10 and plasma cell leukemia (n = 1. In those with acute leukemia, cytogenetic abnormalities were intermediate (44% or poor (56%. The median number of blast cells in bone marrow (BM was 26.0% (range; 0.2-100 before the start of chemotherapy for allo-HCT. Six patients had leukemic involvement of the central nervous system. Stem cell sources were related BM (7%, related peripheral blood (31%, unrelated BM (48% and unrelated cord blood (CB (14%. Results Engraftment was achieved in 33 (79% of 42 patients. Median time to engraftment was 17 days (range: 9-32. At five years, the cumulative probabilities of acute graft-versus-host disease (GVHD and chronic GVHD were 63% and 37%, respectively. With a median follow-up of 85 months for surviving patients, the five-year Kaplan-Meier estimates of leukemia-free survival rate and overall survival (OS were 17% and 19%, respectively. At five years, the cumulative probability of non-relapse mortality was 38%. In the univariable analyses of the influence of pre-transplant variables on OS, poor-risk cytogenetics, number of BM blasts (>26%, MDS overt AML and CB as stem cell source were

  1. Zonal Difference and Prognostic Significance of Foxp3 Regulatory T Cell Infiltration in Breast Cancer

    OpenAIRE

    Kim, Sewha; Lee, Anbok; Lim, Woosung; Park, Sanghui; Cho, Min Sun; Koo, Heasoo; Moon, Byung-In; Sung, Sun Hee

    2014-01-01

    Purpose Forkhead box P3 (Foxp3) is known as the most specific marker for regulatory T lymphocytes, which play an important role in immune tolerance to disturb antitumor immunity. The present study aimed to investigate the prognostic significance of Foxp3 regulatory T lymphocyte (Foxp3 Treg) infiltration in breast cancer. Methods Immunohistochemical studies with Foxp3, CD4, and CD8 were performed on representative full tissue sections from 143 patients with invasive ductal carcinoma, not other...

  2. Pancratistatin induces apoptosis in clinical leukemia samples with minimal effect on non-cancerous peripheral blood mononuclear cells

    Directory of Open Access Journals (Sweden)

    McNulty James

    2010-03-01

    Full Text Available Abstract Background Pancratistatin, a natural compound extracted from Hymenocallis littoralis, can selectively induce apoptosis in several cancer cell lines. In this ex vivo study, we evaluated the effect of pancratistatin on peripheral blood mononuclear cells obtained from 15 leukemia patients prior to clinical intervention of newly diagnosed patients, as well as others of different ages in relapse and at various disease progression states. Results Mononuclear cells from healthy volunteers and leukemia patients were exposed to 1 μM pancratistatin for up to 48 h. Irrespective of leukemia type, pancratistatin induced apoptosis in the leukemic samples, with minimal effects on non-cancerous peripheral blood mononuclear control cells. Conclusion Our results show that pancratistatin is an effective and selective anti-cancer agent with potential for advancement to clinical trials.

  3. 5-Ene-4-thiazolidinones induce apoptosis in mammalian leukemia cells.

    Science.gov (United States)

    Senkiv, Julia; Finiuk, Nataliya; Kaminskyy, Danylo; Havrylyuk, Dmytro; Wojtyra, Magdalena; Kril, Iryna; Gzella, Andrzej; Stoika, Rostyslav; Lesyk, Roman

    2016-07-19

    The article presents the synthesis of 5-ene-4-thiazolidinone derivatives with pyrazole core linked by enamine group. The structure and purity of compounds were confirmed by analytical and spectral data including X-ray analysis. Target compounds were screened for their anticancer activity and selective antileukemic action was confirmed. 5-[5-(2-Hydroxyphenyl)-3-phenyl-4,5-dihydropyrazol-1-ylmethylene]-3-(3-acetoxyphenyl)-2-thioxothiazolidin-4-one (compound 1) was selected as most active agent against HL-60 and HL-60/ADR cell lines; IC50 = 118 nM/HL-60 with low toxicity towards pseudonormal cells. The mitochondria-depended apoptosis was identified as the main mode of 1 action. Moreover compound's effect induces G0/G1 arrest of the treated cells and causes inhibition of cell division and is related with activation of ROS production. PMID:27089210

  4. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells

    DEFF Research Database (Denmark)

    Kirstetter, Peggy; Schuster, Mikkel B; Bereshchenko, Oksana;

    2008-01-01

    Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p...... penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.......42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete...

  5. Persistent complete molecular remission after nilotinib and graft-versus-leukemia effect in an acute lymphoblastic leukemia patient with cytogenetic relapse after allogeneic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Farnsworth Paul

    2012-09-01

    Full Text Available Abstract We report the successful treatment and sustained molecular remission using single agent nilotinib in a relapsed Philadelphia chromosome positive (Ph+ acute lymphoblastic leukemia patient after allogeneic hematopoietic stem cell transplantation. Compared to previously published studies, this is the first report where a patient did not receive additional chemotherapy after relapse, nor did she receive donor lymphocyte infusions. With nilotinib, the patient reverted back to normal blood counts and 100% donor reconstitution by single tandem repeat (STR chimerism analysis in the bone marrow and in peripheral blood, granulocytes, T and B-lymphocytes. This report also highlights the use of nilotinib in combination with extracorporeal photopheresis (ECP for concomitant graft-versus-host disease. Our data suggests that ECP, together with nilotinib, did not adversely affect the overall Graft-versus-leukemia (GVL effect.

  6. The feasibility of in vivo imaging of infiltrating blood cells for predicting the functional prognosis after spinal cord injury.

    Science.gov (United States)

    Yokota, Kazuya; Saito, Takeyuki; Kobayakawa, Kazu; Kubota, Kensuke; Hara, Masamitsu; Murata, Masaharu; Ohkawa, Yasuyuki; Iwamoto, Yukihide; Okada, Seiji

    2016-01-01

    After a spinal cord injury (SCI), a reliable prediction of the potential functional outcome is essential for determining the optimal treatment strategy. Despite recent advances in the field of neurological assessment, there is still no satisfactory methodology for predicting the functional outcome after SCI. We herein describe a novel method to predict the functional outcome at 12 hours after SCI using in vivo bioluminescence imaging. We produced three groups of SCI mice with different functional prognoses: 50 kdyn (mild), 70 kdyn (moderate) and 90 kdyn (severe). Only the locomotor function within 24 hours after SCI was unable to predict subsequent functional recovery. However, both the number of infiltrating neutrophils and the bioluminescence signal intensity from infiltrating blood cells were found to correlate with the severity of the injury at 12 hours after SCI. Furthermore, a strong linear relationship was observed among the number of infiltrating neutrophils, the bioluminescence signal intensity, and the severity of the injury. Our findings thus indicate that in vivo bioluminescence imaging is able to accurately predict the long-term functional outcome in the hyperacute phase of SCI, thereby providing evidence that this imaging modality could positively contribute to the future development of tailored therapeutic approaches for SCI. PMID:27156468

  7. Differential protective effects of immune lymphoid cells against transplanted line Ib leukemia and immune polioencephalomyelitis. [X radiation, mice

    Energy Technology Data Exchange (ETDEWEB)

    Duffey, P.S.; Lukasewycz, O.A.; Olson, D.S.; Murphy, W.H.

    1978-12-01

    The capacity of immune cells obtained from the major lymphoid compartments to protect C58 mice from transplanted line Ib leukemia, and from an age-dependent autoimmune CNS disease (immune polioencephalomyelitis = IPE) elicited by immunizing old C58 mice with inactivated Ib cells was quantified. Cells used for comparative adoptive protection tests were harvested from the major lymphoid compartments 14 to 15 days after young C58 mice were immunized with inactivated Ib cell preparations. Regression curves were plotted from survival data and the log/sub 10/PD/sub 50/ values were determined. Immune spleen (ISC) and peritoneal cells (IPEC) were significantly more protective against transplanted Ib cells than immune lymph node (ILNC), thymic (ITC), and marrow cells (IMC). In contrast, IPEC and IMC were not protective against IPE and ITC were only marginally protective. ILNC afforded significant protection to transplantable leukemia but were only marginally protective to IPE. When ISC were treated with anti-thy 1.2 serum and complement, protection against transplanted leukemia and IPE was reduced > 99%. When donors of immune lymphoid cells were treated with 12.5 mg of cortisone acetate daily for 2 days before lymphoid cells were harvested, protection against transplanted Ib cells by ISC was reduced by approximately 90% whereas protection against IPE was totally eliminated. Considered together, these results indicate that the protective mechanisms to transplantable leukemia and IPE differ significantly in the same indicator mouse strain.

  8. Collateral methotrexate resistance in cisplatin-selected murine leukemia cells

    Directory of Open Access Journals (Sweden)

    Bhushan A.

    1999-01-01

    Full Text Available Resistance to anticancer drugs is a major cause of failure of many therapeutic protocols. A variety of mechanisms have been proposed to explain this phenomenon. The exact mechanism depends upon the drug of interest as well as the tumor type treated. While studying a cell line selected for its resistance to cisplatin we noted that the cells expressed a >25,000-fold collateral resistance to methotrexate. Given the magnitude of this resistance we elected to investigate this intriguing collateral resistance. From a series of investigations we have identified an alteration in a membrane protein of the resistant cell as compared to the sensitive cells that could be the primary mechanism of resistance. Our studies reviewed here indicate decreased tyrosine phosphorylation of a protein (molecular mass = 66 in the resistant cells, which results in little or no transfer of methotrexate from the medium into the cell. Since this is a relatively novel function for tyrosine phosphorylation, this information may provide insight into possible pharmacological approaches to modify therapeutic regimens by analyzing the status of this protein in tumor samples for a better survival of the cancer patients.

  9. Promoter methylation and expression levels of selected hematopoietic genes in pediatric B-cell acute lymphoblastic leukemia

    OpenAIRE

    Musialik, Ewa; Bujko, Mateusz; Kober, Paulina; Agnieszka WYPYCH; Gawle-Krawczyk, Karolina; Matysiak, Michal; Siedlecki, Janusz Aleksander

    2015-01-01

    Background Precursor B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common neoplasm in children and is characterized by genetic and epigenetic aberrations in hematopoietic transcription factor (TF) genes. This study evaluated promoter DNA methylation and aberrant expression levels of early- and late-acting hematopoietic TF genes homeobox A4 and A5 (HOXA4 and HOXA5), Meis homeobox 1 (MEIS1), T-cell acute lymphocytic leukemia 1 (TAL1), and interferon regulatory factors 4 and 8 (IR...

  10. Chaetoglobosin A preferentially induces apoptosis in chronic lymphocytic leukemia cells by targeting the cytoskeleton

    DEFF Research Database (Denmark)

    Knudsen, Peter Boldsen; Hanna, B.; Ohl, S.;

    2013-01-01

    family that showed preferential induction of apoptosis in CLL cells, even under culture conditions that mimic lymphoid tissues. In vitro testing of 89 CLL cases revealed effective targeting of CLL cells by Chaetoglobosin A, independent of bad prognosis characteristics, like 17p deletion or TP53 mutation...... novel drugs that target CLL cells also in protective microenvironments, we performed a fungal extract screen using cocultures of primary CLL cells with bone marrow-derived stromal cells. A metabolite produced by Penicillium aquamarinium was identified as Chaetoglobosin A, a member of the cytochalasan...... treatment with PI3K and BTK inhibitors, suggesting this compound as a novel potential drug for CLL.Leukemia accepted article preview online, 27 November 2013. doi:10.1038/leu.2013.360....

  11. Regulation of intracellular calcium in resting and stimulated rat basophilic leukemia cells

    International Nuclear Information System (INIS)

    Intracellular calcium regulation was studied in a cell line of mast cells, the rat basophilic leukemia (RBL) cells with the purpose of determining (1) The properties of the plasma membrane calcium permeability pathway and (2) The role of intracellular calcium stores. The first set of experiments showed that depolarization did not induce calcium entry or secretion in resting cells and did inhibit antigen-stimulated calcium uptake and secretion. In the second set of experiments the ionic basis of antigen-induced depolarization was studied using the fluorescent potential-sensitive probe bis-oxonol. The properties of the calcium entry pathway were more consistent with a calcium channel than a calcium transport mechanism such as Na:Ca exchange. The third set of experiments examined the effects of the proton ionophore carbonyl cyanide m-chlorophenylhydrazone (CCCP) on RBL cells. CCCP inhibited antigen-stimulated 45Ca uptake and secretion by depolarizing the plasma membrane

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

    Science.gov (United States)

    Wiestner, Adrian

    2015-12-01

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

  13. Pro-apoptotic activity of α-bisabolol in preclinical models of primary human acute leukemia cells

    Directory of Open Access Journals (Sweden)

    Fato Romana

    2011-04-01

    Full Text Available Abstract Background We previously demonstrated that the plant-derived agent α-bisabolol enters cells via lipid rafts, binds to the pro-apoptotic Bcl-2 family protein BID, and may induce apoptosis. Here we studied the activity of α-bisabolol in acute leukemia cells. Methods We tested ex vivo blasts from 42 acute leukemias (14 Philadelphia-negative and 14 Philadelphia-positive B acute lymphoid leukemias, Ph-/Ph+B-ALL; 14 acute myeloid leukemias, AML for their sensitivity to α-bisabolol in 24-hour dose-response assays. Concentrations and time were chosen based on CD34+, CD33+my and normal peripheral blood cell sensitivity to increasing α-bisabolol concentrations for up to 120 hours. Results A clustering analysis of the sensitivity over 24 hours identified three clusters. Cluster 1 (14 ± 5 μM α-bisabolol IC50 included mainly Ph-B-ALL cells. AML cells were split into cluster 2 and 3 (45 ± 7 and 65 ± 5 μM IC50. Ph+B-ALL cells were scattered, but mainly grouped into cluster 2. All leukemias, including 3 imatinib-resistant cases, were eventually responsive, but a subset of B-ALL cells was fairly sensitive to low α-bisabolol concentrations. α-bisabolol acted as a pro-apoptotic agent via a direct damage to mitochondrial integrity, which was responsible for the decrease in NADH-supported state 3 respiration and the disruption of the mitochondrial membrane potential. Conclusion Our study provides the first evidence that α-bisabolol is a pro-apoptotic agent for primary human acute leukemia cells.

  14. Upregulation of T-Cell-Specific Transcription Factor Expression in Pediatric T-Cell Acute Lymphoblastic Leukemia (T-ALL)

    OpenAIRE

    Müge Sayitoğlu; Yücel Erbilgin; Özden Hatırnaz; İnci Yıldız; Tiraje Celkan; Sema Anak; Ömer Devecioğlu; Gönül Aydoğan; Serap Karaman; Nazan Sarper; Çetin Timur; Ümit Üre; Uğur Özbek

    2012-01-01

    Objective: T-cell acute lymphoblastic leukemia (T-ALL) is associated with recurrent chromosomal aberrations andabnormal ectopic gene expression during T-cell development. In order to gain insight into the pathogenesis of T-ALLthis study aimed to measure the level of expression of 7 T-cell oncogenes (LMO2, LYL1, TAL1, TLX1, TLX3, BMI1, andCALM-AF10) in pediatric T-ALL patients Material and Methods: LMO2, LYL1, TLX1, TLX3, BMI1, TAL1, and CALM-AF10 expression was measured usingquantitative real...

  15. Development and characterization of a three-dimensional co-culture model of tumor T cell infiltration.

    Science.gov (United States)

    Alonso-Nocelo, M; Abuín, C; López-López, R; de la Fuente, M

    2016-01-01

    Tumor growth and metastasis entangle the alteration and recruitment of non-malignant cells to the primary tumor, among them immune cells, constituting the tumor microenvironment (TME). Communication between tumor cells and their stroma has been shown as a fundamental driving force of the tumoral process. A great deal of effort has been focused on depicting their specific interactions and crosstalk. However, most research has been carried out in 2D conventional cultures that alter cell morphology and intracellular signaling processes. Considering these premises, we have developed a 3D cell co-culture model to mimic T cell infiltration into the tumor mass and explore tumor-immune cells interactions in the TME. Expression of specific cell markers and assessment of cell proliferation were carried out to characterize the proposed 3D co-culture model. Additionally, the study and profiling of the secretome revealed a subset of particular cancer-related inflammation proteins prompted upon 3D cultivation of tumor cells in presence of lymphocytes, pointing out an intercellular communication. Altogether, these results suggest that our 3D cell co-culture model can be a useful tool to identify and study critical factors mediating the crosstalk between tumor and immune cells in the TME. Finally, the potential of this model as a drug-screening platform has been explored using docetaxel as a model antitumoral compound. PMID:27078888

  16. Markers of T cell infiltration and function associate with favorable outcome in vascularized high-grade serous ovarian carcinoma.

    Directory of Open Access Journals (Sweden)

    Katelin N Townsend

    Full Text Available BACKGROUND: When T cells infiltrate the tumor environment they encounter a myriad of metabolic stressors including hypoxia. Overcoming the limitations imposed by an inadequate tumor vasculature that contributes to these stressors may be a crucial step to immune cells mounting an effective anti-tumor response. We sought to determine whether the functional capacity of tumor infiltrating lymphocytes (TIL could be influenced by the tumor vasculature and correlated this with survival in patients with ovarian cancer. METHODOLOGY AND PRINCIPAL FINDINGS: In 196 high-grade serous ovarian tumors, we confirmed that the tumor vascularity as measured by the marker CD31 was associated with improved patient disease-specific survival. We also found that tumors positive for markers of TIL (CD8, CD4 and forkhead box P3 (FoxP3 and T cell function (granzyme B and T-cell restricted intracellular antigen-1 (TIA-1 correlated significantly with elevated vascularity. In vitro, hypoxic CD8 T cells showed reduced cytolytic activity, secreted less effector cytokines and upregulated autophagy. Survival analysis revealed that patients had a significant improvement in disease-specific survival when FoxP3 expressing cells were present in CD31-high tumors compared to patients with FoxP3 expressing cells in CD31-low tumors [HR: 2.314 (95% CI 1.049-5.106; p = 0.0377]. Patients with high vascular endothelial growth factor (VEGF expressing tumors containing granzyme B positive cells had improved survival compared to patients with granzyme B positive cells in VEGF-low tumors [HR: 2.522 (95% CI 1.097-5.799; p = 0.0294]. SIGNIFICANCE: Overall, this data provides a rationale for developing strategies aimed at improving the adaptability and function of TIL to hypoxic tumor conditions.

  17. Cyanobacteria from Terrestrial and Marine Sources Contain Apoptogens Able to Overcome Chemoresistance in Acute Myeloid Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Liwei Liu

    2014-04-01

    Full Text Available In this study, we investigated forty cyanobacterial isolates from biofilms, gastropods, brackish water and symbiotic lichen habitats. Their aqueous and organic extracts were used to screen for apoptosis-inducing activity against acute myeloid leukemia cells. A total of 28 extracts showed cytotoxicity against rat acute myeloid leukemia (IPC-81 cells. The design of the screen made it possible to eliminate known toxins, such as microcystins and nodularin, or known metabolites with anti-leukemic activity, such as adenosine and its analogs. A cytotoxicity test on human embryonic kidney (HEK293T fibroblasts indicated that 21 of the 28 extracts containing anti-acute myeloid leukemia (AML activity showed selectivity in favor of leukemia cells. Extracts L26-O and L30-O were able to partly overcome the chemotherapy resistance induced by the oncogenic protein Bcl-2, whereas extract L1-O overcame protection from the deletion of the tumor suppressor protein p53. In conclusion, cyanobacteria are a prolific resource for anti-leukemia compounds that have potential for pharmaceutical applications. Based on the variety of cellular responses, we also conclude that the different anti-leukemic compounds in the cyanobacterial extracts target different elements of the death machinery of mammalian cells.

  18. Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation

    International Nuclear Information System (INIS)

    T-cell large granular lymphocytic (T-LGL) leukemia is a clonal disease characterized by the expansion of mature CD3+CD8+ cytotoxic T cells. It is often associated with autoimmune disorders and immune-mediated cytopenias. Our recent findings suggest that up to 40% of T-LGL patients harbor mutations in the STAT3 gene, whereas STAT5 mutations are present in 2% of patients. In order to identify putative disease-causing genetic alterations in the remaining T-LGL patients, we performed exome sequencing from three STAT mutation-negative patients and validated the findings in 113 large granular lymphocytic (LGL) leukemia patients. On average, 11 CD8+ LGL leukemia cell-specific high-confidence nonsynonymous somatic mutations were discovered in each patient. Interestingly, all patients had at least one mutation that affects either directly the STAT3-pathway (such as PTPRT) or T-cell activation (BCL11B, SLIT2 and NRP1). In all three patients, the STAT3 pathway was activated when studied by RNA expression or pSTAT3 analysis. Screening of the remaining 113 LGL leukemia patients did not reveal additional patients with same mutations. These novel mutations are potentially biologically relevant and represent rare genetic triggers for T-LGL leukemia, and are associated with similar disease phenotype as observed in patients with mutations in the STAT3 gene

  19. Efficiency of AUY922 in mice with adult T-cell leukemia/lymphoma

    Science.gov (United States)

    ISHIKAWA, CHIE; SENBA, MASACHIKA; MORI, NAOKI

    2016-01-01

    Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATLL is associated with poor prognosis mainly due to resistance to chemotherapy, which highlights the requirement for alternative therapies. The chaperone heat shock protein (HSP) 90 assist proteins involved in the onset and progression of ATLL. In the present study, the efficacy of a second generation HSP90 inhibitor termed AUY922 was investigated in ATLL. In vitro, AUY922 induced marked inhibition of cell viability in the HTLV-1-infected T-cell lines HUT-102 and MT-4. In immunodeficient mice bearing HUT-102 xenotransplants, AUY922 markedly retarded tumor growth, compared with the control group. Apoptosis was evident in hematoxylin and eosin stained- and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-labeled tissue sections from AUY922-treated mice. In addition, AUY922 significantly reduced the serum levels of the surrogate tumor markers soluble interleukin-2 receptor and soluble cluster of differentiation 30. Overall, the present results demonstrate that AUY922 has potent anti-ATLL activity, thus providing a rationale for continuing the clinical development of HSP90 inhibitors in clinical trials for the treatment of patients with ATLL. PMID:27347156

  20. Hydroquinone induces DNA hypomethylation-independent overexpression of retroelements in human leukemia and hematopoietic stem cells.

    Science.gov (United States)

    Conti, Anastasia; Rota, Federica; Ragni, Enrico; Favero, Chiara; Motta, Valeria; Lazzari, Lorenza; Bollati, Valentina; Fustinoni, Silvia; Dieci, Giorgio

    2016-06-10

    Hydroquinone (HQ) is an important benzene-derived metabolite associated with acute myelogenous leukemia risk. Although altered DNA methylation has been reported in both benzene-exposed human subjects and HQ-exposed cultured cells, the inventory of benzene metabolite effects on the epigenome is only starting to be established. In this study, we used a monocytic leukemia cell line (THP-1) and hematopoietic stem cells (HSCs) from cord blood to investigate the effects of HQ treatment on the expression of the three most important families of retrotransposons in the human genome: LINE-1, Alu and Endogenous retroviruses (HERVs), that are normally subjected to tight epigenetic silencing. We found a clear tendency towards increased retrotransposon expression in response to HQ exposure, more pronounced in the case of LINE-1 and HERV. Such a partial loss of silencing, however, was generally not associated with HQ-induced DNA hypomethylation. On the other hand, retroelement derepression was also observed in the same cells in response to the hypomethylating agent decitabine. These observations suggest the existence of different types of epigenetic switches operating at human retroelements, and point to retroelement activation in response to benzene-derived metabolites as a novel factor deserving attention in benzene carcinogenesis studies. PMID:27154225