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Sample records for leukemia hairy cell

  1. Leukemia - B-Cell Prolymphocytic Leukemia and Hairy Cell Leukemia

    MedlinePlus

    ... and Hairy Cell Leukemia: Introduction Request Permissions Leukemia - B-cell Prolymphocytic Leukemia and Hairy Cell Leukemia: Introduction ... t k e P Types of Cancer Leukemia - B-cell Prolymphocytic Leukemia and Hairy Cell Leukemia Guide ...

  2. General Information About Hairy Cell Leukemia

    MedlinePlus

    ... 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 ...

  3. Hairy Cell Leukemia Treatment Option Overview

    MedlinePlus

    ... 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 ...

  4. Eliminating Hairy Cell Leukemia Minimal Residual Disease

    Cancer.gov

    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.

  5. Current therapeutic options in hairy cell leukemia.

    PubMed

    Mikler, Evgeny; Mascarenhas, John

    2014-03-01

    Hairy cell leukemia (HCL) is a B-cell chronic lymphoproliferative disorder that was initially described as leukemic reticuloendotheliosis. The disease is characterized by monocytopenia, organomegaly, constitutional symptoms, and bone marrow fibrosis. Significant advances have improved the diagnosis and management of HCL over the last 55 years. Although HCL has an indolent course, most patients will require treatment of the disease. Indications to initiate therapy include disease-related symptoms, signs of bone marrow failure, or frequent infections. Asymptomatic patients without cytopenias can be observed without the need for therapeutic interventions. Therapeutic options usually consist of chemotherapy, immunotherapy, biological agents, and surgery.

  6. Treating Multiply Relapsed or Refractory Hairy Cell Leukemia

    Cancer.gov

    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.

  7. Hairy-cell leukemia: a rare blood disorder in Asia.

    PubMed

    Josephine, F P; Nissapatorn, V

    2006-01-01

    We report a 68-year-old Indian man who was referred to the Hematology Unit for investigation for thrombocytopenia, an incidental finding during a pre-operative screening for prostatectomy. Physical examination was unremarkable. There was no splenomegaly, hepatomegaly or lymphadenopathy. Complete blood counts showed normal hemoglobin and total white cell count with moderate thrombocytopenia. Hairy-cell leukemia was diagnosed based on peripheral blood film, bone-marrow aspirate and trephine biopsy findings, supported by immunophenotyping results by flow cytometry. The purpose of this report is to create awareness of this uncommon presentation and to emphasize that a single-lineage cytopenia or absence of splenomegaly does not exclude the diagnosis of hairy-cell leukemia. Careful attention to morphological detail is important for early diagnosis, especially when low percentages of "hairy" cells are present in the peripheral blood and bone marrow. Early diagnosis is important to ensure that patients obtain maximum benefit from the newer therapeutic agents that have greatly improved the prognosis in this rare disorder.

  8. 75 FR 54496 - Diseases Associated With Exposure to Certain Herbicide Agents (Hairy Cell Leukemia and Other...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-08

    ... Cell Leukemia and Other Chronic B-Cell Leukemias, Parkinson's Disease and Ischemic Heart Disease... Federal Register (75 FR 53202), an amendment to 38 CFR 3.309 to add hairy cell leukemia and other chronic B-cell leukemias, Parkinson's disease and ischemic heart disease to the list of diseases subject...

  9. Toxoplasmic Encephalitis with Untreated Hairy Cell Leukemia Variant

    PubMed Central

    Ikebe, Taichi; Sasaki, Hitohiro; Takata, Hiroyuki; Miyazaki, Yasuhiko; Ohtsuka, Eiichi; Saburi, Yoshio; Ogata, Masao; Shirao, Kuniaki

    2016-01-01

    Toxoplasmic encephalitis is a rare infectious complication in patients with hematological malignancy except for allogeneic hematopoietic stem cell transplantation (HSCT). We herein report a case of possible toxoplasmic encephalitis with untreated hairy cell leukemia variant. Magnetic resonance imaging showed multiple nodules with surrounding edema in the entire cerebrum. A polymerase chain reaction analysis for Toxoplasma gondii was negative. Her signs and symptoms fully recovered by empirical therapy with sulfadiazine and pyrimethamine. Toxoplasmic encephalitis may occur in patients who undergo non-allogeneic HSCT for hematological malignancies, even in those who have not been treated. PMID:27803415

  10. Underexpression of RhoH in Hairy Cell Leukemia.

    PubMed

    Galiègue-Zouitina, Sylvie; Delestré, Laure; Dupont, Caroline; Troussard, Xavier; Shelley, Carl Simon

    2008-06-15

    The cause of hairy cell leukemia (HCL) is unknown. Current treatments seem effective only for a limited period of time. In addition, a significant proportion of patients remain refractive to all treatment options. These considerations indicate the need to develop alternative therapeutic strategies for HCL. Here, we report that HCL is characterized by underexpression of RhoH. In vitro reconstitution of RhoH expression inhibits the aberrant adhesion and transendothelial migration that drives disease pathogenesis. In an in vivo model of HCL, RhoH reconstitution limits malignant progression and protects against mortality. These findings provide the proof of principle that RhoH reconstitution represents a potential new approach to the treatment of HCL.

  11. Hairy cell leukemia: short review, today's recommendations and outlook

    PubMed Central

    Maevis, V; Mey, U; Schmidt-Wolf, G; Schmidt-Wolf, I G H

    2014-01-01

    Hairy cell leukemia (HCL) is part of the low-grade non-Hodgkin lymphoma family and represents approximately 2% of all leukemias. Treatment with splenectomy and interferon-α historically belonged to the first steps of therapeutic options, achieving partial responses/remissions (PR) in most cases with a median survival between 4 and 6 years in the 1980s. The introduction of the purine analogs (PA) pentostatin and cladribine made HCL a well-treatable disease: overall complete response rates (CRR) range from 76 to 98%, with a median disease-free survival (DFS) of 16 years a normal lifespan can be reached and HCL-related deaths are rare. However, insufficient response to PA with poorer prognosis and relapse rates of 30–40% after 5–10 years of follow-up may require alternative strategies. Minimal residual disease can be detected by additional examinations of bone marrow specimens after treatment with PA. The use of immunotherapeutic monoclonal antibodies (mAB) like rituximab as a single agent or in combination with a PA or more recently clinical trials with recombinant immunotoxins (RIT) show promising results to restrict these problems. Recently, the identification of the possible disease-defining BRAF V600E mutation may allow the development of new therapeutic targets. PMID:24531447

  12. Immunoconjugates in the management of hairy cell leukemia.

    PubMed

    Kreitman, Robert J; Pastan, Ira

    2015-12-01

    Hairy cell leukemia (HCL) is an indolent B-cell malignancy effectively treated but not often cured by purine analog therapy; after multiple courses of purine analogs, patients can become purine analog resistant and in need of alternative therapies. Complete remission to single-agent purine analog is often accompanied by minimal residual disease (MRD), residual HCL cells detectable by immunologic methods, considered a risk factor for eventual relapse. Several different non-chemotherapy approaches are being used to target relapsed and refractory HCL, including inhibitors of BRAF, but so far only monoclonal antibody (MAb)-based approaches have been reported to eliminate MRD in a high percentage of patients. One of the MAb-based options for HCL currently under clinical investigation involves recombinant immunotoxins, containing a fragment of a MAb and a bacterial toxin. The bacterial toxin, a highly potent fragment from Pseudomonas exotoxin, catalytically ADP-ribosylates elongation factor 2 (EF2), resulting in protein synthesis inhibition and apoptotic cell death. Recombinant immunotoxins tested in HCL patients include LMB-2, targeting CD25, and BL22, targeting CD22. An affinity matured version of BL22, termed moxetumomab pasudotox (formerly HA22 or CAT-8015) achieved high CR rates in phase I, and is currently undergoing multicenter Phase 3 testing. Phase I testing was without dose-limiting toxicity, although 2 patients had grade 2 hemolytic uremic syndrome (HUS) with transient grade 1 abnormalities in platelets and creatinine. Preclinical work is underway to identify residues on moxetumomab pasudotox leading to immunogenicity. Moxetumomab pasudotox is undergoing pivotal testing for relapsed and refractory HCL.

  13. Development of hairy cell leukemia in a patient after cardiac transplantation.

    PubMed

    Tsao, Lawrence; Chu, Kimberly E; Bhagat, Govind; Alobeid, Bachir

    2006-02-01

    Post-transplant lymphoproliferative disorders (PTLDs) are well-recognized complications of bone marrow and solid organ transplantation, comprising a heterogenous group of lymphoproliferations with a spectrum of morphologic, phenotypic and molecular features. Although PTLDs are usually Epstein-Barr virus-driven B-cell lymphoproliferations, T/natural killer-cell lymphoproliferations, multiple myeloma, and Hodgkin's lymphoma are also recognized as part of the PTLD spectrum. Hairy cell leukemia, a low-grade B-cell lymphoproliferation, has not been recognized as part of the PTLD spectrum. We report the first case of hairy cell leukemia occurring after cardiac transplantation. It is unclear whether this case, similar to other cases of low-grade B-cell lymphoproliferations reported after transplantation, is related to immunosuppression and therefore part of the spectrum of PTLDs, or merely represents coincidental event occurring in an immunocompromised patient.

  14. Leukemic meningitis in a patient with hairy cell leukemia. A case report

    SciTech Connect

    Wolfe, D.W.; Scopelliti, J.A.; Boselli, B.D.

    1984-09-15

    Central nervous system involvement has not previously been described in patients with hairy cell leukemia (HCL). A patient is reported who presented with meningeal involvement as his initial symptom of HCL. Diagnosis was established by morphologic and cytochemical studies of his cerebrospinal fluid (CSF) and bone marrow. Treatment with whole-brain irradiation and intrathecal chemotherapy was successful in clearing leukemic cells from the CSF with resolution of symptoms.

  15. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia.

    PubMed

    Grever, Michael R; Abdel-Wahab, Omar; Andritsos, Leslie A; Banerji, Versha; Barrientos, Jacqueline; Blachly, James S; Call, Timothy G; Catovsky, Daniel; Dearden, Claire; Demeter, Judit; Else, Monica; Forconi, Francesco; Gozzetti, Alessandro; Ho, Anthony D; Johnston, James B; Jones, Jeffrey; Juliusson, Gunnar; Kraut, Eric; Kreitman, Robert J; Larratt, Loree; Lauria, Francesco; Lozanski, Gerard; Montserrat, Emili; Parikh, Sameer A; Park, Jae H; Polliack, Aaron; Quest, Graeme R; Rai, Kanti R; Ravandi, Farhad; Robak, Tadeusz; Saven, Alan; Seymour, John F; Tadmor, Tamar; Tallman, Martin S; Tam, Constantine; Tiacci, Enrico; Troussard, Xavier; Zent, Clive S; Zenz, Thorsten; Zinzani, Pier Luigi; Falini, Brunangelo

    2017-02-02

    Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.

  16. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia

    PubMed Central

    Abdel-Wahab, Omar; Andritsos, Leslie A.; Banerji, Versha; Barrientos, Jacqueline; Blachly, James S.; Call, Timothy G.; Catovsky, Daniel; Dearden, Claire; Demeter, Judit; Else, Monica; Forconi, Francesco; Gozzetti, Alessandro; Ho, Anthony D.; Johnston, James B.; Jones, Jeffrey; Juliusson, Gunnar; Kraut, Eric; Kreitman, Robert J.; Larratt, Loree; Lauria, Francesco; Lozanski, Gerard; Montserrat, Emili; Parikh, Sameer A.; Park, Jae H.; Polliack, Aaron; Quest, Graeme R.; Rai, Kanti R.; Ravandi, Farhad; Robak, Tadeusz; Saven, Alan; Seymour, John F.; Tadmor, Tamar; Tallman, Martin S.; Tam, Constantine; Tiacci, Enrico; Troussard, Xavier; Zent, Clive S.; Zenz, Thorsten; Zinzani, Pier Luigi; Falini, Brunangelo

    2017-01-01

    Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients. PMID:27903528

  17. High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias.

    PubMed

    Waterfall, Joshua J; Arons, Evgeny; Walker, Robert L; Pineda, Marbin; Roth, Laura; Killian, J Keith; Abaan, Ogan D; Davis, Sean R; Kreitman, Robert J; Meltzer, Paul S

    2014-01-01

    To understand the genetic mechanisms driving variant and IGHV4-34-expressing hairy-cell leukemias, we performed whole-exome sequencing of leukemia samples from ten affected individuals, including six with matched normal samples. We identified activating mutations in the MAP2K1 gene (encoding MEK1) in 5 of these 10 samples and in 10 of 21 samples in a validation set (overall frequency of 15/31), suggesting potential new strategies for treating individuals with these diseases.

  18. [Case with hairy cell leukemia-Japanese variant following radiotherapy for orbital adnexal MALT lymphoma].

    PubMed

    Nakamura, Yuichi; Kayano, Hidekazu; Kakegawa, Emi; Uchida, Yumiko; Shimada, Tsuneyuki; Wakimoto, Naoki; Ito, Yoshihiro; Bessho, Masami

    2010-11-01

    We report a patient with hairy cell leukemia Japanese variant (HCL-Jv) that developed after radiotherapy for orbital adnexal MALT lymphoma. A 78-year-old man was diagnosed as having MALT lymphoma in the left conjunctiva in December 2003. The patient was treated by local radiotherapy and the tumor disappeared. Thereafter, he gradually developed leukocytosis and mild splenomegaly. In May 2009, the leukocyte count was 34,300 with 80% lymphoid cells. A diagnosis of HCL-Jv was made since the lymphoid cells showed a hairy morphology with round nuclei and indistinct nucleoli. These cells expressed CD11c, CD19, CD20, CD103 and showed weak reaction for tartrate-resistant acid phosphatase (TRAP). Bone marrow was infiltrated by atypical cells with an intrasinusoidal pattern. No treatment was needed as the patient was asymptomatic without anemia, thrombocytopenia or lymphadenopathy. Results of the immunoglobulin light chain expression and the heavy chain rearrangement in the tumor cells indicated that the two mature B-lymphoid neoplasms, MALT lymphoma and HCL-Jv, in this patient were derived from independent clones. This appears to be the first reported case of HCL-Jv associated with other lymphoid tumor. Further analysis is needed to clarify the risk of secondary malignancy in HCL-Jv.

  19. Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia

    PubMed Central

    O'Brien, Susan; Jorgensen, Jeffrey; Pierce, Sherry; Faderl, Stefan; Ferrajoli, Alessandra; Koller, Charles; Challagundla, Pramoda; York, Sergernne; Brandt, Mark; Luthra, Rajyalakshmi; Burger, Jan; Thomas, Deborah; Keating, Michael; Kantarjian, Hagop

    2011-01-01

    We conducted this study to determine the feasibility and safety of cladribine followed by rituximab in patients with hairy cell leukemia including the vari-ant form (HCLv). Cladribine 5.6 mg/m2 given IV over 2 hours daily for 5 days was followed ∼ 1 month later with rituximab 375 mg/m2 IV weekly for 8 weeks. Responses were recorded and BM minimal residual disease (MRD) was evaluated after the completion of rituximab. Thirty-six patients have been treated including 5 with HCLv. Median age was 57 years (range, 37-89). All patients (100%) have achieved complete response (CR), defined as presence of no hairy cells in BM and blood with normalization of counts (absolute neutrophil count [ANC]> 1.5 × 109/L, hemoglobin [Hgb] > 12.0 g/dL, platelets [PLT] > 100 × 109/L), as well as resolution of splenomegaly. There were no grade 3 or 4 nonhematologic adverse events directly related to the treatment. Only 1 patient (with HCLv) has relapsed; median CR duration has not been reached (range,1+-63+ months). Three patients with HCLv died including 1 with relapsed disease and 2 from unrelated malignancies. Median survival duration has not been reached (range, 2+-64+ months). Treatment with clad-ribine followed by rituximab is effective tk;4and may increase CR rate. This study was registered at www.clinicaltrials.gov as NCT00412594. PMID:21821712

  20. Hematopoietic Stem Cell Origin of BRAFV600E Mutations in Hairy Cell Leukemia

    PubMed Central

    Chung, Young Rock; Lito, Piro; Teruya-Feldstein, Julie; Hu, Wenhuo; Beguelin, Wendy; Monette, Sebastien; Duy, Cihangir; Rampal, Raajit; Telis, Leon; Patel, Minal; Kim, Min Kyung; Huberman, Kety; Bouvier, Nancy; Berger, Michael F.; Melnick, Ari M.; Rosen, Neal; Tallman, Martin S.

    2014-01-01

    Hairy cell leukemia (HCL) is a chronic lymphoproliferative disorder characterized by somatic BRAFV600E mutations. The malignant cell in HCL has immunophenotypic features of a mature B cell, but no normal counterpart along the continuum of developing B lymphocytes has been delineated as the cell of origin. We find that the BRAFV600E mutation is present in hematopoietic stem cells (HSCs) in HCL patients, and that these patients exhibit marked alterations in hematopoietic stem/progenitor cell (HSPC) frequencies. Quantitative sequencing analysis revealed a mean BRAFV600E-mutant allele frequency of 4.97% in HSCs from HCL patients. Moreover, transplantation of BRAFV600E-mutant HSCs from an HCL patient into immunodeficient mice resulted in stable engraftment of BRAFV600E-mutant human hematopoietic cells, revealing the functional self-renewal capacity of HCL HSCs. Consistent with the human genetic data, expression of BRafV600E in murine HSPCs resulted in a lethal hematopoietic disorder characterized by splenomegaly, anemia, thrombocytopenia, increased circulating soluble CD25, and increased clonogenic capacity of B lineage cells—all classic features of human HCL. In contrast, restricting expression of BRafV600E to the mature B cell compartment did not result in disease. Treatment of HCL patients with vemurafenib, an inhibitor of mutated BRAF, resulted in normalization of HSPC frequencies and increased myeloid and erythroid output from HSPCs. These findings link the pathogenesis of HCL to somatic mutations that arise in HSPCs and further suggest that chronic lymphoid malignancies may be initiated by aberrant HSCs. PMID:24871132

  1. Treatment of hairy cell leukemia: long-term results in a developing country.

    PubMed

    Ruiz-Delgado, Guillermo J; Tarín-Arzaga, Luz C; Alarcón-Urdaneta, Carlos; Calderón-García, Jacqueline; Gómez-Almaguer, David; Ruiz-Argüelles, Guillermo J

    2012-05-01

    Twenty-nine consecutive patients with hairy cell leukemia (HCL) were treated in two institutions with interferon (IFN, n = 18) or cladribine (n = 11), between July 1987 and May 2011. Median age was 62 (range 29-83) years; there were 21 males and 8 females. Seven of the 18 patients in the IFN group (39%) achieved a complete remission (CR), whereas all the patients in the 2-CDA group entered a CR. Three patients in the 2-CDA group relapsed and needed an additional course of the drug, 2, 3 and 6 years after the initial one. The median overall survival (OS) of the whole group has not been reached, being above 217 months, the 217-month OS being 91%. The survival of patients treated with either IFN or 2-CDA was not statistically different (94% OS at 217 months versus 91% OS at 133 months, respectively). The data that we present here suggest that treatment of HCL with either 2-CDA or IFN is equally effective; treatment costs with IFN are substantially lower than those of the purine analog.

  2. Hairy cell leukemia in kidney transplantation: lesson from a rare disorder.

    PubMed

    Vinante, Fabrizio; Tomei, Paola; Zaza, Gianluigi; Zamò, Alberto; Lupo, Antonio

    2013-01-01

    We report here on the diagnosis and successful treatment of a case of hairy cell leukemia (HCL) that arose 15 years after kidney transplantation in a 51-year-old patient. As soon as the diagnosis was made, HCL was treated with 2-CDA, obtaining complete hematological remission. Immunosuppression with the calcineurin inhibitor cyclosporin was maintained, and the graft was preserved. In kidney transplant recipients supported with immunosuppressive drugs, post-transplant lymphoproliferative diseases (PTLDs) are frequent and typically related to immunosuppression via a loss of control of infectious/EBV-related proliferative stimuli. To date, HCL has not been considered among PTLDs. Recently, however, the oncogenic mutation V600E of the BRAF protein kinase has been found to be a hallmark of HCL, and calcineurin inhibitors have been shown to interfere with signaling downstream of V600E BRAF early on by counteracting senescence-associated mechanisms that protect against the oncogenic potential of the mutated kinase. Such a biochemical link between the oncogene-dependent signaling and calcineurin inhibitor activities suggests that HCL in transplanted patients might be a peculiar type of PTLD based on the presence of a specific mutation. This mechanism might also be involved in other neoplasias bearing the same or similar mutations, such as melanoma and non-melanoma skin cancer.

  3. Hairy cell leukemia with translocation (11;20)(q13;q11) and overexpression of cyclin D1.

    PubMed

    Ishida, F; Kitano, K; Ichikawa, N; Ito, T; Kohara, Y; Taniguchi, T; Motokura, T; Kiyosawa, K

    1999-08-01

    We report on a male Japanese patient with hairy cell leukemia (HCL). A cytogenetic study with lipopolysaccharide stimuli showed a novel translocation (11;20)(q13;q11) in 10% of the analyzed cells. Northern blot analysis and RT-PCR analysis for cyclin D1 revealed the overexpression of cyclin D1, although the southern blot analysis of PRAD1 gene showed no rearrangement. In this particular case, the t(11;20)(q13;q11) might play some role in the oncogenesis of HCL and the overexpression of cyclin D1.

  4. T-box-expressed-in-T-cells (T-bet) expression by the tumor cells of hairy-cell leukemia correlates with interferon-gamma production.

    PubMed

    Jöhrens, Korinna; Moos, Verena; Schneider, Thomas; Anagnostopoulos, Ioannis

    2009-10-01

    Hairy cell leukemia (HCL) is an uncommon B-cell malignancy with unknown pathogenesis. In an earlier study, we demonstrated that HCL cells highly express the transcription factor T-box-expressed-in-T-cells (T-bet). T-bet is the master regulator of the T-helper (Th)1 cell response regulating interferon gamma (IFN-gamma) production and also plays a central role in the T-cell independent Th1-like B-cell response. Here, we demonstrate by fluorescence activated cell sorting (FACS) analysis that neoplastic cells from the peripheral blood of five patients with HCL showed an enhanced expression of IFN-gamma after stimulation. Additionally, a comparison with 55 healthy individuals revealed a significant elevation of IFN-gamma in the sera of patients with HCL. Based on our recent findings that a non-neoplastic B-cell subset, the monocytoid B-cells, are T-bet positive and produce IFN-gamma, we propose that monocytoid and hairy B-cells have a similar function and that the T-bet-IFN-gamma axis is involved in the pathogenesis of HCL.

  5. Indium 111-labeled platelet kinetic studies and platelet-associated IgG in hairy cell leukemia

    SciTech Connect

    Panzer, S.; Lechner, K.; Neumann, E.; Meryn, S.; Haubenstock, A.

    1986-07-15

    In order to study the pathogenesis of thrombocytopenia in patients with hairy cell leukemia (HCL), levels of platelet-associated IgG (PAIgG), platelet life span (MLS), and the sequestration site of autologous /sup 111/In-labeled platelets were measured in nine patients with HCL. Splenectomized patients (n = 4) had a higher platelet count (x = 122.5 X 10(9)/l; range, 80-190 X 10(9)/l) as well as higher levels of PAIgG (x = 10.7%; range, 5.8-16.9%), than nonsplenectomized patients (platelets x = 76 X 10(9)/l, range 40-100 X 10(9)/l; PAIgG x = 3.2%, range 2.2-4.2%). A normal recovery of /sup 111/In-labeled platelets was found in splenectomized patients, whereas a very low recovery was observed in the nonsplenectomized group (x = 70.2%, range, 50-82.5%, versus x = 22.4%, range, 15-28.2%). The MLS was borderline normal in all patients. The site of sequestration was the spleen in nonsplenectomized patients. The low recovery of /sup 111/In-labeled platelets in nonsplenectomized patients suggests hypersplenism with pooling as a major cause of thrombocytopenia, in addition to impaired thrombocytopoiesis and possible immune-mediated platelet destruction.

  6. A comprehensive immunophenotypic marker analysis of hairy cell leukemia in paraffin-embedded bone marrow trephine biopsies--a tissue microarray study.

    PubMed

    Tóth-Lipták, Judit; Piukovics, Klára; Borbényi, Zita; Demeter, Judit; Bagdi, Enikő; Krenács, László

    2015-01-01

    Hairy cell leukemia (HCL) is an uncommon B cell lymphoproliferation characterized by a unique immunophenotype. Due to low number of circulating neoplastic cells and 'dry tap' aspiration, the diagnosis is often based on BM trephine biopsy. We have performed a consecutive immunohistochemical analysis to evaluate diagnostic usefulness of various HCL markers (CD11c, CD25, CD68, CD103, CD123, CD200, annexin A1, cyclin D1, DBA.44, HBME-1, phospho-ERK1/2, TRAP, and T-bet) currently available against fixation resistant epitopes. We analyzed tissue microarrays consisting of samples gained from 73 small B-cell lymphoma cases, including hairy cell leukemia (HCL) (n = 32), HCL variant (HCL-v) (n = 4), B-cell chronic lymphocytic leukemia (B-CLL) (n = 11), lymphoplasmacytic lymphoma (LPL) (n = 3), mantle cell lymphoma (MCL) (n = 10), splenic diffuse red pulp small B cell lymphoma (SDRPL) (n = 2), splenic B cell marginal zone lymphoma (SMZL) (n = 8), and splenic B cell lymphoma/leukemia, unclassifiable (SBCL) (n = 3) cases. The HCL cases were 100% positive for all but 2 (DBA.44 and CD123) of these markers. Annexin A1 showed 100% specificity and accuracy, which was followed by CD123, pERK, CD103, HBME-1, CD11c, CD25, CD68, cyclin D1, CD200, T-bet, DBA.44, and TRAP, in decreasing order. In conclusion, our results reassured the high specificity of annexin A1 and pERK, as well as the diagnostic value of standard HCL markers of CD11c, CD25, CD103, and CD123 also in paraffin-embedded BM samples. Additional markers, including HBME-1, cyclin D1, CD200, and T-bet also represent valuable tools in the differential diagnosis of HCL and its mimics.

  7. Leukemia

    MedlinePlus

    ... exist, including hairy cell leukemia, myelodysplastic syndromes and myeloproliferative disorders. Factors that may increase your risk of developing some types of leukemia include: Previous cancer treatment. People who've had certain types of ...

  8. Hairy cell leukemia

    MedlinePlus

    ... LE, Heslop HE, Weitz JI, Anastasi J, eds. Hematology: Basic Principles and Practice . 6th ed. Philadelphia, PA: ... 5/20/2016 Updated by: Todd Gersten, MD, Hematology/Oncology, Florida Cancer Specialists & Research Institute, Wellington, FL. ...

  9. Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior.

    PubMed

    Forconi, Francesco; Sozzi, Elisa; Cencini, Emanuele; Zaja, Francesco; Intermesoli, Tamara; Stelitano, Caterina; Rigacci, Luigi; Gherlinzoni, Filippo; Cantaffa, Renato; Baraldi, Anna; Gallamini, Andrea; Zaccaria, Alfonso; Pulsoni, Alessandro; Gobbi, Marco; Tassi, Maristella; Raspadori, Donatella; Leoncini, Lorenzo; Rinaldi, Andrea; Sabattini, Elena; Bertoni, Francesco; Pileri, Stefano A; Lauria, Francesco

    2009-11-19

    Hairy cell leukemia (HCL) is generally responsive to single-agent cladribine, and only a minority of patients are refractory and with poor prognosis. HCLs generally express mutated (M) and, in a minority, unmutated (UM) IGHV. In a multicenter clinical trial in newly diagnosed HCL, we prospectively investigated clinical and molecular parameters predicting response and event-free survival after single-agent cladribine. Of 58 HCLs, 6 expressed UM-IGHV (UM-HCL) and 52 M-IGHV (M-HCL). Beneficial responses were obtained in 53 of 58 patients (91%), whereas treatment failures were observed in 5 of 58 patients (9%). Failures were associated significantly with UM-IGHV (5 of 5 failures vs 1 of 53 beneficial responses had UM-IGHV, P < .001), leukocytosis (3 of 5 vs 3 of 53, P = .006), and bulky spleen (4 of 5 vs 4 of 53, P < .001). The UM-HCL not benefiting from cladribine characteristically had bulky spleen (4 of 5, 80%), leukocytosis (3 of 5, 60%), and TP53 defects (2 of 5, 40%), and progressed rapidly after first treatment (median event-free survival, 7.5 months). Our data suggest that UM-HCLs identify the minor subgroup failing cladribine treatment and with more aggressive disease. High incidence of TP53 dysfunction indicates a potential mechanism of resistance to cladribine in the UM-HCL group. Overall, our data provide new molecular elements relevant for treatment concerns in HCL.

  10. Medical History, Lifestyle, and Occupational Risk Factors for Hairy Cell Leukemia: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

    PubMed Central

    Slager, Susan L.; Hughes, Ann Maree; Smith, Alex; Glimelius, Bengt; Habermann, Thomas M.; Berndt, Sonja I.; Staines, Anthony; Norman, Aaron D.; Cerhan, James R.; Sampson, Joshua N.; Morton, Lindsay M.; Clavel, Jacqueline

    2014-01-01

    Background Little is known about the etiology of hairy cell leukemia (HCL), a rare B-cell lymphoproliferative disorder with marked male predominance. Our aim was to identify key risk factors for HCL. Methods A pooled analysis of individual-level data for 154 histologically confirmed HCL cases and 8834 controls from five case–control studies, conducted in Europe and Australia, was undertaken. Age-, race and/or ethnicity-, sex-, and study-adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression. Results The usual patterns for age and sex in HCL were observed, with a median age of 55 years and sex ratio of 3.7 males to females. Cigarette smoking was inversely associated with HCL (OR = 0.51, 95% CI = 0.37 to 0.71) with dose–response relationships observed for duration, frequency, and lifetime cigarette smoking (P trend < .001). In contrast, occupation as a farmer was positively associated with HCL (OR = 2.34, 95% CI = 1.36 to 4.01), with a dose–response relationship observed for duration (OR = 1.82, 95% CI = 0.85 to 3.88 for ≤10 years vs never; and OR = 2.98, 95% CI = 1.50 to 5.93 for >10 years vs never; P trend = .025). Adult height was also positively associated with HCL (OR = 2.69, 95% CI = 1.39 to 5.29 for upper vs lower quartile of height). The observed associations remained consistent in multivariate analysis. Conclusions Our observations of an increased risk of HCL from farming exposures and decreased risk from smoking exposures, independent of one another, support a multifactorial origin and an etiological specificity of HCL compared with other non-Hodgkin lymphoma subtypes. The positive association with height is a novel finding that needs replication. PMID:25174032

  11. Requisite analytic and diagnostic performance characteristics for the clinical detection of BRAF V600E in hairy cell leukemia: a comparison of 2 allele-specific PCR assays.

    PubMed

    Brown, Noah A; Weigelin, Helmut C; Bailey, Nathanael; Laliberte, Julie; Elenitoba-Johnson, Kojo S J; Lim, Megan S; Betz, Bryan L

    2015-09-01

    Detection of high-frequency BRAF V600E mutations in hairy cell leukemia (HCL) has important diagnostic utility. However, the requisite analytic performance for a clinical assay to routinely detect BRAF V600E mutations in HCL has not been clearly defined. In this study, we sought to determine the level of analytic sensitivity needed for formalin-fixed, paraffin-embedded (FFPE) and frozen samples and to compare the performance of 2 allele-specific polymerase chain reaction (PCR) assays. Twenty-nine cases of classic HCL, including 22 FFPE bone marrow aspirates and 7 frozen specimens from blood or bone marrow were evaluated using a laboratory-developed allele-specific PCR assay and a commercially available allele-specific quantitative PCR assay-myT BRAF Ultra. Also included were 6 HCL variant and 40 non-HCL B-cell lymphomas. Two cases of classic HCL, 1 showing CD5 expression, were truly BRAF V600E-negative based on negative results by PCR and sequencing despite high-level leukemic involvement. Among the remaining 27 specimens, V600E mutations were detected in 88.9% (17/20 FFPE; 7/7 frozen) and 81.5% (15/20 FFPE; 7/7 frozen), for the laboratory-developed and commercial assays, respectively. No mutations were detected among the 46 non-HCL lymphomas. Both assays showed an analytic sensitivity of 0.3% involvement in frozen specimens and 5% in FFPE tissue. On the basis of these results, an assay with high analytic sensitivity is required for the clinical detection of V600E mutations in HCL specimens. Two allele-specific PCR assays performed well in both frozen and FFPE bone marrow aspirates, although detection in FFPE tissue required 5% or more involvement.

  12. The Droplet Digital PCR: A New Valid Molecular Approach for the Assessment of B-RAF V600E Mutation in Hairy Cell Leukemia

    PubMed Central

    Guerrini, Francesca; Paolicchi, Matteo; Ghio, Francesco; Ciabatti, Elena; Grassi, Susanna; Salehzadeh, Serena; Ercolano, Giacomo; Metelli, Maria R.; Del Re, Marzia; Iovino, Lorenzo; Petrini, Iacopo; Carulli, Giovanni; Cecconi, Nadia; Rousseau, Martina; Cervetti, Giulia; Galimberti, Sara

    2016-01-01

    Hairy cell leukemia (HCL) is a chronic lymphoproliferative B-cell disorder where the B-RAF V600E mutation has been recently detected, as reported for solid neoplasias but not for other B-cell lymphomas. The digital droplet PCR (dd-PCR) is a molecular technique that, without standard references, is able to accurately quantitate DNA mutations. ddPCR could be an useful instrument for the detection of the B-RAF V600E mutation in HCL, where the minimal residual disease monitoring is fundamental for planning a patients-targeted treatment in the era of new anti-CD20 and anti-RAF compounds. This retrospective study enrolled 47 patients observed at the Hematology Unit of the University of Pisa, Italy, from January 2005 to January 2014: 27 patients were affected by “classic” HCL, two by the variant HCL (vHCL), and 18 by splenic marginal zone lymphoma (SMZL). The aim of the study was to compare dd-PCR to “classic” quantitative PCR (QT-PCR) in terms of sensitivity and specificity and to demonstrate its possible use in HCL. Results showed that: (1) the sensitivity of dd-PCR is about half a logarithm superior to QT-PCR (5 × 10-5 vs. 2.5 × 10-4), (2) the specificity of the dd-PCR is comparable to QT-PCR (no patient with marginal splenic lymphoma or HCL variant resulted mutated), (3) its high sensitivity would allow to use dd-PCR in the monitoring of MRD. At the end of treatment, among patients in complete remission, 33% were still MRD-positive by dd-PCR versus 28% by QT-PCR versus 11% by the evaluation of the B-cell clonality, after 12 months, dd-PCR was comparable to QT-PCR and both detected the B-RAF mutation in 15% of cases defined as MRD-negative by IgH rearrangement. Moreover, (4) the feasibility and the costs of dd-PCR are comparable to those of QT-PCR. In conclusion, our study supports the introduction of dd-PCR in the scenario of HCL, also during the follow-up. PMID:27790140

  13. The Droplet Digital PCR: A New Valid Molecular Approach for the Assessment of B-RAF V600E Mutation in Hairy Cell Leukemia.

    PubMed

    Guerrini, Francesca; Paolicchi, Matteo; Ghio, Francesco; Ciabatti, Elena; Grassi, Susanna; Salehzadeh, Serena; Ercolano, Giacomo; Metelli, Maria R; Del Re, Marzia; Iovino, Lorenzo; Petrini, Iacopo; Carulli, Giovanni; Cecconi, Nadia; Rousseau, Martina; Cervetti, Giulia; Galimberti, Sara

    2016-01-01

    Hairy cell leukemia (HCL) is a chronic lymphoproliferative B-cell disorder where the B-RAF V600E mutation has been recently detected, as reported for solid neoplasias but not for other B-cell lymphomas. The digital droplet PCR (dd-PCR) is a molecular technique that, without standard references, is able to accurately quantitate DNA mutations. ddPCR could be an useful instrument for the detection of the B-RAF V600E mutation in HCL, where the minimal residual disease monitoring is fundamental for planning a patients-targeted treatment in the era of new anti-CD20 and anti-RAF compounds. This retrospective study enrolled 47 patients observed at the Hematology Unit of the University of Pisa, Italy, from January 2005 to January 2014: 27 patients were affected by "classic" HCL, two by the variant HCL (vHCL), and 18 by splenic marginal zone lymphoma (SMZL). The aim of the study was to compare dd-PCR to "classic" quantitative PCR (QT-PCR) in terms of sensitivity and specificity and to demonstrate its possible use in HCL. Results showed that: (1) the sensitivity of dd-PCR is about half a logarithm superior to QT-PCR (5 × 10(-5) vs. 2.5 × 10(-4)), (2) the specificity of the dd-PCR is comparable to QT-PCR (no patient with marginal splenic lymphoma or HCL variant resulted mutated), (3) its high sensitivity would allow to use dd-PCR in the monitoring of MRD. At the end of treatment, among patients in complete remission, 33% were still MRD-positive by dd-PCR versus 28% by QT-PCR versus 11% by the evaluation of the B-cell clonality, after 12 months, dd-PCR was comparable to QT-PCR and both detected the B-RAF mutation in 15% of cases defined as MRD-negative by IgH rearrangement. Moreover, (4) the feasibility and the costs of dd-PCR are comparable to those of QT-PCR. In conclusion, our study supports the introduction of dd-PCR in the scenario of HCL, also during the follow-up.

  14. Supportive Care for Chronic Lymphocytic Leukemia

    MedlinePlus

    ... Chronic Lymphocytic Leukemia Supportive Care for Chronic Lymphocytic Leukemia Supportive care for chronic lymphocytic leukemia (CLL) is ... Treating Hairy Cell Leukemia More In Chronic Lymphocytic Leukemia About Chronic Lymphocytic Leukemia Causes, Risk Factors, and ...

  15. Monoclonal antibody HBME-1 reacts with a minor subset of B cells with villous surface and can be useful in the diagnosis of hairy cell leukemia and other indolent lymphoproliferations of villous B lymphocytes.

    PubMed

    Krenács, László; Tóth-Lipták, Judit; Demeter, Judit; Piukovics, Klára; Borbényi, Zita; Gogolák, Péter; Sári, Eszter; Bagdi, Enikő

    2013-12-01

    The Hector Battifora mesothelial epitope-1 (HBME-1) monoclonal antibody has been generated against human mesothelioma cells and recognizes a biochemically unknown membrane epitope. We have accidentally found that the HBME-1 reacts with scattered lymphocytes showing villous surface in hyperplastic lymphoid tissue. To evaluate its reactivity pattern, we have performed a consecutive immunohistochemical study in nonneoplastic bone marrow and lymphoid samples (n = 40), as well as in malignant lymphoproliferations (n = 427), including hairy cell leukemia (HCL) (n = 72), HCL variant (HCL-v) (n = 13), splenic diffuse red pulp small B cell lymphoma (SDRPL) (n = 8), splenic B cell marginal zone lymphoma (SMZL) (n = 59), and splenic B cell lymphoma/leukemia, not further classifiable on bone marrow morphology (SBCL) (n = 37) cases. The staining pattern of HBME-1 was compared to DBA.44. HBME-1(+) villous lymphocytes were constantly detected in low number in nonneoplastic lymphoid tissues. With multicolor immunofluorescence staining, HBME-1(+) lymphocytes showed a CD20(+)/CD79a(+)/IgM(+) B cell phenotype. In B cell lymphoproliferations of villous lymphocytes, HBME-1 reactivity was demonstrated in 96 % of HCL, 39 % of HCL-v, 50 % of SDRPL, 12 % of SMZL, and 19 % of SBCL cases. Nodal and extranodal marginal zone lymphoma cases were positive in 12 % of the cases. A small minority (4 %) of the other B cell lymphomas and no T cell lymphoma revealed tumor cell reactivity with HBME-1. In conclusion, our study has established that HBME-1 reacts with a minor subset of B lymphocytes and a small proportion of B cell lymphomas, which has not been described previously. We suggest that HBME-1 can be a useful marker in the diagnosis of HCL and other indolent lymphoproliferations of villous B lymphocytes.

  16. Treatment of Chronic Lymphocytic Leukemia by Risk Group

    MedlinePlus

    ... Chronic Lymphocytic Leukemia Typical Treatment of Chronic Lymphocytic Leukemia Treatment options for chronic lymphocytic leukemia (CLL) vary ... Treating Hairy Cell Leukemia More In Chronic Lymphocytic Leukemia About Chronic Lymphocytic Leukemia Causes, Risk Factors, and ...

  17. Occupational exposure to solvents and hairy cell leukaemia

    PubMed Central

    Clavel, J.; Mandereau, L.; Conso, F.; Limasset, J. C.; Pourmir, I.; Flandrin, G.; Hemon, D.

    1998-01-01

    OBJECTIVES: The role of occupational exposures in hairy cell leukaemia was investigated through a multicentre, hospital based, case-control study. This paper analyses the role of exposure to solvents other than benzene in hairy cell leukaemia. METHODS: The study included 226 male cases and 425 matched controls, exposure to solvents was evaluated by expert case by case review of the detailed data on occupational exposures generated by specific interviews. Also, exposure to solvents was evaluated with an independently constructed job exposure matrix (JEM). RESULTS: No association was found between hairy cell leukaemia and previous employment in a job exposed to solvents (odds ratio (OR) 0.9 95% confidence interval (95% CI) 0.6 to 1.3). ORs for the main occupational tasks exposed to solvents were around 1 and did not increase with the frequency or the duration of the tasks. No specific type of paint or glue was found to be significantly associated with hairy cell leukaemia. No association was found with exposure to solvents, taken as a whole, with either expert assessments or the JEM. No association was found with aromatic, chlorinated, or oxygenated subgroups of solvents. The ORs did not increase with the average intensity of exposure assessed by the experts, with the frequency of use, or with the duration of exposure. Finally, no association was found with non-occupational exposure to solvents. CONCLUSIONS: The study did not show any association between exposure to solvents and hairy cell leukaemia.   PMID:9536165

  18. [Acute plasma cell leukemia].

    PubMed

    Monsalbe, V; Domíngues, C; Roa, I; Busel, D; González, S

    1989-01-01

    Plasma Cell Leukemia is a very rare form of plasmocytic dyscrasia, whose clinical and pathological characteristics warrant its recognition as a distinct subentity. We report the case of a 60 years old man who presented a rapidly fatal acute plasma cell leukemia, with multiple osteolytic lesions, hipercalcemia, renal and cardiac failure.

  19. Leukemia

    MedlinePlus

    ... version of this page please turn Javascript on. Leukemia What Is Leukemia? Leukemia is a cancer of the blood cells. ... diagnosed with leukemia are over 50 years old. Leukemia Starts in Bone Marrow Click for more information ...

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

    ClinicalTrials.gov

    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

  1. Childhood Leukemia--A Look at the Past, the Present and the Future.

    ERIC Educational Resources Information Center

    Findeisen, Regina; Barber, William H.

    1997-01-01

    Provides an overview of childhood leukemia. The causes, the survival period, different types (acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia), symptoms, treatment, side effects of treatment (including learning problems), and the expected future direction of…

  2. Donor cell leukemia.

    PubMed

    Ruiz-Arguelles, Alejandro

    2012-04-01

    Minimal residual disease refers to the tumour cells that are still present in a given patient after completion of a therapeutic scheme. The demonstration and quantification of residual neoplastic cells has a crucial impact in clinical decision making, for it might prompt continuation of treatment, while the absence of such cells might serve as evidence to withdraw therapy. Therefore, both sensitivity and specificity of the methods used to unravel residual neoplastic cells must be highly reliable and robust. Flow cytometry has been widely used for this purpose, and its clinical performance depends mainly on the criteria of interpretation, rather than in the technique by itself; molecular biology techniques have proved to be highly sensitive and specific but unfortunately they cannot be used in all patients or in all types of leukemia. Finally, the development of donor cell leukemia in transplanted patients, might mimic residual disease and add more confusion to an already controversial issue. These topics are discussed in this paper.

  3. [1 alpha(OH) D3 (Alfarol) is effective for the treatment of chronic B cell leukemia: a case report].

    PubMed

    Hashimoto, E; Takeuchi, H; Saitou, M; Hirashima, K

    1989-10-01

    We reported a case of chronic B-cell leukemia reacted to the administration of 1 alpha (OH)D3 (Alfarol-CHUGAI Pharm. Co.), The patient showed pancytopenia with IgM-kappa type monoclonal protein in the serum. The bone marrow aspiration was failed due to a dry tap, but the biopsied specimen showed a marked infiltration of small sized lymphoid cells with wide cytoplasm. The leukemic cells from peripheral blood showed a morphology of atypical hairy cells, Surface markers of the leukemic cells were IgM, D(kappa)+, CD 19+, CD 20+, CD 21- and HLADR+, The leukemic cells showed no L-tartrate resistant acid phosphatase sensitivity. This case was diagnosed as a chronic B-cell leukemia closely related to a hairy cell leukemia. The treatment with estrogen-chlorambucil compound (Bestrabucil-KUREHA Chem, Co.) or splenic irradiation was not effective. However, after two months' administration of Alfarol the regular blood transfusion was not needed because of increment of the Hb concentration. After eight months of its administration, the bone marrow aspirate showed a marked decrease in the number of the leukemic cells and a restoration of normal hematopoietic cells. This experience suggested that Alfarol in usefull for the treatment of chronic B cell leukemia including hairy cell leukemia and chronic lymphocytic leukemia.

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

    ClinicalTrials.gov

    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

  5. MK2206 in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Leukemia

    ClinicalTrials.gov

    2014-04-28

    Accelerated Phase Chronic Myelogenous Leukemia; Acute Leukemias of Ambiguous Lineage; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder; Acute Undifferentiated Leukemia; Aggressive NK-cell Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Blastic Plasmacytoid Dendritic Cell Neoplasm; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Intraocular Lymphoma; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Myeloid/NK-cell Acute Leukemia; Noncutaneous Extranodal Lymphoma; Post-transplant Lymphoproliferative Disorder; Primary Central Nervous System Hodgkin Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Unspecified Childhood

  6. PLASMA CELL LEUKEMIA

    PubMed Central

    de Larrea, Carlos Fernandez; Kyle, Robert A.; Durie, Brian GM; Ludwig, Heinz; Usmani, Saad; Vesole, David H.; Hajek, Roman; Miguel, Jésus San; Sezer, Orhan; Sonneveld, Pieter; Kumar, Shaji K.; Mahindra, Anuj; Comenzo, Ray; Palumbo, Antonio; Mazumber, Amitabha; Anderson, Kenneth C.; Richardson, Paul G.; Badros, Ashraf Z.; Caers, Jo; Cavo, Michele; LeLeu, Xavier; Dimopoulos, Meletios A.; Chim, CS; Schots, Rik; Noeul, Amara; Fantl, Dorotea; Mellqvist, Ulf-Henrik; Landgren, Ola; Chanan-Khan, Asher; Moreau, Philippe; Fonseca, Rafael; Merlini, Giampaolo; Lahuerta, JJ; Bladé, Joan; Orlowski, Robert Z.; Shah, Jatin J.

    2014-01-01

    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-pathologic 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 diagnosis be reexamined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem-cell transplantation (HDT/ASCT) if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL. PMID:23288300

  7. Entospletinib and Obinutuzumab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2017-03-24

    Anemia; B-Cell Prolymphocytic Leukemia; Fatigue; Fever; Grade 1 Follicular Lymphoma; Grade 2 Follicular Lymphoma; Grade 3a Follicular Lymphoma; Hairy Cell Leukemia; Lymphadenopathy; Lymphocytosis; Lymphoplasmacytic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Night Sweats; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma; Richter Syndrome; Splenomegaly; Thrombocytopenia; Weight Loss

  8. Leukemia

    MedlinePlus

    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. ...

  9. Immune phenotype and some enzyme patterns in phorbol ester-induced chronic lymphocytic leukemia cells.

    PubMed

    Babusíková, O; Mesárosová, A; Kusenda, J; Koníková, E; Klobusická, M; Hrivnáková, A

    1995-01-01

    Leukemic cells from 10 patients with B-chronic lymphocytic leukemia (B-CLL) were isolated and cultured in the presence of 12-0-tetradecanoylphorbol 13-acetate (TPA) at a concentration of 8 x 10(-7) mol for 72 hours. Cells were analyzed before cultivation and after 72 h of cultivation with and without TPA for changes in surface membrane (Sm) and cytoplasmic (cyt) markers expression, presence of receptor for mouse rosette forming cells (MRFC) and some enzyme profiles. All B-CLL cases studied showed typical B-cell phenotype. TPA treatment induced hairy cell leukemia (HCL) characteristics, given by the membrane CD22 and CD25 expression and TRAP positivity in the majority of the cases tested. Cells had hairy cell-like morphology with more intensive cytoplasmic immunoglobulin (CIg) fluorescence staining, absent receptor for MRFC and increased activity of purine nucleosidephosphorylase. In common these changes indicate that TPA can induce hairy cell characteristics on B-CLL cells in vitro suggesting the more mature differentiation stage of HCL compared with CLL. Furthermore, we originally demonstrated that the CD22, present in the cell membrane after TPA, could be detected in the majority of unaffected B-CLL cells in their cytoplasm. From the technical point of view some intracellular CD markers and Igs of B-CLL cells in viable cells in suspension assayed by flow cytometry are described in this study.

  10. Plasma cell leukemia.

    PubMed

    Albarracin, Flavio; Fonseca, Rafael

    2011-05-01

    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 splenomegaly. The diagnostic evaluation of a patient with suspected PCL should include a review of the peripheral blood smear, bone marrow aspiration and biopsy, serum protein electrophoresis (SPEP) with immunofixation, and protein electrophoresis of an aliquot from a 24h urine collection (UPEP). The diagnosis is made when a monoclonal population of PCs is present in the peripheral blood with an absolute PC count exceeding 2000/μL and PC comprising 20% or more of the peripheral blood white cells. The prognosis of PCL is poor with a median survival of 7 to 11 months. Survival is even shorter (2 to 7 months) when PCL occurs in the context of refractory or relapsing MM. There have been no prospective randomized trials investigating the treatment of PCL. Recommendations are primarily based upon data from small retrospective series, case reports, and extrapolation of data from patients with MM. In general, patients are treated with induction therapy followed by hematopoietic cell transplantation (HCT) in those who are appropriate candidates for this approach. The best induction regimen for PCL is not known and there is great variability in clinical practice. Newer agents that are being incorporated into frontline and salvage therapy for MM have also demonstrated activity in PCL such as Immunomodulatory agents and the use of bortezomib with different combinations.

  11. Plasma cell leukemia

    PubMed Central

    Albarracin, Flavio; Fonseca, Rafael

    2014-01-01

    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 splenomegaly. The diagnostic evaluation of a patient with suspected PCL should include a review of the peripheral blood smear, bone marrow aspiration and biopsy, serum protein electrophoresis (SPEP) with immunofixation, and protein electrophoresis of an aliquot from a 24h urine collection (UPEP). The diagnosis is made when a monoclonal population of PCs is present in the peripheral blood with an absolute PC count exceeding 2000/μL and PC comprising 20% or more of the peripheral blood white cells. The prognosis of PCL is poor with a median survival of 7 to 11 months. Survival is even shorter (2 to 7 months) when PCL occurs in the context of refractory or relapsing MM. There have been no prospective randomized trials investigating the treatment of PCL. Recommendations are primarily based upon data from small retrospective series, case reports, and extrapolation of data from patients with MM. In general, patients are treated with induction therapy followed by hematopoietic cell transplantation (HCT) in those who are appropriate candidates for this approach. The best induction regimen for PCL is not known and there is great variability in clinical practice. Newer agents that are being incorporated into frontline and salvage therapy for MM have also demonstrated activity in PCL such as Immunomodulatory agents and the use of bortezomib with different combinations. PMID:21295388

  12. Hairy cell leukaemia and occupational exposure to benzene.

    PubMed Central

    Clavel, J; Conso, F; Limasset, J C; Mandereau, L; Roche, P; Flandrin, G; Hémon, D

    1996-01-01

    OBJECTIVES: The role of occupational exposures in hairy cell leukaemia (HCL) was investigated through a multicentre, hospital based, case-control study. This paper analyses the role of exposure to benzene in HCL. METHODS: A population of 226 male cases of HCL and 425 matched controls were included in the study. Benzene exposure was evaluated by expert review of the detailed data on occupational exposures generated by case-control interviews. RESULTS: No association was found between HCL and employment in a job exposed to benzene (odds ratio (OR) 0.9 (95% confidence interval (95% CI) 0.6-1.3)). The sample included 125 subjects, 34 cases (15%), and 91 controls (21%) who had been exposed to benzene, as individually assessed by the experts, for at least one hour a month during one of their jobs. Benzene exposure was not associated with a risk of HCL (OR 0.8 (0.5-1.2)). No trend towards an increase in OR was detected for increasing exposures, the percentage of work time involving exposure to > 1 ppm, or the duration of exposure. No findings suggested a particular risk period, when the OR associated with the time since first or last exposure, or since the end of exposure, were examined. CONCLUSIONS: In conclusion, with the low exposures prevalent in the sample, the study did not show any association between benzene exposure and HCL. PMID:8983464

  13. 64 FR 30349 - Prospective Grant of Exclusive License: Drug and Method for the Therapeutic Treatment of Leukemia...

    Federal Register 2010, 2011, 2012, 2013, 2014

    1999-06-07

    ... the Therapeutic Treatment of Leukemia, Lymphoma, Hair Cell Leukemia, Hodgkin's Disease and Other..., Hodgkin's disease and other hematologic malignancies and for the treatment of Graft-versus-Host Disease... the therapeutic treatment of refractory Leukemia, Lymphoma, Hairy Cell Leukemia, Hodgkin's disease...

  14. Expression of an accessory cell phenotype by hairy cells during lymphocyte colony formation in agar culture.

    PubMed

    Farcet, J P; Gourdin, M F; Testa, U; Andre, C; Jouault, H; Reyes, F

    1983-01-01

    Human T lymphocytes require the cooperation of accessory cells to generate lymphocyte colonies in agar culture under PHA stimulation. Various hairy cell enriched fractions, as well as normal monocytes, have been found to be able to initiate colony formation by normal lymphocytes. Leukemic monocytes from CMML patients were also effective, but not the leukemic lymphocytes from CLL patients. The phenotype expressed by HC in agar colonies was further studied using cell surface and enzymatic markers. We have concluded that HC in agar culture in the presence of both normal T lymphocytes and PHA lose the B phenotype that they express in vivo and function like an accessory cell in contrast to normal or leukemic B lymphocytes.

  15. Protein hairy enhancer of split-1 expression during differentiation of muscle-derived stem cells into neuron-like cells.

    PubMed

    Huang, Mina; Guo, Zhanpeng; Liu, Kun; Mei, Xifan; Fang, Shiqiang; Zeng, Jinhao; Wang, Yansong; Yuan, Yajiang

    2012-10-05

    Muscle-derived stem cells were isolated from the skeletal muscle of Sprague-Dawley neonatal rats aged 3 days old. Cells at passage 5 were incubated in Dulbecco's modified Eagle's medium supplemented with 10% (v/v) fetal bovine serum, 20 μg/L nerve growth factor, 20 μg/L basic fibroblast growth factor and 1% (v/v) penicillin for 6 days. Cells presented with long processes, similar to nerve cells. Connections were formed between cell processes. Immunocytochemical staining with neuron specific enolase verified that cells differentiated into neuron-like cells. Immunofluorescence cytochemistry and western blot results revealed that the expression of protein hairy enhancer of split-1 was significantly reduced. These results indicate that low expression of protein hairy enhancer of split-1 participates in the differentiation of muscle-derived stem cells into neuron-like cells.

  16. Selective T-Cell Depletion to Reduce GVHD (Patients) Receiving Stem Cell Tx to Treat Leukemia, Lymphoma or MDS

    ClinicalTrials.gov

    2016-09-21

    Graft vs Host Disease; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myelomonocytic, Chronic; Leukemia, Lymphocytic; Lymphoma; Lymphoma, Mantle-cell; Lymphoma, Non-Hodgkin; Hodgkin Disease

  17. Cordycepin disrupts leukemia association with mesenchymal stromal cells and eliminates leukemia stem cell activity

    PubMed Central

    Liang, Shu-Man; Lu, Yi-Jhu; Ko, Bor-Sheng; Jan, Yee-Jee; Shyue, Song-Kun; Yet, Shaw-Fang; Liou, Jun-Yang

    2017-01-01

    Maintaining stemness of leukemic stem cells (LSCs) and reciprocal interactions between leukemia and stromal cells support leukemic progression and resistance to chemotherapy. Targeting the niche-based microenvironment is thus a new approach for leukemia therapy. Cordycepin is an analogue of adenosine and has been suggested to possess anti-leukemia properties. However, whether cordycepin influences association of leukemia and mesenchymal stromal cells has never been investigated. Here we show that cordycepin reduces CD34+CD38− cells in U937 and K562 cells and induces Dkk1 expression via autocrine and paracrine regulation in leukemia and mesenchymal stromal/stem cells (MSCs). Cordycepin suppresses cell attachment of leukemia with MSCs and downregulates N-cadherin in leukemia and VCAM-1 in MSCs. Moreover, incubation with leukemic conditioned media (CM) significantly induces IL-8 and IL-6 expression in MSCs, which is abrogated by cordycepin. Suppression of leukemic CM-induced VCAM-1 and IL-8 by cordycepin in MSCs is mediated by impairing NFκB signaling. Finally, cordycepin combined with an adenosine deaminase inhibitor prolongs survival in a leukemic mouse model. Our results indicate that cordycepin is a potential anti-leukemia therapeutic adjuvant via eliminating LSCs and disrupting leukemia-stromal association. PMID:28266575

  18. Lenalidomide With or Without Rituximab in Treating Patients With Progressive or Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Prolymphocytic Leukemia, or Non-Hodgkin Lymphoma Previously Treated With Donor Stem Cell Transplant

    ClinicalTrials.gov

    2014-04-03

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

  19. Sensory Cells of the Fish Ear: A Hairy Enigma

    NASA Technical Reports Server (NTRS)

    Popper, A. N.; Saidel, W. M.

    1995-01-01

    Analysis of the structure of the ears in teleost fishes has led to the tentative suggestion that otolithic endorgans may function differently, in different species. Recently, evidence has demonstrated different 'types' of sensory hair cells can be found in the ears of teleost fishes, and individual hair cell types are found in discrete regions of individual sensory, epithelia. The presence of multiple hair cell types in fishes provides strong support to the hypothesis of regional differences in the responses of individual otolithic sensory epithelia. The finding of hair cell types in fishes that closely resemble those found in amniote vestibular endorgans also suggests that hair cell heterogeneity arose earlier in the evolution of the vertebrate ear than previously thought.

  20. Accumulation of cell wall-bound phenolic metabolites and their upliftment in hairy root cultures of tomato (Lycopersicon esculentum Mill.).

    PubMed

    Mandal, Sudhamoy; Mitra, Adinpunya

    2008-07-01

    Alkaline hydrolysis of cell wall material of tomato hairy roots yielded ferulic acid as the major phenolic compound. Other phenolics were 4-hydroxybenzoic acid, vanillic acid, 4-hydroxybenzaldehyde, vanillin and 4-coumaric acid. The content of phenolics was much higher at the early stage of hairy root growth. The ferulic acid content decreased up to 30 days and then sharply increased to 360 microg/g at 60 days of growth. Elicitation of hairy root cultures with Fusarium mat extract (FME) increased ferulic acid content 4-fold after 24 h. As the pathogen-derived elicitors have specific receptors in plants, FME may thus be used for inducing resistance against Fusarium oxysporum f. sp. lycopersici.

  1. Nivolumab in Treating Patients With HTLV-Associated T-Cell Leukemia/Lymphoma

    ClinicalTrials.gov

    2017-02-20

    Acute Adult T-Cell Leukemia/Lymphoma; Adult T-Cell Leukemia/Lymphoma; CD3 Positive; CD4-Positive Neoplastic Cells Present; Chronic Adult T-Cell Leukemia/Lymphoma; HTLV-1 Infection; Hypercalcemia; Lymphomatous Adult T-Cell Leukemia/Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Smoldering Adult T-Cell Leukemia/Lymphoma

  2. Chronic B-Cell Leukemias and Agent Orange

    MedlinePlus

    ... survivors' benefits . Research on B-cell leukemias and herbicides The Health and Medicine Division (HMD) (formally known ... sufficient evidence of an association between exposure to herbicides and chronic lymphocytic leukemia. In 2003, VA recognized ...

  3. Speed of leukemia development and genetic diversity in xenograft models of T cell acute lymphoblastic leukemia

    PubMed Central

    Poglio, Sandrine; Lewandowski, Daniel; Calvo, Julien; Caye, Aurélie; Gros, Audrey; Laharanne, Elodie; Leblanc, Thierry; Landman-Parker, Judith; Baruchel, André; Soulier, Jean; Ballerini, Paola; Clappier, Emmanuelle; Pflumio, Françoise

    2016-01-01

    T cell acute lymphoblastic leukemia (T-ALL) develops through accumulation of multiple genomic alterations within T-cell progenitors resulting in clonal heterogeneity among leukemic cells. Human T-ALL xeno-transplantation in immunodeficient mice is a gold standard approach to study leukemia biology and we recently uncovered that the leukemia development is more or less rapid depending on T-ALL sample. The resulting human leukemia may arise through genetic selection and we previously showed that human T-ALL development in immune-deficient mice is significantly enhanced upon CD7+/CD34+ leukemic cell transplantations. Here we investigated the genetic characteristics of CD7+/CD34+ and CD7+/CD34− cells from newly diagnosed human T-ALL and correlated it to the speed of leukemia development. We observed that CD7+/CD34+ or CD7+/CD34− T-ALL cells that promote leukemia within a short-time period are genetically similar, as well as xenograft-derived leukemia resulting from both cell fractions. In the case of delayed T-ALL growth CD7+/CD34+ or CD7+/CD34− cells were either genetically diverse, the resulting xenograft leukemia arising from different but branched subclones present in the original sample, or similar, indicating decreased fitness to mouse micro-environment. Altogether, our work provides new information relating the speed of leukemia development in xenografts to the genetic diversity of T-ALL cell compartments. PMID:27191650

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

    SciTech Connect

    Wang, Jiying; Rao, Qing; Wang, Min; Wei, Hui; Xing, Haiyan; Liu, Hang; Wang, Yanzhong; Tang, Kejing; Peng, Leiwen; Tian, Zheng; Wang, Jianxiang

    2009-09-04

    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.

  5. Obatoclax Mesylate, Vincristine Sulfate, Doxorubicin Hydrochloride, and Dexrazoxane Hydrochloride in Treating Young Patients With Relapsed or Refractory Solid Tumors, Lymphoma, or Leukemia

    ClinicalTrials.gov

    2014-04-30

    Acute Leukemias of Ambiguous Lineage; Acute Undifferentiated Leukemia; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Small Intestine Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

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

    ClinicalTrials.gov

    2017-03-27

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

  7. [Presence of B cell clones in acute myelomonocytic leukemia].

    PubMed

    Novoa, Viviana; Nuñez, Neri; Cervellini, Mirta; Starosta, Aida; Carballo, Orlando G

    2010-01-01

    The coexistence of acute myeloid leukemia and chronic lymphocytic leukemia in the same patient is rare. The majority of the cases correspond to patients that developed acute leukemia during the evolutionary course of a chronic lymphatic leukemia following treatment with chemotherapy drugs. We report a case of acute myelomonocytic leukemia concurrent with untreated B-cell chronic lymphocytic leukemia in which the use of flow cytometry analysis with a large panel of monoclonal antibodies, allowed the demonstration of different pathological populations and determine immunophenotyping patterns. Published cases of simultaneous chronic lymphocytic leukemia and acute leukemia are reviewed. The use of multiparametric flow cytometry to differentiate the populations demonstrates the utility of this technology in the diagnosis of these hematological malignancies.

  8. Human T-cell leukemia virus types I and II exhibit different DNase I protection patterns

    SciTech Connect

    Altman, R.; Harrich, D.; Garcia, J.A. ); Gaynor, R.B. Wadsworth Veterans Hospital, Los Angeles, CA )

    1988-04-01

    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.

  9. Molecular Hallmarks of Adult T Cell Leukemia

    PubMed Central

    Yamagishi, Makoto; Watanabe, Toshiki

    2012-01-01

    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 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 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. PMID:23060864

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

    ClinicalTrials.gov

    2016-12-04

    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

  11. A Case of T-cell Acute Lymphoblastic Leukemia Relapsed As Myeloid Acute Leukemia.

    PubMed

    Paganin, Maddalena; Buldini, Barbara; Germano, Giuseppe; Seganfreddo, Elena; Meglio, Annamaria di; Magrin, Elisa; Grillo, Francesca; Pigazzi, Martina; Rizzari, Carmelo; Cazzaniga, Giovanni; Khiabanian, Hossein; Palomero, Teresa; Rabadan, Raul; Ferrando, Adolfo A; Basso, Giuseppe

    2016-09-01

    A 4-year-old male with the diagnosis of T-cell acute lymphoblastic leukemia (T-ALL) relapsed after 19 months with an acute myeloid leukemia (AML). Immunoglobulin and T-cell receptor gene rearrangements analyses reveal that both leukemias were rearranged with a clonal relationship between them. Comparative genomic hybridization (Array-CGH) and whole-exome sequencing analyses of both samples suggest that this leukemia may have originated from a common T/myeloid progenitor. The presence of homozygous deletion of p16/INK4A, p14/ARF, p15/INK4B, and heterozygous deletion of WT1 locus remained stable in the leukemia throughout phenotypic switch, revealing that this AML can be genetically associated to T-ALL.

  12. Laser activated nanothermolysis of leukemia cells monitored by photothermal microscopy

    NASA Astrophysics Data System (ADS)

    Lapotko, Dmitri; Lukianova, Ekaterina; Shnip, Alexander; Zheltov, George; Potapnev, Michail; Savitsky, Valeriy; Klimovich, Olga; Oraevsky, Alexander

    2005-04-01

    We are developing new diagnostic and therapeutic technologies for leukemia based on selective targeting of leukemia cells with gold nanoparticles and thermomechanical destruction of the tumor cells with laser-induced microbubbles. Clusters of spherical gold nanoparticles that have strong optical absorption of laser pulses at 532 nm served as nucleation sites of vapor microbubbles. The nanoparticles were targeted selectively to leukemia cells using leukemia-specific surface receptors and a set of two monoclonal antibodies. Application of a primary myeloid-specific antibody to tumor cells followed by targeting the cells with 30-nm nanoparticles conjugated with a secondary antibody (IgG) resulted in formation of nanoparticulate clusters due to aggregation of IgGs. Formation of clusters resulted in substantial decrease of the damage threshold for target cells. The results encourage development of Laser Activated Nanothermolysis as a Cell Elimination Therapy (LANCET) for leukemia. The proposed technology can be applied separately or in combination with chemotherapy for killing leukemia cells without damage to other blood cells. Potential applications include initial reduction of concentration of leukemia cells in blood prior to chemotherapy and treatment of residual tumor cells after the chemotherapy. Laser-induced bubbles in individual cells and cell damage were monitored by analyzing profile of photothermal response signals over the entire cell after irradiation with a single 10-ns long laser pulse. Photothermal microscopy was utilized for imaging formation of microbubbles around nanoparticulate clusters.

  13. Clearance of donor cell leukemia by means of graft versus leukemia effect: A case report.

    PubMed

    Ruiz-Delgado, Guillermo J; León Peña, Andrés A; Gómez-de-León, Andrés; Ruiz-Argüelles, Guillermo J

    2016-09-01

    Donor cell leukemia (DCL) is a rare complication of hematopoietic stem cell transplantation (HSCT). Its incidence has been reported between 0.12 and 5%, although the majority of cases are anecdotal. The mechanisms of leukemogenesis in DCL may be distinct from other types of leukemia. Here we describe a case of a 27-year-old woman with a diagnosis of biphenotypic acute leukemia who received a HSCT and developed a DCL. We briefly discuss the possible pathogenesis, diagnosis, and treatment of DCL.

  14. Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia and Persistent/Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm

    ClinicalTrials.gov

    2017-03-13

    Adult Acute Myeloid Leukemia in Remission; Donor; Early Relapse of Acute Myeloid Leukemia; Late Relapse of Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Blastic Plasmacytoid Dendritic Cell Neoplasm

  15. Alvocidib in Treating Patients With B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2013-07-01

    B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  16. [Lysosomal enzyme activity in white blood cells in leukemias].

    PubMed

    Rybakova, L P; Kharchenko, M F

    1996-01-01

    Total enzyme activity of acidic hydrolases and total neutral proteinase were compared in the post-nuclear fraction of leukocytes from healthy subjects and leukemia patients. The levels of acidic phosphotase and neutral proteinase in lymphoid cells of healthy donors were 11 and 7 times lower than those in myeloid cells, respectively. Patients suffering chronic myeloid leukemia revealed enhanced levels of beta-glucuronidase and neutral proteinases whereas B-chronic lymphoid leukemia involved acidic hydrolase concentrations lower than normal. As chronic myeloid leukemia advanced, neutral proteinase activity dropped dramatically (2.5 times); an aggressive course of B-chronic lymphoid leukemia was accompanied by a 3-fold decrease in acidic hydrolase level. The results may be used as indirect evidence of differences in the role of lysosomal enzymes in the mechanism of protein processing involved in myeloid and lymphoid proliferative pathologies.

  17. Adoptive Immunotherapy For Leukemia With Ex vivo Expanded T Cells

    PubMed Central

    Cruz, Conrad Russell Y.; Bollard, Catherine M.

    2016-01-01

    The development of novel T cell therapies to target leukemia has facilitated the translation of this approach for hematologic malignancies. Different methods of manufacturing leukemia-specific T cells have evolved, along with additional measures to increase the safety of this therapy. This is an overview of expanded T cell therapeutics with a focus on how the manufacturing strategies have been refined, and where the research is heading. PMID:26648070

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

    PubMed Central

    Karami, Hadi; Baradaran, Behzad; Esfahani, Ali; Sakhinia, Masoud; Sakhinia, Ebrahim

    2014-01-01

    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. PMID:24754007

  19. Laser nanothermolysis of human leukemia cells using functionalized plasmonic nanoparticles

    PubMed Central

    Liopo, Anton V.; Conjusteau, André; Konopleva, Marina; Andreeff, Michael; Oraevsky, Alexander A.

    2012-01-01

    In the present work, we present the use of gold nanorods as plasmonic nanoparticles for selective photothermal therapy of human acute (HL-60) and chronicle (K-562) leukemia cells using a near-infrared laser. We improved a published methodology of gold nanorods conjugation to generate high yields of narrow band gold nanorods with an optical absorption centered at 760 nm. The manufactured nanorods were pegylated and conjugated with monoclonal antibody to become non-toxic as biocompatible nanothermolysis agent. Gold nanorods are synthesized and conjugated to CD33 monoclonal antibody. After pegylation, or conjugation with CD33 antibody, gold nanorods were non-toxic to acute and chronic leukemia cells. Our modified gold nanorods CD33 conjugates shown high level of accumulation for both leukemia cell lines, and successful used for nanothermolysis of human leukemia cells in vitro. Each sample was illuminated with 1 or 3 laser shots as for low and for high laser fluence. The radiation was provided by a Quanta Systems q-switched titanium sapphire laser, and the system was designed for maximum sample coverage using non-focused illumination. HL-60 and K-562 cells were treated for 45 min with gold nanorods CD33 conjugated, or with pegylated gold nanorods. The effect of pulsed-laser nanothermolysis for acute and chronic leukemia cells were investigated with cell counting for number of living cells, percentage of cell death and functional parameters such as damage of cell membrane and metabolic activity. Gold nanorods CD33 conjugates significantly increase cell damage for low fluence laser and completely destroyed cancer cells after 3 pulses for low fluence (acute leukemia) and for high fluence laser as for HL-60 (acute) and for K-562 (chronicle) leukemia cells. PMID:22720194

  20. The role of natural killer cells in chronic myeloid leukemia

    PubMed Central

    Danier, Anna Carolyna Araújo; de Melo, Ricardo Pereira; Napimoga, Marcelo Henrique; Laguna-Abreu, Maria Theresa Cerávolo

    2011-01-01

    Chronic myeloid leukemia is a neoplasia resulting from a translocation between chromosomes 9 and 22 producing the BCR-ABL hybrid known as the Philadelphia chromosome (Ph). In chronic myeloid leukemia a proliferation of malignant myeloid cells occurs in the bone marrow due to excessive tyrosine kinase activity. In order to maintain homeostasis, natural killer cells, by means of receptors, identify the major histocompatibility complex on the surface of tumor cells and subsequently induce apoptosis. The NKG2D receptor in the natural killer cells recognizes the transmembrane proteins related to major histocompatibility complex class I chain-related genes A and B (MICA and MICB), and it is by the interaction between NKG2D and MICA that natural killer cells exert cytotoxic activity against chronic myeloid leukemia tumor cells. However, in the case of chronic exposure of the NKG2D receptor, the MICA ligand releases soluble proteins called sMICA from the tumor cell surface, which negatively modulate NKG2D and enable the tumor cells to avoid lysis mediated by the natural killer cells. Blocking the formation of sMICA may be an important antitumor strategy. Treatment using tyrosine kinase inhibitors induces modulation of NKG2DL expression, which could favor the activity of the natural killer cells. However this mechanism has not been fully described in chronic myeloid leukemia. In the present study, we analyze the role of natural killer cells to reduce proliferation and in the cellular death of tumor cells in chronic myeloid leukemia. PMID:23049299

  1. T-cell acute lymphoid leukemia resembling Burkitt leukemia cell morphology: A case report

    PubMed Central

    YUE, QINGFANG; LIU, XINYUE; CHEN, LEI; LIU, ZHONGPING; CHEN, WANXIN

    2015-01-01

    Biphenotypic acute leukemia (BAL) is an uncommon type of cancer, which accounts for <5% of all adult ALs. Based upon a previously described scoring system, the European Group for the Immunological Classification of Leukemias (EGIL) proposed a set of diagnostic criteria for BAL. This scoring system is based upon the number and degree of specificity of several markers for myeloid or T/B-lymphoid blasts. The present study describes a case of T-cell acute lymphoblastic leukemia (T-ALL) with Burkitt-like cytology, which according to the French-American-British classification, corresponded to a diagnosis of Burkitt type L3 ALL. Flow cytometry analysis demonstrated that the blasts were positive for T-lymphoid markers, cytoplasmic cluster of differentiation (CD)3, CD7 and CD56, and myeloid markers, CD13, CD33 and CD15. At first, a diagnosis of BAL was suggested by the EGIL score, however, according to the 2008 World Health Organization criteria, a case of T-ALL with aberrant myeloid markers was established. The study also reviewed the literature and discussed the limitations of the EGIL scoring system in clinical decision making, to aid in the selection of an appropriate therapeutic regimen. PMID:25663889

  2. 75 FR 53202 - Diseases Associated With Exposure to Certain Herbicide Agents (Hairy Cell Leukemia and Other...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-31

    ... between myocardial oxygen supply and demand.'' 75 FR 14393; See Harrison's Principles of Internal Medicine...; it typically occurs when there is an imbalance between myocardial oxygen supply and demand.'' 75...

  3. 75 FR 14391 - Diseases Associated With Exposure to Certain Herbicide Agents (Hairy Cell Leukemia and Other...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-25

    ... myocardial oxygen supply and demand. Therefore, for purposes of this regulation, the term ``IHD'' includes, but is not limited to, acute, subacute, and old myocardial infarction; atherosclerotic...

  4. PIG7 promotes leukemia cell chemosensitivity via lysosomal membrane permeabilization

    PubMed Central

    Niu, Ting; Wu, Yu; Li, Jianjun; Wang, Fangfang; Zheng, Yuhuan; Liu, Ting

    2016-01-01

    PIG7 localizes to lysosomal membrane in leukemia cells. Our previous work has shown that transduction of pig7 into a series of leukemia cell lines did not result in either apoptosis or differentiation of most tested cell lines. Interestingly, it did significantly sensitize these cell lines to chemotherapeutic drugs. Here, we further investigated the mechanism underlying pig7-induced improved sensitivity of acute leukemia cells to chemotherapy. Our results demonstrated that the sensitization effect driven by exogenous pig7 was more effective in drug-resistant leukemia cell lines which had lower endogenous pig7 expression. Overexpression of pig7 did not directly activate the caspase apoptotic pathway, but decreased the lysosomal stability. The expression of pig7 resulted in lysosomal membrane permeabilization (LMP) and lysosomal protease (e.g. cathepsin B, D, L) release. Moreover, we also observed increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential (ΔΨm) induced by pig7. Some autophagy markers such as LC3I/II, ATG5 and Beclin-1, and necroptosis maker MLKL were also stimulated. However, intrinsic antagonism such as serine/cysteine protease inhibitors Spi2A and Cystatin C prevented downstream effectors from triggering leukemia cells, which were only on the “verge of apoptosis”. When combined with chemotherapy, LMP increased and more proteases were released. Once this process was beyond the limit of intrinsic antagonism, it induced programmed cell death cooperatively via caspase-independent and caspase-dependent pathways. PMID:26716897

  5. PIG7 promotes leukemia cell chemosensitivity via lysosomal membrane permeabilization.

    PubMed

    Liu, Jiazhuo; Peng, Leiwen; Niu, Ting; Wu, Yu; Li, Jianjun; Wang, Fangfang; Zheng, Yuhuan; Liu, Ting

    2016-01-26

    PIG7 localizes to lysosomal membrane in leukemia cells. Our previous work has shown that transduction of pig7 into a series of leukemia cell lines did not result in either apoptosis or differentiation of most tested cell lines. Interestingly, it did significantly sensitize these cell lines to chemotherapeutic drugs. Here, we further investigated the mechanism underlying pig7-induced improved sensitivity of acute leukemia cells to chemotherapy. Our results demonstrated that the sensitization effect driven by exogenous pig7 was more effective in drug-resistant leukemia cell lines which had lower endogenous pig7 expression. Overexpression of pig7 did not directly activate the caspase apoptotic pathway, but decreased the lysosomal stability. The expression of pig7 resulted in lysosomal membrane permeabilization (LMP) and lysosomal protease (e.g. cathepsin B, D, L) release. Moreover, we also observed increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential (ΔΨm) induced by pig7. Some autophagy markers such as LC3I/II, ATG5 and Beclin-1, and necroptosis maker MLKL were also stimulated. However, intrinsic antagonism such as serine/cysteine protease inhibitors Spi2A and Cystatin C prevented downstream effectors from triggering leukemia cells, which were only on the "verge of apoptosis". When combined with chemotherapy, LMP increased and more proteases were released. Once this process was beyond the limit of intrinsic antagonism, it induced programmed cell death cooperatively via caspase-independent and caspase-dependent pathways.

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

    ClinicalTrials.gov

    2016-10-24

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

  7. B-cell leukemia/lymphoma panel

    MedlinePlus

    ... FR. The acute leukemias. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 25th ed. Philadelphia, PA: ... JO. Non-Hodgkin lymphomas. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 25th ed. Philadelphia, PA: ...

  8. Understanding Leukemia

    MedlinePlus

    ... the leukemia cells crowd out or suppress the development of normal cells. The rate at which leukemia progresses and how the cells replace the normal blood and marrow cells are different with each type of leukemia. Acute myeloid leukemia (AML) and acute ...

  9. Donor cell-derived acute myeloblastic leukemia after allogeneic peripheral blood hematopoietic stem cell transplantation for juvenile myelomonocytic leukemia.

    PubMed

    Cetin, Zafer; Tezcan, Gulsun; Karauzum, Sibel Berker; Kupesiz, Alphan; Manguoglu, Ayse Esra; Yesilipek, Akif; Luleci, Guven; Hazar, Volkan

    2006-11-01

    Despite its rarity, donor cell leukemia (DCL) is a most intriguing entity. We report here the case of a 5 year-old girl with juvenile myelomonocytic leukemia and normal female karyotype who developed acute myeloblastic leukemia with a karyotype of 46, X, t(X; 7) (p21; p11.2), der(7) t(3; 7) (q13.3; q22) 5 months after peripheral blood hematopoietic stem cell transplantation from her HLA-matched sister. We performed the analysis of short tandem repeat sequence markers to DNA obtained from donor peripheral blood, patient's peripheral blood including leukemic blasts and patient's hair root. This analysis showed that the leukemic blood DNA matched the donor blood DNA and not the patient's DNA, thus confirming DCL. To our knowledge, this is the first case of DCL after peripheral blood SCT for juvenile myelomonocytic leukemia.

  10. Laboratory Treated T Cells in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, or Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-12-08

    CD19-Positive Neoplastic Cells Present; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mantle Cell Lymphoma; Refractory Non-Hodgkin Lymphoma; Refractory Small Lymphocytic Lymphoma

  11. Leukomogenic factors downregulate heparanase expression in acute myeloid leukemia cells

    SciTech Connect

    Eshel, Rinat; Ben-Zaken, Olga; Vainas, Oded; Nadir, Yona; Minucci, Saverio; Polliack, Aaron; Naparstek, Ella; Vlodavsky, Israel; Katz, Ben-Zion; E-mail: bkatz@tasmc.healt.gov.il

    2005-10-07

    Heparanase is a heparan sulfate-degrading endoglycosidase expressed by mature monocytes and myeloid cells, but not by immature hematopoietic progenitors. Heparanase gene expression is upregulated during differentiation of immature myeloid cells. PML-RAR{alpha} and PLZF-RAR{alpha} fusion gene products associated with acute promyelocytic leukemia abrogate myeloid differentiation and heparanase expression. AML-Eto, a translocation product associated with AML FAB M2, also downregulates heparanase gene expression. The common mechanism that underlines the activity of these three fusion gene products involves the recruitment of histone deacetylase complexes to specific locations within the DNA. We found that retinoic acid that dissociates PML-RAR{alpha} from the DNA, and which is used to treat acute promyelocytic leukemia patients, restores heparanase expression to normal levels in an acute promyelocytic leukemia cell line. The retinoic acid effects were also observed in primary acute promyelocytic leukemia cells and in a retinoic acid-treated acute promyelocytic leukemia patient. Histone deacetylase inhibitor reverses the downregulation of heparanase expression induced by the AML-Eto fusion gene product in M2 type AML. In summary, we have characterized a link between leukomogenic factors and the downregulation of heparanase in myeloid leukemic cells.

  12. Acute megakaryoblastic leukemia. Blast cell aggregates simulating metastatic tumor.

    PubMed

    Pui, C H; Rivera, G; Mirro, J; Stass, S; Peiper, S; Murphy, S B

    1985-11-01

    Acute megakaryoblastic leukemia is a rare leukemia that can present diagnostic problems. We describe two children who have this disease and had clumps of blast cells in their bone marrow, a finding usually attributed to metastatic tumor. The megakaryocytic origin of the cells was supported by their cytochemical staining pattern (positive alpha-naphthyl acetate esterase resistant to sodium fluoride inhibition and negative alpha-naphthyl butyrate esterase) and by the presence of factor VIII-related antigen. Ultrastructural studies of blast cells from one patient demonstrated platelet peroxidase. The mechanism of blast cell clump formation in these cases is unknown; nevertheless, awareness that this feature can occur in acute megakaryoblastic leukemia may avoid a misdiagnosis of metastatic solid tumor.

  13. Inhibitory effects of physalin B and physalin F on various human leukemia cells in vitro.

    PubMed

    Chiang, H C; Jaw, S M; Chen, P M

    1992-01-01

    Physalins B and F were isolated and characterized from the ethanolic extract of the whole plant of Physalis angulata L. (Solanaceae). Both physalin B and physalin F inhibited the growth of several human leukemia cells: K562 (erythroleukemia), APM1840 (acute T lymphoid leukemia), HL-60 (acute promyelocytic leukemia), KG-1 (acute myeloid leukemia), CTV1 (acute monocytic leukemia) and B cell (acute B lymphoid leukemia). Physalin F showed a stronger activity against these leukemia cells than physalin B, especially against acute myeloid leukemia (KG-1) and acute B lymphoid leukemia (B cell). From the structural features, the active site seems to be the functional epoxy group for physalin F and the double bond for physalin B located at carbon 5 and 6; the former is much more active than the latter as regards anti-leukemic effects.

  14. GATA2 Inhibition Sensitizes Acute Myeloid Leukemia Cells to Chemotherapy

    PubMed Central

    Cao, Yanan; Xuan, Binbin; Fan, Yingchao; Sheng, Huiming; Zhuang, Wenfang

    2017-01-01

    Drug resistance constitutes one of the main obstacles for clinical recovery of acute myeloid leukemia (AML) patients. Therefore, the treatment of AML requires new strategies, such as adding a third drug. To address whether GATA2 could act as a regulator of chemotherapy resistance in human leukemia cells, we observed KG1a cells and clinical patients’ AML cells with a classic drug (Cerubidine) and Gefitinib. After utilizing chemotherapy, the expression of GATA2 and its target genes (EVI, SCL and WT1) in surviving AML cells and KG1a cells were significantly enhanced to double and quadrupled compared to its original level respectively. Furthermore, with continuous chemotherapeutics, AML cells with GATA2 knockdown or treated with GATA2 inhibitor (K1747) almost eliminated with dramatically reduced expression of WT1, SCL, EVI, and significantly increased apoptotic population. Therefore, we propose that reducing GATA2 expression or inhibition of its transcription activity can relieve the drug resistance of acute myeloid leukemia cells and it would be helpful for eliminating the leukemia cells in patients. PMID:28114350

  15. Leukemia: stem cells, maturation arrest, and differentiation therapy.

    PubMed

    Sell, Stewart

    2005-01-01

    Human myeloid leukemias provide models of maturation arrest and differentiation therapy of cancer. The genetic lesions of leukemia result in a block of differentiation (maturation arrest) that allows myeloid leukemic cells to continue to proliferate and/or prevents the terminal differentiation and apoptosis seen in normal white blood cells. In chronic myeloid leukemia, the bcr-abl (t9/22) translocation produces a fusion product that is an activated tyrosine kinase resulting in constitutive activation cells at the myelocyte level. This activation may be inhibited by imatinib mesylate (Gleevec, STI-571), which blocks the binding of ATP to the activated tyrosine kinase, prevents phosphorylation, and allows the leukemic cells to differentiate and undergo apoptosis. In acute promyelocytic leukemia, fusion of the retinoic acid receptor-alpha with the gene coding for promyelocytic protein, the PML-RAR alpha (t15:17) translocation, produces a fusion product that blocks the activity of the promyelocytic protein, which is required for formation of the granules of promyelocytes and prevents further differentiation. Retinoic acids bind to the retinoic acid receptor (RAR alpha) component of the fusion product, resulting in degradation of the fusion protein by ubiquitinization. This allows normal PML to participate in granule formation and differentiation of the promyelocytes. In one common type of acute myeloid leukemia, which results in maturation arrest at the myeloid precursor level, there is a mutation of FLT3, a transmembrane tyrosine kinase, which results in constitutive activation of the IL-3 receptor. This may be blocked by agents that inhibit farnesyl transferase. In each of these examples, specific inhibition of the genetically altered activation molecules of the leukemic cells allows the leukemic cells to differentiate and die. Because acute myeloid leukemias usually have mutation of more than one gene, combinations of specific inhibitors that act on the effects of

  16. Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2017-03-27

    Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma; T-Cell Large Granular Lymphocyte Leukemia

  17. Acute myeloid leukemia cells polarize macrophages towards a leukemia supporting state in a Growth factor independence 1 dependent manner

    PubMed Central

    Al-Matary, Yahya S.; Botezatu, Lacramioara; Opalka, Bertram; Hönes, Judith M.; Lams, Robert F.; Thivakaran, Aniththa; Schütte, Judith; Köster, Renata; Lennartz, Klaus; Schroeder, Thomas; Haas, Rainer; Dührsen, Ulrich; Khandanpour, Cyrus

    2016-01-01

    The growth of malignant cells is not only driven by cell-intrinsic factors, but also by the surrounding stroma. Monocytes/Macrophages play an important role in the onset and progression of solid cancers. However, little is known about their role in the development of acute myeloid leukemia, a malignant disease characterized by an aberrant development of the myeloid compartment of the hematopoietic system. It is also unclear which factors are responsible for changing the status of macrophage polarization, thus supporting the growth of malignant cells instead of inhibiting it. We report herein that acute myeloid leukemia leads to the invasion of acute myeloid leukemia-associated macrophages into the bone marrow and spleen of leukemic patients and mice. In different leukemic mouse models, these macrophages support the in vitro expansion of acute myeloid leukemia cell lines better than macrophages from non-leukemic mice. The grade of macrophage infiltration correlates in vivo with the survival of the mice. We found that the transcriptional repressor Growth factor independence 1 is crucial in the process of macrophage polarization, since its absence impedes macrophage polarization towards a leukemia supporting state and favors an anti-tumor state both in vitro and in vivo. These results not only suggest that acute myeloid leukemia-associated macrophages play an important role in the progression of acute myeloid leukemia, but also implicate Growth factor independence 1 as a pivotal factor in macrophage polarization. These data may provide new insights and opportunities for novel therapies for acute myeloid leukemia. PMID:27390361

  18. Nilotinib and Imatinib Mesylate After Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-12-09

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; 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; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  19. Inducible T-cell receptor expression in precursor T-cells for leukemia control

    PubMed Central

    Hoseini, Shahabuddin S; Hapke, Martin; Herbst, Jessica; Wedekind, Dirk; Baumann, Rolf; Heinz, Niels; Schiedlmeier, Bernhard; Vignali, Dario AA; van den Brink, Marcel R.M.; Schambach, Axel; Blazar, Bruce R.; Sauer, Martin G.

    2015-01-01

    Co-transplantation of hematopoietic stem cells with those engineered to express leukemia-reactive T cell receptors (TCRs) and differentiated ex vivo into precursor T cells (preTs) may reduce the risk of leukemia relapse. Since expression of potentially self-(leukemia-) reactive TCRs will lead to negative selection or provoke autoimmunity upon thymic maturation, we investigated a novel concept whereby TCR expression set under the control of an inducible promoter would allow timely controlled TCR expression. After in vivo maturation and gene induction, preTs developed potent anti-leukemia effects. Engineered preTs provided protection even after repeated leukemia challenges by giving rise to effector and central memory cells. Importantly, adoptive transfer of TCR-transduced allogeneic preTs mediated anti-leukemia effect without evoking graft-versus-host disease (GVHD). Earlier transgene induction forced CD8+ T cell development, was required to obtain a mature T cell subset of targeted specificity, allowed engineered T cells to efficiently pass positive selection and abrogated the endogenous T cell repertoire. Later induction favored CD4 differentiation and failed to produce a leukemia-reactive population emphasizing the dominant role of positive selection. Taken together, we provide new functional insights for the employment of TCR-engineered precursor cells as a controllable immunotherapeutic modality with significant anti-leukemia activity. PMID:25652739

  20. Philadelphia chromosome-positive leukemia stem cells in acute lymphoblastic leukemia and tyrosine kinase inhibitor therapy.

    PubMed

    Thomas, Xavier

    2012-06-26

    Leukemia stem cells (LSCs), which constitute a minority of the tumor bulk, are functionally defined on the basis of their ability to transfer leukemia into an immunodeficient recipient animal. The presence of LSCs has been demonstrated in acute lymphoblastic leukemia (ALL), of which ALL with Philadelphia chromosome-positive (Ph(+)). The use of imatinib, a tyrosine kinase inhibitor (TKI), as part of front-line treatment and in combination with cytotoxic agents, has greatly improved the proportions of complete response and molecular remission and the overall outcome in adults with newly diagnosed Ph(+) ALL. New challenges have emerged with respect to induction of resistance to imatinib via Abelson tyrosine kinase mutations. An important recent addition to the arsenal against Ph(+) leukemias in general was the development of novel TKIs, such as nilotinib and dasatinib. However, in vitro experiments have suggested that TKIs have an antiproliferative but not an antiapoptotic or cytotoxic effect on the most primitive ALL stem cells. None of the TKIs in clinical use target the LSC. Second generation TKI dasatinib has been shown to have a more profound effect on the stem cell compartment but the drug was still unable to kill the most primitive LSCs. Allogeneic stem cell transplantation (SCT) remains the only curative treatment available for these patients. Several mechanisms were proposed to explain the resistance of LSCs to TKIs in addition to mutations. Hence, TKIs may be used as a bridge to SCT rather than monotherapy or combination with standard chemotherapy. Better understanding the biology of Ph(+) ALL will open new avenues for effective management. In this review, we highlight recent findings relating to the question of LSCs in Ph(+) ALL.

  1. Childhood Leukemia

    MedlinePlus

    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. ...

  2. Exogenous IL-33 overcomes T cell tolerance in murine acute myeloid leukemia

    PubMed Central

    Qin, Lei; Dominguez, Donye; Chen, Siqi; Fan, Jie; Long, Alan; Zhang, Minghui; Fang, Deyu; Zhang, Yi; Kuzel, Timothy M.; Zhang, Bin

    2016-01-01

    Emerging studies suggest that dominant peripheral tolerance is a major mechanism of immune escape in disseminated leukemia. Using an established murine acute myeloid leukemia (AML) model, we here show that systemic administration of recombinant IL-33 dramatically inhibits the leukemia growth and prolongs the survival of leukemia-bearing mice in a CD8+ T cell dependent manner. Exogenous IL-33 treatment enhanced anti-leukemia activity by increasing the expansion and IFN-γ production of leukemia-reactive CD8+ T cells. Moreover, IL-33 promoted dendritic cell (DC) maturation and activation in favor of its cross presentation ability to evoke a vigorous anti-leukemia immune response. Finally, we found that the combination of PD-1 blockade with IL-33 further prolonged the survival, with half of the mice achieving complete regression. Our data establish a role of exogenous IL-33 in reversing T cell tolerance, and suggest its potential clinical implication into leukemia immunotherapy. PMID:27517629

  3. Ponicidin Inhibits Monocytic Leukemia Cell Growth by Induction of Apoptosis

    PubMed Central

    Liu, Jia-Jun; Zhang, Yong; Guang, Wei-Bin; Yang, Hong-Zhi; Lin, Dong-Jun; Xiao, Ruo-Zhi

    2008-01-01

    In this study two monocytic leukemia cell lines, U937 and THP-1 cells, were used to investigate the anti-proliferation effects caused by ponicidin. Cell viability was measured by an MTT assay. Cell apoptosis was assessed by flow cytometry as well as DNA fragmentation analysis. Cell morphology was observed using an inverted microscope and Hoechst 33258 staining. RT-PCR and Western blot analysis were used to detect survivin as well as Bax and Bcl-2 expressions after the cells were treated with different concentrations of ponicidin. The results revealed that ponicidin could inhibit the growth of U937 and THP-1 cells significantly by induction of apoptosis. The suppression was in both time- and dose-dependent manner. Marked morphological changes of cell apoptosis were observed clearly after the cells were treated with ponicidin for 48∼72 h. RT-PCR and Western blot analysis demonstrated that both survivin and Bcl-2 expressions were down-regulated remarkably while Bax expression remained constant before and after apoptosis occurred. We therefore conclude that ponicidin has significant anti-proliferation effects by inducing apoptosis on leukemia cells in vitro, downregulation of survivin as well as Bcl-2 expressions may be the important apoptosis inducing mechanisms. The results suggest that ponicidin may serve as potential therapeutic agent for leukemia. PMID:19330074

  4. Murine leukemia provirus-mediated activation of the Notch1 gene leads to induction of HES-1 in a mouse T lymphoma cell line, DL-3.

    PubMed

    Lee, J S; Ishimoto, A; Honjo, T; Yanagawa, S

    1999-07-23

    Constitutive activation of Notch signaling is known to be associated with tumorigenesis. In a mouse T lymphoma cell line, DL-3, we found that a murine leukemia provirus was inserted in the Notch1 locus, which led to marked expression of a virus-Notch1 fusion mRNA encoding an intracellular portion of the Notch1 protein. Furthermore, expression and nuclear localization of this constitutively active form of Notch1 protein were confirmed. Corresponding to this finding, the transcription of the hairy/enhancer of split (HES-1) gene, a known target of Notch1 signaling, was elevated in this cell line. A potential role for overexpressed HES-1 in the development of the lymphoma was discussed.

  5. Cinnamon effectively inhibits the activity of leukemia stem cells.

    PubMed

    Guan, X; Su, M C; Zhao, R B; Ouyang, H M; Dong, X D; Hu, P; Pei, Q; Lu, J; Li, Z F; Zhang, C R; Yang, T-H

    2016-08-19

    Cinnamon is the main component of Sanyangxuedai, which is one of the effective traditional Chinese medicines for treating malignancies. Leukemia is a prevalent malignant disease that Sanyangxuedai has been used to treat. Although successful in several studies, there is a lack of solid evidence as to why Sanyangxuedai has an effect on leukemia, and little is known about the underlying mechanisms. In this study, the active ingredients of cinnamon were isolated, purified, and identified. The transwell transport pool formed with the Caco-2 cell model was used to filter the active ingredients of cinnamon by simulating the gastrointestinal barrier in vitro. Moreover, the cell morphology, cell cycle status, apoptosis status, and antigenic variation of the cell surface antigens were observed and measured in K562 cells after treatment with the active ingredients of cinnamon. Our results showed that 50-75 μM was a safe concentration of cinnamon extract for treatment of K562 cells for 72 h. The cinnamon extract caused growth inhibition of K562 cells. Cinnamon extract seemed to arrest the cells at the G1 stage and increased the apoptosis rate significantly. Interestingly, cinnamon extract treatment upregulated the expression of erythroid and myeloid differentiation antigens and downregulated that of the megakaryocytic differentiation antigens in a dose-dependent manner. Our findings indicate that cinnamon extract from Sanyangxuedai may be effective for treating leukemia.

  6. Donor cell leukemia: a critical review.

    PubMed

    Ruiz-Argüelles, Guillermo J; Ruiz-Argüelles, Alejandro; Garcés-Eisele, Javier

    2007-01-01

    Approximately 40 cases of DCL have been reported in the literature; cases have been reported after allografts from bone marrow, peripheral blood and cord blood. The study of these cases may provide new insights into the mechanisms of leukemogenesis. Some data suggest that the prevalence of this complication has been under-estimated. Most cases of DCL have occurred following transplantation for leukemia, but there have also been cases reported after transplantation for non-malignant conditions. Various mechanisms have been proposed to explain how DCL arise and are briefly discussed. Additional studies are needed to define with more detail both the true prevalence of this complication and its precise pathogenetic mechanism.

  7. What Is Childhood Leukemia?

    MedlinePlus

    ... in Children About Childhood Leukemia What Is Childhood Leukemia? Cancer starts when cells start to grow out ... start making antibodies to fight them. Types of leukemia in children Leukemia is often described as being ...

  8. Selective elimination of leukemia stem cells: hitting a moving target.

    PubMed

    Crews, Leslie A; Jamieson, Catriona H M

    2013-09-10

    Despite the widespread use of chemotherapeutic cytotoxic agents that eradicate proliferating cell populations, patients suffering from a wide variety of malignancies continue to relapse as a consequence of resistance to standard therapies. In hematologic malignancies, leukemia stem cells (LSCs) represent a malignant reservoir of disease that is believed to drive relapse and resistance to chemotherapy and tyrosine kinase inhibitor (TKIs). Major research efforts in recent years have been aimed at identifying and characterizing the LSC population in leukemias, such as chronic myeloid leukemia (CML), which represents an important paradigm for understanding the molecular evolution of cancer. However, the precise molecular mechanisms that promote LSC-mediated therapeutic recalcitrance have remained elusive. It has become clear that the LSC population evolves during disease progression, thus presenting a serious challenge for development of effective therapeutic strategies. Multiple reports have demonstrated that LSC initiation and propagation occurs as a result of aberrant activation of pro-survival and self-renewal pathways regulated by stem-cell related signaling molecules including β-catenin and Sonic Hedgehog (Shh). Enhanced survival in LSC protective microenvironments, such as the bone marrow niche, as well as acquired dormancy of cells in these niches, also contributes to LSC persistence. Key components of these cell-intrinsic and cell-extrinsic pathways provide novel potential targets for therapies aimed at eradicating this dynamic and therapeutically recalcitrant LSC population. Furthermore, combination strategies that exploit LSC have the potential to dramatically improve the quality and quantity of life for patients that are resistant to current therapies.

  9. Childhood Cancer: Leukemia (For Parents)

    MedlinePlus

    ... acute. Acute childhood leukemias are also divided into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) , depending on ... Bone Marrow Childhood Cancer Neutropenia Stem Cell Transplants Acute Lymphoblastic Leukemia (ALL) Chemotherapy Radiation Therapy Chronic Myelogenous Leukemia (CML) ...

  10. Cannabinoids induce incomplete maturation of cultured human leukemia cells

    SciTech Connect

    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.

  11. Identification of leukemia cell surface proteins in clams

    SciTech Connect

    Reinisch, C.L.; Smolowitz, R.; Miosky, D. Marine Biological Lab., Woods Hole, MA )

    1988-09-01

    Soft-shell clams, Mya arenaria, develop leukemias which, in the advanced stages of disease, kill the host. The authors laboratory has developed an extensive panel of murine monoclonal antibodies to leukemia cells of Mya, and has used these powerful reagents to diagnose the disease with extreme accuracy. They have now ascertained that one membrane-associated protein of approximately 200kD is immunodominant. The function of this protein, regulation of its production and potential site of synthesis are being evaluated. Monoclonal antibodies have also permitted the exploration of the mechanism of leukemogensis. They have evaluated the specific staining pattern of one monoclonal antibody, and have concluded that at least one ontogenic source of leukemic cells may be connective tissue cells lining the sinusoids. Whether or not exposure to severely polluted sites such as New Bedford Harbor stimulates the export of immature hemocytes which then become transformed is at least one possibility amenable to testing using the monoclonal reagents.

  12. Optimizing Management of Patients with Adult T Cell Leukemia-Lymphoma

    PubMed Central

    Yared, Jean A.; Kimball, Amy S.

    2015-01-01

    Adult T cell leukemia-lymphoma is a rare disease with a high mortality rate, and is challenging for the clinician. Early allogeneic stem cell transplant can confer durable remission. As novel therapeutic agents become available to treat T cell malignancies, it is increasingly important that medical oncologists, hematologists, and hematopathologists recognize and accurately diagnose adult T cell leukemia-lymphoma. There is no uniform standard of treatment of adult T cell leukemia-lymphoma, and clinical trials remain critical to improving outcomes. Here we present one management approach based on the recent advances in treatment for adult T cell leukemia-lymphoma patients. PMID:26610571

  13. Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells.

    PubMed

    Petrov, Ivan; Suntsova, Maria; Mutorova, Olga; Sorokin, Maxim; Garazha, Andrew; Ilnitskaya, Elena; Spirin, Pavel; Larin, Sergey; Kovalchuk, Olga; Prassolov, Vladimir; Zhavoronkov, Alex; Roumiantsev, Alexander; Buzdin, Anton

    2016-11-19

    Acute lymphoblast leukemia (ALL) is characterized by overproduction of immature white blood cells in the bone marrow. ALL is most common in the childhood and has high (>80%) cure rate. In contrast, acute myeloid leukemia (AML) has far greater mortality rate than the ALL and is most commonly affecting older adults. However, AML is a leading cause of childhood cancer mortality. In this study, we compare gene expression and molecular pathway activation patterns in three normal blood, seven pediatric ALL and seven pediatric AML bone marrow samples. We identified 172/94 and 148/31 characteristic gene expression/pathway activation signatures, clearly distinguishing pediatric ALL and AML cells, respectively, from the normal blood. The pediatric AML and ALL cells differed by 139/34 gene expression/pathway activation biomarkers. For the adult 30 AML and 17 normal blood samples, we found 132/33 gene expression/pathway AML-specific features, of which only 7/2 were common for the adult and pediatric AML and, therefore, age-independent. At the pathway level, we found more differences than similarities between the adult and pediatric forms. These findings suggest that the adult and pediatric AMLs may require different treatment strategies.

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

    PubMed Central

    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

  15. Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells

    PubMed Central

    Petrov, Ivan; Suntsova, Maria; Mutorova, Olga; Sorokin, Maxim; Garazha, Andrew; Ilnitskaya, Elena; Spirin, Pavel; Larin, Sergey; Zhavoronkov, Alex; Kovalchuk, Olga; Prassolov, Vladimir; Roumiantsev, Alexander; Buzdin, Anton

    2016-01-01

    Acute lymphoblast leukemia (ALL) is characterized by overproduction of immature white blood cells in the bone marrow. ALL is most common in the childhood and has high (>80%) cure rate. In contrast, acute myeloid leukemia (AML) has far greater mortality rate than the ALL and is most commonly affecting older adults. However, AML is a leading cause of childhood cancer mortality. In this study, we compare gene expression and molecular pathway activation patterns in three normal blood, seven pediatric ALL and seven pediatric AML bone marrow samples. We identified 172/94 and 148/31 characteristic gene expression/pathway activation signatures, clearly distinguishing pediatric ALL and AML cells, respectively, from the normal blood. The pediatric AML and ALL cells differed by 139/34 gene expression/pathway activation biomarkers. For the adult 30 AML and 17 normal blood samples, we found 132/33 gene expression/pathway AML-specific features, of which only 7/2 were common for the adult and pediatric AML and, therefore, age-independent. At the pathway level, we found more differences than similarities between the adult and pediatric forms. These findings suggest that the adult and pediatric AMLs may require different treatment strategies. PMID:27870639

  16. [Donor cell leukemia (DCL): A prospective study of its identification and treatment].

    PubMed

    Ruiz-Delgado, Guillermo J; Hernández-Reyes, Jesús; González-Ramírez, Mónica Patricia; Martagón-Herrera, Nora Ángela; Garcés-Eisele, Javier; Ruiz-Argüelles, Alejandro; González-Cortés, Angélica; Ruiz-Argüelles, Guillermo J

    2015-01-01

    Donor-derived malignancies after allogeneic hematopoietic stem cell transplantation and after solid organ transplantation are considered as rare diseases. We have prospectively searched for donor cell leukemia in a 12-year period, in a single institution, in a group of 106 consecutive patients allografted because of leukemia. We have identified seven cases of donor cell leukemia; six were allografted because of relapsed acute lymphoblastic leukemia and one because of paroxysmal nocturnal hemoglobinuria/aplastic anemia. These figures suggest that the real incidence of donor cell leukemia has been underestimated. The six patients with lymphoblastic donor cell leukemia were treated prospectively with a pediatric-inspired combined chemotherapy schedule designed for de novo acute leukemia. A complete response was obtained in three out of six patients with lymphoblastic donor cell leukemia. It is possible to obtain favorable responses in donor cell leukemia patients employing combined chemotherapy. The long-term donor cell leukemia survivors remain as full chimeras and have not needed a second transplant.

  17. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

    PubMed

    Vyas, Paresh; Appelbaum, Frederick R; Craddock, Charles

    2015-01-01

    Allogeneic stem cell transplantation is an increasingly important treatment option in the management of adult acute myeloid leukemia (AML). The major causes of treatment failure remain disease relapse and treatment toxicity. In this review, Dr Vyas presents an overview of important recent data defining molecular factors associated with treatment failure in AML. He also identifies the emerging importance of leukemia stem cell biology in determining both response to therapy and relapse risk in AML. Dr Appelbaum discusses advances in the design and delivery of both myeloablative and reduced-intensity conditioning regimens, highlighting novel strategies with the potential to improve outcome. Dr Craddock discusses the development of both novel conditioning regimens and post-transplantation strategies aimed at reducing the risk of disease relapse.

  18. Reprint of: Allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

    PubMed

    Vyas, Paresh; Appelbaum, Frederick R; Craddock, Charles

    2015-02-01

    Allogeneic stem cell transplantation is an increasingly important treatment option in the management of adult acute myeloid leukemia (AML). The major causes of treatment failure remain disease relapse and treatment toxicity. In this review, Dr Vyas presents an overview of important recent data defining molecular factors associated with treatment failure in AML. He also identifies the emerging importance of leukemia stem cell biology in determining both response to therapy and relapse risk in AML. Dr Appelbaum discusses advances in the design and delivery of both myeloablative and reduced-intensity conditioning regimens, highlighting novel strategies with the potential to improve outcome. Dr Craddock discusses the development of both novel conditioning regimens and post-transplantation strategies aimed at reducing the risk of disease relapse.

  19. Beating the Clock in T-cell Acute Lymphoblastic Leukemia.

    PubMed

    Carroll, William L; Aifantis, Iannis; Raetz, Elizabeth

    2017-02-15

    CDK4/6 inhibition was synergistic with dexamethasone and everolimus but antagonistic with conventional chemotherapy in T-cell acute lymphoblastic leukemia (T-ALL) preclinical models. Cyclin-dependent kinase inhibition in combination with glucocorticoids and mTOR inhibition offers a unique therapeutic opportunity in T-ALL. Clin Cancer Res; 23(4); 873-5. ©2016 AACRSee related article by Pikman et al., p. 1012.

  20. Developing an in vitro model of T cell type of large granular lymphocyte leukemia.

    PubMed

    Ren, Tong; Yang, Jun; Broeg, Katie; Liu, Xin; Loughran, Thomas P; Cheng, Hua

    2013-12-01

    We developed a strategy that can prolong in vitro growth of T cell type of large granular lymphocyte (T-LGL) leukemia cells. Primary CD8+ lymphocytes from T-LGL leukemia patients were stably transduced with the retroviral tax gene derived from human T cell leukemia virus type 2. Expression of Tax overrode replicative senescence and promoted clonal expansion of the leukemic CD8+ T cells. These cells exhibit features characteristic of leukemic LGL, including resistance to FasL-mediated apoptosis, sensitivity to the inhibitors of sphingosine-1-phosphate receptor and IκB kinases as well as expression of cytotoxic gene products such as granzyme B, perforin and IFNγ. Collectively, these results indicate that this leukemia cell model can duplicate the main phenotype and pathophysiological characteristics of the clinical isolates of T-LGL leukemia. This model should be useful for investigating molecular pathogenesis of the disease and for developing new therapeutics targeting T-LGL leukemia.

  1. Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia.

    PubMed

    Stringaris, Kate; Sekine, Takuya; Khoder, Ahmad; Alsuliman, Abdullah; Razzaghi, Bonnie; Sargeant, Ruhena; Pavlu, Jiri; Brisley, Gill; de Lavallade, Hugues; Sarvaria, Anushruthi; Marin, David; Mielke, Stephan; Apperley, Jane F; Shpall, Elizabeth J; Barrett, A John; Rezvani, Katayoun

    2014-05-01

    The majority of patients with acute myeloid leukemia will relapse, and older patients often fail to achieve remission with induction chemotherapy. We explored the possibility that leukemic suppression of innate immunity might contribute to treatment failure. Natural killer cell phenotype and function was measured in 32 consecutive acute myeloid leukemia patients at presentation, including 12 achieving complete remission. Compared to 15 healthy age-matched controls, natural killer cells from acute myeloid leukemia patients were abnormal at presentation, with downregulation of the activating receptor NKp46 (P=0.007) and upregulation of the inhibitory receptor NKG2A (P=0.04). Natural killer cells from acute myeloid leukemia patients had impaired effector function against autologous blasts and K562 targets, with significantly reduced CD107a degranulation, TNF-α and IFN-γ production. Failure to achieve remission was associated with NKG2A overexpression and reduced TNF-α production. These phenotypic and functional abnormalities were partially restored in the 12 patients achieving remission. In vitro co-incubation of acute myeloid leukemia blasts with natural killer cells from healthy donors induced significant impairment in natural killer cell TNF-α and IFN-γ production (P=0.02 and P=0.01, respectively) against K562 targets and a trend to reduced CD107a degranulation (P=0.07). Under transwell conditions, the inhibitory effect of AML blasts on NK cytotoxicity and effector function was still present, and this inhibitory effect was primarily mediated by IL-10. These results suggest that acute myeloid leukemia blasts induce long-lasting changes in natural killer cells, impairing their effector function and reducing the competence of the innate immune system, favoring leukemia survival.

  2. [Development of acute myeloid leukemia from donor cells after allogeneic peripheral blood stem cell transplantation in a female patient with acute monoblastic leukemia].

    PubMed

    2011-01-01

    Development of leukemia from donor cells is a rare complication of allogeneic blood stem cells (BSC). The paper describes a case of evolving acute myeloid leukemia of a graft in a patient with resistant acute monoblastic leukemia after related allogeneic peripheral BSC transplantation. The rarity of this complication, difficulties in providing evidence for the donor origin of a leukemic clone demonstrate a need for all-round careful dynamic assessment of the hematopoietic system after allogeneic transplantation, by applying the current cytogenetic (fluorescence in situ hybridization) and molecular (hypervariable genomic region amplification test using the polymerase chain reaction, hypervariable number of tandem repeats (VNTR), and short number of tandem repeats (STR)) techniques, which permits errors to be avoided in the assessment of a clinical situation and in the diagnosis of leukemia from donor cells. There is no developed policy for treatment of acute graft-versus-leukemia.

  3. PHF6 mutations in T-cell acute lymphoblastic leukemia.

    PubMed

    Van Vlierberghe, Pieter; Palomero, Teresa; Khiabanian, Hossein; Van der Meulen, Joni; Castillo, Mireia; Van Roy, Nadine; De Moerloose, Barbara; Philippé, Jan; González-García, Sara; Toribio, María L; Taghon, Tom; Zuurbier, Linda; Cauwelier, Barbara; Harrison, Christine J; Schwab, Claire; Pisecker, Markus; Strehl, Sabine; Langerak, Anton W; Gecz, Jozef; Sonneveld, Edwin; Pieters, Rob; Paietta, Elisabeth; Rowe, Jacob M; Wiernik, Peter H; Benoit, Yves; Soulier, Jean; Poppe, Bruce; Yao, Xiaopan; Cordon-Cardo, Carlos; Meijerink, Jules; Rabadan, Raul; Speleman, Frank; Ferrando, Adolfo

    2010-04-01

    Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males. In this study, we report the identification of inactivating mutations and deletions in the X-linked plant homeodomain finger 6 (PHF6) gene in 16% of pediatric and 38% of adult primary T-ALL samples. Notably, PHF6 mutations are almost exclusively found in T-ALL samples from male subjects. Mutational loss of PHF6 is importantly associated with leukemias driven by aberrant expression of the homeobox transcription factor oncogenes TLX1 and TLX3. Overall, these results identify PHF6 as a new X-linked tumor suppressor in T-ALL and point to a strong genetic interaction between PHF6 loss and aberrant expression of TLX transcription factors in the pathogenesis of this disease.

  4. 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

    PubMed Central

    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) HA1 and SMCY. All CD34+ subpopulations expressed similar levels of mHAgs irrespective of disease phase, suggesting that in the SCT setting, mHAgs are the best target for GVL. Furthermore, WT1 was consistently overexpressed in advanced phase (AdP) CML in all CD34+ subpopulations, and mature progenitors of chronic phase (CP) CML compared to healthy individuals. PRAME overexpression was limited to more mature AdP-CML progenitors only. Conversely, only CP-CML progenitors had PR3 overexpression, suggesting that PR1-peptide vaccines are only appropriate in CP-CML. Surface expression of WT1 protein in the most primitive hematopoietic stem cells in AdP-CML suggest that they could be targets for WT1 peptide-based vaccines, which in combination with PRAME, could additionally improve targeting differentiated progeny, and benefit patients responding suboptimally to tyrosine kinase inhibitors, or enhance GVL effects in SCT patients. PMID:18548092

  5. Long noncoding RNA expression in dermal papilla cells contributes to hairy gene regulation.

    PubMed

    Lin, Chang-Min; Liu, Yang; Huang, Keng; Chen, Xian-Cai; Cai, Bo-Zhi; Li, Hai-Hong; Yuan, Yan-Ping; Zhang, Huan; Li, Yu

    2014-10-24

    Dermal papilla (DP) cells may be the source of dermal-derived signaling molecules involved in hair-follicle development and postnatal hair cycling. Early-passage DP cells can induce hair growth in vivo, but, on further culture, this ability is lost. The cellular mechanisms underlying the hair-follicle induction property of early-passage DP cells are unclear. Long noncoding RNAs (lncRNAs) are an important class of genes involved in various biological functions. They are aberrantly expressed and play roles in the regulation of the Wnt signaling pathway, a critical point in maintaining hair-induction activity. LncRNA microarray revealed 1683 upregulated and 1773 downregulated lncRNAs in passage-4 DP cells compare with passage-10 DP cells. To investigate the relation between lncRNAs and coding genes in WNT signaling, we constructed a coding-noncoding gene co-expression network using lncRNAs and coding genes that were differentially expressed between the passage-4 and -10 DP cells. RP11-766N7.3, H19 and HOTAIR are specific lncRNAs that were aberrantly expressed in DP cells and played an important role in regulating Wnt signaling. This study may provide potential targets for discovering the hair-follicle induction mechanism of early-passage DP cells.

  6. AMPK protects leukemia-initiating cells in myeloid leukemias from metabolic stress in the bone marrow

    PubMed Central

    Saito, Yusuke; Chapple, Richard H.; Lin, Angelique; Kitano, Ayumi; Nakada, Daisuke

    2015-01-01

    SUMMARY How cancer cells adapt to metabolically adverse conditions in patients and strive to proliferate is a fundamental question in cancer biology. Here we show that AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase, confers metabolic stress resistance to leukemia-initiating cells (LICs) and promotes leukemogenesis. Upon dietary restriction, MLL-AF9-induced murine AML activated AMPK and maintained leukemogenic potential. AMPK deletion significantly delayed leukemogenesis and depleted LICs by reducing the expression of glucose transporter 1 (Glut1), compromising glucose flux, and increasing oxidative stress and DNA damage. LICs were particularly dependent on AMPK to suppress oxidative stress in the hypoglycemic bone marrow environment. Strikingly, AMPK inhibition synergized with physiological metabolic stress caused by dietary restriction and profoundly suppressed leukemogenesis. Our results indicate that AMPK protects LICs from metabolic stress, and that combining AMPK inhibition with physiological metabolic stress potently suppresses AML by inducing oxidative stress and DNA damage. PMID:26440282

  7. Fludarabine Phosphate, Low-Dose Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies or Kidney Cancer

    ClinicalTrials.gov

    2016-10-10

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); 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 Chronic Lymphocytic Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Childhood Renal Cell Carcinoma; Chronic Phase Chronic Myelogenous Leukemia; Clear Cell Renal Cell Carcinoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Splenic Marginal Zone Lymphoma; Stage III Renal Cell Cancer; Stage IV Renal Cell Cancer; T-cell Large Granular Lymphocyte Leukemia; Type 1 Papillary Renal Cell Carcinoma; Type 2 Papillary Renal Cell Carcinoma; Waldenström Macroglobulinemia

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

    PubMed Central

    Kurz, Susanne; Bigl, Marina; 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

  9. Cytotoxicity of (-)-vitisin B in human leukemia cells.

    PubMed

    Wu, Shing-Sheng; Chen, Lih-Geeng; Lin, Ren-Jye; Lin, Shyr-Yi; Lo, Yueh-E; Liang, Yu-Chih

    2013-07-01

    Vitis thunbergii var. taiwaniana (VTT) is an indigenous Taiwanese wild grape and is used as a folk medicine in Taiwan. VTT is rich in polyphenols, especially quercetin and resveratrol derivatives, which were demonstrated to exhibit inhibitory activities against carcinogenesis and prevent some neurodegenerative diseases. (-)-Vitisin B is one of the resveratrol tetramers extracted from VTT. In this study, we investigated the mechanisms of (-)-vitisin B on the induction of apoptosis in human HL-60 promyelocytic leukemia cells. First, (-)-vitisin B significantly inhibited cell proliferation through inducing cell apoptosis. This effect appeared to occur in a time- and dose-dependent manner. Cell-cycle distribution was also examined, and we found that (-)-vitisin B significantly induced a sub-G1 population in a dose-dependent manner. In addition, (-)-vitisin B exhibited stronger inhibitory effects on cell proliferation than resveratrol. Second, (-)-vitisin B dose dependently induced apoptosis-related protein expressions, such as the cleavage form of caspase-3, caspase-8, caspase-9, poly(ADP ribose) polymerase, and the proapoptotic Bax protein. Third, (-)-vitisin B treatment also resulted in increases in c-Jun N-terminal kinase (JNK) phosphorylation and Fas ligand (FasL) expression. Moreover, the (-)-vitisin B-induced FasL expression and caspase-3 activation could be reversed by a JNK inhibitor. These results suggest that (-)-vitisin B-induced apoptosis of leukemia cells might be mediated through activation of JNK and Fas death-signal transduction.

  10. Obatoclax, Fludarabine, and Rituximab in Treating Patients With Previously Treated Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2013-09-27

    B-cell Chronic Lymphocytic Leukemia; Leukemia; Prolymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia

  11. A case of T cell prolymphocytic leukemia involving blast transformation.

    PubMed

    Ichikawa, Kunimoto; Noguchi, Masaaki; Imai, Hidenori; Sekiguchi, Yasunobu; Wakabayashi, Mutsumi; Sawada, Tomohiro; Komatsu, Norio

    2011-05-01

    We report a case of T cell prolymphocytic leukemia (T-PLL) involving blast transformation. At the initial diagnosis, most peripheral blood cells demonstrated proliferation of indolent T cell small cell variants, i.e., small to medium prolymphocytes with inconspicuous nucleoli and a normal karyotype. These cells were positive for surface CD4, CD5, and CD7, and cytoplasmic CD3, but negative for surface CD3 and CD8 and cytoplasmic terminal deoxynucleotidyl transferase (TdT). The T cell receptor (TCR) Cβ1 gene was rearranged in the cells. Large prolymphocytes with prominent nucleoli, irregular nuclei, and cytoplasmic vacuoles that exhibited chromosome 8 trisomy were observed about 1.5 years later. The CD4+CD8- single positive effector memory T cells transformed into surface CD4+CD8+ double positive precursor T cells. The clonal TCR gene rearrangement patterns of these cells were identical throughout the clinical course, suggesting clonal blast transformation. The CD4+CD8+ cells demonstrated increased chromosome 8 trisomy combined with complex chromosome abnormalities with t(14;14)(q11.2;q32) containing a 14q32 chromosome after transformation. T cell leukemia 1a (TCL1a) (14q32.1) may be implicated in this case. The TCL1a oncoprotein is expressed in approximately 70% of T-PLL cases. The disease gradually developed resistance to chemotherapy, and the patient died of the disease. It is known that indolent T-PLL can become aggressive. Therefore, similar transformations may occur in other aggressive T-PLL cases, particularly those involving trisomy 8 and TCL1a.

  12. Stem Cell Hierarchy and Clonal Evolution in Acute Lymphoblastic Leukemia

    PubMed Central

    Lang, Fabian; Wojcik, Bartosch; Rieger, Michael A.

    2015-01-01

    Cancer is characterized by a remarkable intertumoral, intratumoral, and cellular heterogeneity that might be explained by the cancer stem cell (CSC) and/or the clonal evolution models. CSCs have the ability to generate all different cells of a tumor and to reinitiate the disease after remission. In the clonal evolution model, a consecutive accumulation of mutations starting in a single cell results in competitive growth of subclones with divergent fitness in either a linear or a branching succession. Acute lymphoblastic leukemia (ALL) is a highly malignant cancer of the lymphoid system in the bone marrow with a dismal prognosis after relapse. However, stabile phenotypes and functional data of CSCs in ALL, the so-called leukemia-initiating cells (LICs), are highly controversial and the question remains whether there is evidence for their existence. This review discusses the concepts of CSCs and clonal evolution in respect to LICs mainly in B-ALL and sheds light onto the technical controversies in LIC isolation and evaluation. These aspects are important for the development of strategies to eradicate cells with LIC capacity. Common properties of LICs within different subclones need to be defined for future ALL diagnostics, treatment, and disease monitoring to improve the patients' outcome in ALL. PMID:26236346

  13. 63 FR 60361 - Licensing Opportunity and/or Cooperative Research and Development Agreement (``CRADA...

    Federal Register 2010, 2011, 2012, 2013, 2014

    1998-11-09

    ..., Lymphoma, Hairy Cell Leukemia, Hodgkin's Disease, and Other Hematologic Malignancies AGENCY: National... treatment of refractory Leukemia, Lymphoma, Hairy Cell Leukemia, Hodgkin's disease and other hematologic... for the therapy of chronic lymphocytic leukemia, lymphoma, Hodgkin's disease and Hairy Cell...

  14. Restoration of WNT4 inhibits cell growth in leukemia-derived cell lines

    PubMed Central

    2013-01-01

    Background WNT signaling pathways are significantly altered during cancer development. Vertebrates possess two classes of WNT signaling pathways: the “canonical” WNT/β-catenin signaling pathway, and the “non-canonical” pathways including WNT/Ca2+ and WNT/Planar cell polarity [PCP] signaling. WNT4 influences hematopoietic progenitor cell expansion and survival; however, WNT4 function in cancer development and the resulting implications for oncogenesis are poorly understood. The aim of this study was twofold: first, to determine the expression of WNT4 in mature peripheral blood cells and diverse leukemia-derived cells including cell lines from hematopoietic neoplasms and cells from patients with leukemia; second, to identify the effect of this ligand on the proliferation and apoptosis of the blast-derived cell lines BJAB, Jurkat, CEM, K562, and HL60. Methods We determined WNT4 expression by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in peripheral blood mononuclear cells (PBMCs) and T- and B-lymphocytes from healthy individuals, as well as from five leukemia-derived cell lines and blasts derived from patients with leukemia. To analyze the effect of WNT4 on cell proliferation, PBMCs and cell lines were exposed to a commercially available WNT4 recombinant human protein. Furthermore, WNT4 expression was restored in BJAB cells using an inducible lentiviral expression system. Cell viability and proliferation were measured by the addition of WST-1 to cell cultures and counting cells; in addition, the progression of the cell cycle and the amount of apoptosis were analyzed in the absence or presence of WNT4. Finally, the expression of WNT-pathway target genes was measured by qRT-PCR. Results WNT4 expression was severely reduced in leukemia-derived cell lines and blasts derived from patients with leukemia. The exposure of cell lines to WNT4 recombinant protein significantly inhibited cell proliferation; inducing WNT4 expression in BJAB

  15. Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer

    ClinicalTrials.gov

    2016-06-13

    Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  16. Phytosphingosine promotes megakaryocytic differentiation of myeloid leukemia cells.

    PubMed

    Han, Sang Hee; Kim, Jusong; Her, Yerim; Seong, Ikjoo; Park, Sera; Bhattarai, Deepak; Jin, Guanghai; Lee, Kyeong; Chung, Gukhoon; Hwang, Sungkee; Bae, Yun Soo; Kim, Jaesang

    2015-12-01

    We report that phytosphingosine, a sphingolipid found in many organisms and implicated in cellular signaling, promotes megakaryocytic differentiation of myeloid leukemia cells. Specifically, phytosphingosine induced several hallmark changes associated with megakaryopoiesis from K562 and HEL cells including cell cycle arrest, cell size increase and polyploidization. We also confirmed that cell type specific markers of megakaryocytes, CD41a and CD42b are induced by phytosphingosine. Phospholipids with highly similar structures were unable to induce similar changes, indicating that the activity of phytosphingosine is highly specific. Although phytosphingosine is known to activate p38 MAPK-mediated apoptosis, the signaling mechanisms involved in megakaryopoiesis appear to be distinct. In sum, we present another model for dissecting molecular details of megakaryocytic differentiation which in large part remains obscure.

  17. Phytosphingosine promotes megakaryocytic differentiation of myeloid leukemia cells

    PubMed Central

    Han, Sang Hee; Kim, Jusong; Her, Yerim; Seong, Ikjoo; Park, Sera; Bhattarai, Deepak; Jin, Guanghai; Lee, Kyeong; Chung, Gukhoon; Hwang, Sungkee; Bae, Yun Soo; Kim, Jaesang

    2015-01-01

    We report that phytosphingosine, a sphingolipid found in many organisms and implicated in cellular signaling, promotes megakaryocytic differentiation of myeloid leukemia cells. Specifically, phytosphingosine induced several hallmark changes associated with megakaryopoiesis from K562 and HEL cells including cell cycle arrest, cell size increase and polyploidization. We also confirmed that cell type specific markers of megakaryocytes, CD41a and CD42b are induced by phytosphingosine. Phospholipids with highly similar structures were unable to induce similar changes, indicating that the activity of phytosphingosine is highly specific. Although phytosphingosine is known to activate p38 mitogen-activated protein kinase (MAPK)-mediated apoptosis, the signaling mechanisms involved in megakaryopoiesis appear to be distinct. In sum, we present another model for dissecting molecular details of megakaryocytic differentiation which in large part remains obscure. [BMB Reports 2015; 48(12): 691-695] PMID:26077028

  18. Presence of Gumprecht shadows (smudge cells) in bovine leukemia virus-positive cattle.

    PubMed

    Panei, Carlos Javier; Larsen, Alejandra; González, Ester Teresa; Echeverría, María Gabriela

    2013-11-01

    Enzootic Bovine Leukosis is a chronic disease caused by the bovine leukemia virus (BLV). Smudge cells, also known as Gumprecht shadows, are not simple artifacts of slide preparation, but ragged lymphoid cells found mainly in peripheral blood smears from human patients with chronic lymphocytic leukemia. In this study, we report the presence of Gumprecht shadows in peripheral blood from BLV-positive cattle.

  19. Preclinical approaches in chronic myeloid leukemia: from cells to systems.

    PubMed

    Clarke, Cassie J; Holyoake, Tessa L

    2017-03-01

    Advances in the design of targeted therapies for the treatment of chronic myeloid leukemia (CML) have transformed the prognosis for patients diagnosed with this disease. However, leukemic stem cell persistence, drug intolerance, drug resistance, and advanced-phase disease represent unmet clinical needs demanding the attention of CML investigators worldwide. The availability of appropriate preclinical models is essential to efficiently translate findings from the bench to the clinic. Here we review the current approaches taken to preclinical work in the CML field, including examples of commonly used in vivo models and recent successes from systems biology-based methodologies.

  20. [Effect of Ikaros in B Cell Acute Lymphoblastic Leukemia].

    PubMed

    Zhang, Hai-Ying; Bai, Hai

    2015-08-01

    The Ikaros - a DNA-binding zinc finger protein, acting as a regulator of chromatin remodeling and gene transcription, is crucial for regulating the development and function of the immune system and acting as a master regulator of hematopoietic differentiation. Function-loss mutations of IKZF1, gene encoding Ikaros are frequent in B cell acute lymphoblastic leukemia (B-ALL) and are associated with a poor prognosis. This review briefly summarizes the available data regarding the structure and function of Ikaros, the role of Ikaros as a tumor suppressor in B-ALL, and its regulation mechanism.

  1. Cell death in leukemia: passenger protein regulation by topoisomerase inhibitors.

    PubMed

    Jahnke, Ulrike; Higginbottom, Karen; Newland, Adrian C; Cotter, Finbarr E; Allen, Paul D

    2007-10-05

    Etoposide is a potent inducer of mitotic catastrophe; a type of cell death resulting from aberrant mitosis. It is important in p53 negative cells where p53 dependent apoptosis and events at the G1 and G2 cell cycle checkpoints are compromised. Passenger proteins regulate many aspects of mitosis and siRNA interference or direct inhibition of Aurora B kinase results in mitotic catastrophe. However, there is little available data of clinical relevance in leukaemia models. Here, in p53 negative K562 myeloid leukemia cells, etoposide-induced mitotic catastrophe is shown to be time and/or concentration dependent. Survivin and Aurora remained bound to chromosomes. Survivin and Aurora were also associated with Cdk1 and were shown to form complexes, which in pull down experiments, included INCENP. There was no evidence of Aurora B kinase suppression. These data suggests etoposide will complement Aurora B kinase inhibitors currently in clinical trials for cancer.

  2. Targeting prohibitins induces apoptosis in acute myeloid leukemia cells

    PubMed Central

    Pomares, Helena; Palmeri, Claudia M; Iglesias-Serret, Daniel; Moncunill-Massaguer, Cristina; Saura-Esteller, José; Núñez-Vázquez, Sonia; Gamundi, Enric; Arnan, Montserrat; Preciado, Sara; Albericio, Fernando; Lavilla, Rodolfo; Pons, Gabriel; González-Barca, Eva M

    2016-01-01

    Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins (PHBs). In this study, the pro-apoptotic effect of fluorizoline was assessed in two cell lines and 21 primary samples from patients with debut of acute myeloid leukemia (AML). Fluorizoline induced apoptosis in AML cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespectively of patients' clinical or genetic features. In addition, fluorizoline inhibited the clonogenic capacity and induced differentiation of AML cells. Fluorizoline increased the mRNA and protein levels of the pro-apoptotic BCL-2 family member NOXA both in cell lines and primary samples analyzed. These results suggest that targeting PHBs could be a new therapeutic strategy for AML. PMID:27542247

  3. Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma

    ClinicalTrials.gov

    2017-04-04

    Adult T Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Stage II Adult T-Cell Leukemia/Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Contiguous Adult Lymphoblastic Lymphoma; Stage II Non-Contiguous Adult Lymphoblastic Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-Cell Leukemia/Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-Cell Leukemia/Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  4. Divergent effects of supraphysiologic Notch signals on leukemia stem cells and hematopoietic stem cells.

    PubMed

    Chiang, Mark Y; Shestova, Olga; Xu, Lanwei; Aster, Jon C; Pear, Warren S

    2013-02-07

    The leukemia stem cell (LSC) hypothesis proposes that a subset of cells in the bulk leukemia population propagates the leukemia.We tested the LSC hypothesis in a mouse model of Notch-induced T-cell acute lymphoblastic leukemia (T-ALL) in which the tumor cells were largely CD4+ CD8+ T cells. LSC activity was enriched but rare in the CD8+ CD4 HSA(hi) immature single-positive T-cell subset. Although our murine T-ALL model relies on transduction of HSCs, we were unable to isolate Notch-activated HSCs to test for LSC activity. Further analysis showed that Notch activation in HSCs caused an initial expansion of hematopoietic and T-cell progenitors and loss of stem cell quiescence, which was followed by progressive loss of long-term HSCs and T-cell production over several weeks. Similar results were obtained in a conditional transgenic model in which Notch activation is induced in HSCs by Cre recombinase. We conclude that although supraphysiologic Notch signaling in HSCs promotes LSC activity in T-cell progenitors, it extinguishes self-renewal of LT-HSCs. These results provide further evidence for therapeutically targeting T-cell progenitors in T-ALL while also underscoring the need to tightly regulate Notch signaling to expand normal HSC populations for clinical applications.

  5. Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement.

    PubMed

    Bardini, M; Woll, P S; Corral, L; Luc, S; Wittmann, L; Ma, Z; Lo Nigro, L; Basso, G; Biondi, A; Cazzaniga, G; Jacobsen, S E W

    2015-01-01

    Distinct from other forms of acute lymphoblastic leukemia (ALL), infant ALL with mixed lineage leukemia (MLL) gene rearrangement, the most common leukemia occurring within the first year of life, might arise without the need for cooperating genetic lesions. Through Ig/TCR rearrangement analysis of MLL-AF4+ infant ALL at diagnosis and xenograft leukemias from mice transplanted with the same diagnostic samples, we established that MLL-AF4+ infant ALL is composed of a branching subclonal architecture already at diagnosis, frequently driven by an Ig/TCR-rearranged founder clone. Some MLL-AF4+ clones appear to be largely quiescent at diagnosis but can reactivate and dominate when serially transplanted into immunodeficient mice, whereas other dominant clones at diagnosis can become more quiescent, suggesting a dynamic competition between actively proliferating and quiescent subclones. Investigation of paired diagnostic and relapse samples suggested that relapses often occur from subclones already present but more quiescent at diagnosis. Copy-number alterations identified at relapse might contribute to the activation and expansion of previously quiescent subclones. Finally, each of the identified subclones is able to contribute to the diverse phenotypic pool of MLL-AF4+ leukemia-propagating cells. Unraveling of the subclonal architecture and dynamics in MLL+ infant ALL may provide possible explanations for the therapy resistance and frequent relapses observed in this group of poor prognosis ALL.

  6. Adaptive immunity to leukemia is inhibited by cross-reactive induced regulatory T cells

    PubMed Central

    Manlove, Luke S.; Berquam-Vrieze, Katherine E.; Pauken, Kristen E.; Williams, Richard T.; Jenkins, Marc K.; Farrar, Michael A.

    2015-01-01

    BCR-ABL+ acute lymphoblastic leukemia patients have transient responses to current therapies. However, the fusion of BCR to ABL generates a potential leukemia-specific antigen that could be a target for immunotherapy. We demonstrate that the immune system can limit BCR-ABL+ leukemia progression although ultimately this immune response fails. To address how BCR-ABL+ leukemia escapes immune surveillance, we developed a peptide: MHC-II tetramer that labels endogenous BCR-ABL-specific CD4+ T cells. Naïve mice harbored a small population of BCR-ABL-specific T cells that proliferated modestly upon immunization. The small number of naïve BCR-ABL specific T cells was due to negative selection in the thymus, which depleted BCR-ABL specific T cells. Consistent with this observation, we saw that BCR-ABL specific T cells were cross-reactive with an endogenous peptide derived from ABL. Despite this cross-reactivity, the remaining population of BCR-ABL reactive T cells proliferated upon immunization with the BCR-ABL fusion peptide and adjuvant. In response to BCR-ABL+ leukemia, BCR-ABL specific T cells proliferated and converted into regulatory T cells (Treg cells), a process that was dependent on cross-reactivity with self-antigen, TGFβ1, and MHC-II antigen presentation by leukemic cells. Treg cells were critical for leukemia progression in C57Bl/6 mice, as transient Treg cell ablation led to extended survival of leukemic mice. Thus, BCR-ABL+ leukemia actively suppresses anti-leukemia immune responses by converting cross-reactive leukemia-specific T cells into Treg cells. PMID:26378075

  7. Docosahexaenoic Acid Induces Apoptosis in Primary Chronic Lymphocytic Leukemia Cells

    PubMed Central

    Gyan, Emmanuel; Tournilhac, Olivier; Halty, Christelle; Veyrat-Masson, Richard; Akil, Saïda; Berger, Marc; Hérault, Olivier; Callanan, Mary; Bay, Jacques-Olivier

    2015-01-01

    Chronic lymphocytic leukemia is an indolent disorder with an increased infectious risk remaining one of the main causes of death. Development of therapies with higher safety profile is thus a challenging issue. Docosahexaenoic acid (DHA, 22:6) is an omega-3 fatty acid, a natural compound of normal cells, and has been shown to display antitumor potency in cancer. We evaluated the potential in vitro effect of DHA in primary CLL cells. DHA induces high level of in vitro apoptosis compared to oleic acid in a dose-dependent and time-dependent manner. Estimation of IC50 was only of 4.813 µM, which appears lower than those reported in solid cancers. DHA is highly active on CLL cells in vitro. This observation provides a rationale for further studies aiming to understand its mechanisms of action and its potent in vivo activity. PMID:26734128

  8. Synchronous Occurrence of Chronic Myeloid Leukemia and Mantle Cell Lymphoma

    PubMed Central

    Li, Ying; Gray, Brian Allen; May, William Stratford

    2017-01-01

    Chronic myeloid leukemia (CML) and mantle cell lymphoma (MCL) are hematologic malignancies that originate from different oligopotent progenitor stem cells, namely, common myeloid and lymphoid progenitor cells, respectively. Although blastic transformation of CML can occur in the lymphoid lineage and CML has been related to non-Hodgkin lymphoma on transformation, to our knowledge, de novo and synchronous occurrence of CML and MCL has not been reported. Herein, we report the first case of synchronous CML and MCL in an otherwise healthy 38-year-old man. Potential etiologies and pathological relationships between the two malignancies are explored, including the possibility that the downstream effects of BCR-ABL may link it to an overexpression of cyclin D1, which is inherent to the etiology of MCL. PMID:28270940

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

    PubMed Central

    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

  10. Resistance to RadLV-induced leukemia: non-participation of splenic natural killer cells

    SciTech Connect

    St.-Pierre, Y.; Hugo, P.; Lemieux, S.; Lussier, G.; Potworowski, E.F.

    1988-08-01

    The phenotypic expression of genetically determined resistance to radiation leukemia virus (RadLV)-induced leukemia in mice has been shown to reside in the bone marrow. Because the bone marrow contains precursors of natural killer (NK) cells, known to play a role in retrovirally induced infections, and because these cells have been suggested as participating in resistance to radiation-induced leukemia, it was pertinent to establish whether their levels differed in strains of mice susceptible and resistant to leukemia. We therefore tested splenic NK cell levels in C57BL/Ka (susceptible) and B10.A(5R) (resistant) mice before viral inoculation, immediately after viral inoculation, and throughout the preleukemic period and showed that they were not different. This indicates that splenic NK cell levels have no bearing on the resistance to RadLV-induced leukemia and that other immune or non-immune mechanisms must be sought.

  11. Effects of Manisa propolis on telomerase activity in leukemia cells obtained from the bone marrow of leukemia patients.

    PubMed

    Cogulu, O; Biray, C; Gunduz, C; Karaca, E; Aksoylar, S; Sorkun, K; Salih, B; Ozkinay, F

    2009-11-01

    Propolis is a resinous material collected by honeybees and obtained from beehives that has anticancer effects by inducing apoptosis. The aim of this study is to investigate the effect of propolis on human telomerase reverse transcriptase (hTERT) in the leukemia cells obtained from leukemia patients. Four different bone marrow cell cultures from each of four leukemia cases were prepared. The 60 ng/ml, 30 ng/ml and 15 ng/ml working concentrations of propolis were administered to three cultures of each patient, while one culture contained only culture medium. hTERT mRNA expression levels of cells were detected at 24 h, 48 h and 72 h using the LightCycler 2.0 instrument. A significant decrease in hTERT expression levels was observed in the 60 ng/ml concentration of propolis. In conclusion, Manisa propolis may also have a potential effect on the expression of hTERT in leukemia-particularly owing to its constituent chrysin.

  12. Therapeutic Advances in Leukemia and Myelodysplastic Syndrome Over the Past 40 Years

    PubMed Central

    Kantarjian, Hagop; O'Brien, Susan; Cortes, Jorge; Wierda, William; Faderl, Stefan; Garcia-Manero, Guillermo; Issa, Jean-Pierre; Estey, Elihu; Keating, Michael; Freireich, Emil J.

    2015-01-01

    Major therapeutic progress has been accomplished in leukemia and myelodysplastic syndrome (MDS) over the past 40 years, which may not be fully appreciated by the larger medical community. The objective of this review was to briefly highlight the treatment breakthroughs in leukemia and MDS. Therapeutic progress happened through better understanding of disease pathophysiologies and rational development of targeted agents, like imatinib mesylate in chronic myeloid leukemia (CML), and through astute, empirical discoveries in the clinic, like all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia (APL) and chlorodeoxyadenosine in hairy cell leukemia (HCL). Today, the 5- to 10-year survival rates in patients with APL and HCL exceed 80%. In patients with CML, imatinib therapy has been associated with estimated 5- to 7-year survival rates from 85% to 90%. In patients with adult acute lymphocytic leukemia, modern intensive regimens have improved the 5-year survival rates from 20% up to 40%. In patients with chronic lymphocytic leukemia, chemoimmunotherapy recently produced high rates of quality responses and improved long-term outcome. In younger patients with acute myeloid leukemia (AML), the 5-year survival rates range from 40% to 50%, although elderly AML remains a therapeutic challenge. In patients with MDS, it was recently demonstrated that epigenetic therapy with hypomethylating agents improved survival. Much therapeutic progress has been witnessed in leukemia and MDS, and much more is expected to occur soon. PMID:18798533

  13. What Is Acute Myeloid Leukemia?

    MedlinePlus

    ... Acute Myeloid Leukemia (AML) What Is Acute Myeloid Leukemia? Cancer starts when cells in a part of ... the body from doing their jobs. Types of leukemia Not all leukemias are the same. There are ...

  14. What Is Chronic Lymphocytic Leukemia?

    MedlinePlus

    ... About Chronic Lymphocytic Leukemia What Is Chronic Lymphocytic Leukemia? Cancer starts when cells in the body begin ... the lymph nodes, liver, and spleen. What is leukemia? Leukemia is a cancer that starts in the ...

  15. What Is Chronic Myeloid Leukemia?

    MedlinePlus

    ... About Chronic Myeloid Leukemia What Is Chronic Myeloid Leukemia? Cancer starts when cells in the body begin ... is the same as for adults. What is leukemia? Leukemia is a cancer that starts in the ...

  16. CART19 to Treat B-Cell Leukemia or Lymphoma That Are Resistant or Refractory to Chemotherapy

    ClinicalTrials.gov

    2017-01-09

    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

  17. What Is Acute Lymphocytic Leukemia (ALL)?

    MedlinePlus

    ... Adults About Acute Lymphocytic Leukemia (ALL) What Is Acute Lymphocytic Leukemia? Cancer starts when cells in the body begin ... Acute Lymphocytic Leukemia Research and Treatment? More In Acute Lymphocytic Leukemia About Acute Lymphocytic Leukemia Causes, Risk Factors, and ...

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

    NASA Astrophysics Data System (ADS)

    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.

  19. Leydig cell damage after testicular irradiation for lymphoblastic leukemia

    SciTech Connect

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

    1985-01-01

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

  20. Hairy AdS solitons

    NASA Astrophysics Data System (ADS)

    Anabalón, Andrés; Astefanesei, Dumitru; Choque, David

    2016-11-01

    We construct exact hairy AdS soliton solutions in Einstein-dilaton gravity theory. We examine their thermodynamic properties and discuss the role of these solutions for the existence of first order phase transitions for hairy black holes. The negative energy density associated to hairy AdS solitons can be interpreted as the Casimir energy that is generated in the dual filed theory when the fermions are antiperiodic on the compact coordinate.

  1. Identification of H7 as a novel peroxiredoxin I inhibitor to induce differentiation of leukemia cells

    PubMed Central

    Qin, Dongjun; Chen, Yingyi; Liu, Chuanxu; Xia, Li; Wang, Tongdan; Lei, Hu; Yu, Yun; Huang, Min; Tong, Yin; Xu, Hanzhang; Gao, Fenghou

    2016-01-01

    Identifying novel targets to enhance leukemia-cell differentiation is an urgent requirment. We have recently proposed that inhibiting the antioxidant enzyme peroxiredoxin I (Prdx I) may induce leukemia-cell differentiation. However, this concept remains to be confirmed. In this work, we identified H7 as a novel Prdx I inhibitor through virtual screening, in vitro activity assay, and surface plasmon resonance assay. Cellular thermal shift assay showed that H7 directly bound to Prdx I but not to Prdxs II–V in cells. H7 treatment also increased reactive oxygen species (ROS) level and cell differentiation in leukemia cells, as reflected by the upregulation of the cell surface differentiation marker CD11b/CD14 and the morphological maturation of cells. The differentiation-induction effect of H7 was further observed in some non-acute promyelocytic leukemia (APL) and primary leukemia cells apart from APL NB4 cells. Moreover, the ROS scavenger N-acetyl cysteine significantly reversed the H7-induced cell differentiation. We demonstrated as well that H7-induced cell differentiation was associated with the activation of the ROS-Erk1/2-C/EBPβ axis. Finally, we showed H7 treatment induced cell differentiation in an APL mouse model. All of these data confirmed that Prdx I was novel target for inducing leukemia-cell differentiation and that H7 was a novel lead compound for optimizing Prdx I inhibition. PMID:26716647

  2. Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells.

    PubMed

    Sánchez-Martínez, Diego; Lanuza, Pilar M; Gómez, Natalia; Muntasell, Aura; Cisneros, Elisa; Moraru, Manuela; Azaceta, Gemma; Anel, Alberto; Martínez-Lostao, Luis; Villalba, Martin; Palomera, Luis; Vilches, Carlos; García Marco, José A; Pardo, Julián

    2016-01-01

    Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments.

  3. Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells

    PubMed Central

    Sánchez-Martínez, Diego; Lanuza, Pilar M.; Gómez, Natalia; Muntasell, Aura; Cisneros, Elisa; Moraru, Manuela; Azaceta, Gemma; Anel, Alberto; Martínez-Lostao, Luis; Villalba, Martin; Palomera, Luis; Vilches, Carlos; García Marco, José A.; Pardo, Julián

    2016-01-01

    Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments. PMID:27833611

  4. MLL leukemia induction by genome editing of human CD34+ hematopoietic cells

    PubMed Central

    Buechele, Corina; Breese, Erin H.; Schneidawind, Dominik; Lin, Chiou-Hong; Jeong, Johan; Duque-Afonso, Jesus; Wong, Stephen H. K.; Smith, Kevin S.; Negrin, Robert S.; Porteus, Matthew

    2015-01-01

    Chromosomal rearrangements involving the mixed-lineage leukemia (MLL) gene occur in primary and treatment-related leukemias and confer a poor prognosis. Studies based primarily on mouse models have substantially advanced our understanding of MLL leukemia pathogenesis, but often use supraphysiological oncogene expression with uncertain implications for human leukemia. Genome editing using site-specific nucleases provides a powerful new technology for gene modification to potentially model human disease, however, this approach has not been used to re-create acute leukemia in human cells of origin comparable to disease observed in patients. We applied transcription activator-like effector nuclease–mediated genome editing to generate endogenous MLL-AF9 and MLL-ENL oncogenes through insertional mutagenesis in primary human hematopoietic stem and progenitor cells (HSPCs) derived from human umbilical cord blood. Engineered HSPCs displayed altered in vitro growth potentials and induced acute leukemias following transplantation in immunocompromised mice at a mean latency of 16 weeks. The leukemias displayed phenotypic and morphologic similarities with patient leukemia blasts including a subset with mixed phenotype, a distinctive feature seen in clinical disease. The leukemic blasts expressed an MLL-associated transcriptional program with elevated levels of crucial MLL target genes, displayed heightened sensitivity to DOT1L inhibition, and demonstrated increased oncogenic potential ex vivo and in secondary transplant assays. Thus, genome editing to create endogenous MLL oncogenes in primary human HSPCs faithfully models acute MLL-rearranged leukemia and provides an experimental platform for prospective studies of leukemia initiation and stem cell biology in a genetic subtype of poor prognosis leukemia. PMID:26311362

  5. MLL leukemia induction by genome editing of human CD34+ hematopoietic cells.

    PubMed

    Buechele, Corina; Breese, Erin H; Schneidawind, Dominik; Lin, Chiou-Hong; Jeong, Johan; Duque-Afonso, Jesus; Wong, Stephen H K; Smith, Kevin S; Negrin, Robert S; Porteus, Matthew; Cleary, Michael L

    2015-10-01

    Chromosomal rearrangements involving the mixed-lineage leukemia (MLL) gene occur in primary and treatment-related leukemias and confer a poor prognosis. Studies based primarily on mouse models have substantially advanced our understanding of MLL leukemia pathogenesis, but often use supraphysiological oncogene expression with uncertain implications for human leukemia. Genome editing using site-specific nucleases provides a powerful new technology for gene modification to potentially model human disease, however, this approach has not been used to re-create acute leukemia in human cells of origin comparable to disease observed in patients. We applied transcription activator-like effector nuclease-mediated genome editing to generate endogenous MLL-AF9 and MLL-ENL oncogenes through insertional mutagenesis in primary human hematopoietic stem and progenitor cells (HSPCs) derived from human umbilical cord blood. Engineered HSPCs displayed altered in vitro growth potentials and induced acute leukemias following transplantation in immunocompromised mice at a mean latency of 16 weeks. The leukemias displayed phenotypic and morphologic similarities with patient leukemia blasts including a subset with mixed phenotype, a distinctive feature seen in clinical disease. The leukemic blasts expressed an MLL-associated transcriptional program with elevated levels of crucial MLL target genes, displayed heightened sensitivity to DOT1L inhibition, and demonstrated increased oncogenic potential ex vivo and in secondary transplant assays. Thus, genome editing to create endogenous MLL oncogenes in primary human HSPCs faithfully models acute MLL-rearranged leukemia and provides an experimental platform for prospective studies of leukemia initiation and stem cell biology in a genetic subtype of poor prognosis leukemia.

  6. Epigenetics in T-cell acute lymphoblastic leukemia.

    PubMed

    Peirs, Sofie; Van der Meulen, Joni; Van de Walle, Inge; Taghon, Tom; Speleman, Frank; Poppe, Bruce; Van Vlierberghe, Pieter

    2015-01-01

    Normal T-cell development is a strictly regulated process in which hematopoietic progenitor cells migrate from the bone marrow to the thymus and differentiate from early T-cell progenitors toward mature and functional T cells. During this maturation process, cooperation between a variety of oncogenes and tumor suppressors can drive immature thymocytes into uncontrolled clonal expansion and cause T-cell acute lymphoblastic leukemia (T-ALL). Despite improved insights in T-ALL disease biology and comprehensive characterization of its genetic landscape, clinical care remained largely similar over the past decades and still consists of high-dose multi-agent chemotherapy potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable side effects, clinical outcome is still extremely poor in a significant subset of T-ALL patients as a result of therapy resistance or hematological relapses. Recent genetic studies have identified recurrent somatic alterations in genes involved in DNA methylation and post-translational histone modifications in T-ALL, suggesting that epigenetic homeostasis is critically required in restraining tumor development in the T-cell lineage. In this review, we provide an overview of the epigenetic regulators that could be implicated in T-ALL disease biology and speculate how the epigenetic landscape of T-ALL could trigger the development of epigenetic-based therapies to further improve the treatment of human T-ALL.

  7. Complete suppression of in vivo growth of human leukemia cells by specific immunotoxins: nude mouse models

    SciTech Connect

    Hara, H.; Seon, B.K.

    1987-05-01

    In this study, immunotoxins containing monoclonal anti-human T-cell leukemia antibodies are shown to be capable of completely suppressing the tumor growth of human T-cell leukemia cells in vivo without any overt undersirable toxicity. These immunotoxins were prepared by conjugating ricin A chain (RA) with our monoclonal antibodies, SN1 and SN2, directed specifically to the human T-cell leukemia cell surface antigens TALLA and GP37, respectively. The authors have shown that these monoclonal antibodies are highly specific for human T-cell leukemia cells and do not react with various normal cells including normal T and B cells, thymocytes, and bone marrow cells. Ascitic and solid human T-cell leukemia cell tumors were generated in nude mice. The ascitic tumor was generated by transplanting Ichikawa cells (a human T-cell leukemia cell) i.p. into nude mice, whereas the solid tumor was generated by transplanting s.c. MOLT-4 cells (a human T-cell leukemia cell line) and x-irradiated human fibrosarcoma cells into x-irradiated nude mice. To investigate the efficacy of specific immunotoxins in suppression the in vivo growth of the ascitic tumor, they divided 40 nude mice that were injected with Ichikawa cells into four groups. None of the mice in group 4 that were treated with SN1-RA and SN2-RA showed any signs of a tumor or undesirable toxic effects for the 20 weeks that they were followed after the transplantation. Treatment with SN1-RA plus SN2-RA completely suppressed solid tumor growth in 4 of 10 nude mice carrying solid tumors and partially suppressed the tumor growth in the remaining 6 nude mice. These results strongly suggest that SN1-RA and SN2-RA may be useful for clinical treatment.

  8. Molecular Pathology of Adult T-Cell Leukemia/Lymphoma.

    PubMed

    Ohshima, Koichi

    2015-01-01

    Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm of highly pleomorphic lymphoid cells. ATLL is usually widely disseminated, and it is caused by human T-cell leukemia virus type 1 (HTLV-1). It is a disease with a long latency, and affected individuals are usually exposed to the virus very early in life. The cumulative incidence of ATLL is estimated to be 2.5% among HTLV-1 carriers. ATLL cells express CD2, CD3, CD5, CD4, and CD25, as well as CCR4 and FoxP3 of the regulatory T-cell marker. HTLV-1 is causally linked to ATLL, but infection alone is not sufficient to result in neoplastic transformation. A significant finding in this connection is that the Tax viral protein leads to transcriptional activation of many genes, while the HTLV-1 basic leucine zipper factor is thought to be important for T-cell proliferation and oncogenesis. Half of ATLL cases retain the ability to express HTLV-1 Tax, which is a target of HTLV-1-specific cytotoxic T lymphocytes (CTL). An increase in HTLV-1-specific CTL responses is observed in some asymptomatic HTLV-1 carriers. Although HTLV-1-specific CTL are also present in the peripheral blood of ATLL patients, they do not expand sufficiently. We investigated the clinicopathological features and analyzed the staining of Tax-specific CTL and FoxP3. Tax-specific CTL correlated inversely with FoxP3, an increase in the ratio of CD163+ tumor-associated macrophages was associated with worse clinical prognosis, and ATLL cell lines proliferated significantly following direct co-culture with M2 macrophages. Several clinical variants of ATLL have been identified: acute, lymphomatous, chronic, and smoldering. Oligo-array comparative genomic hybridization revealed that genomic loss of 9p21.3 was a significant characteristic of acute-type, but not of chronic-type ATLL. Furthermore, we found that genomic alteration of CD58, which is implicated in immune escape, is more frequently observed in acute than in chronic ATLL. Interestingly

  9. Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells.

    PubMed

    Tang, Ruoping; Faussat, Anne-Marie; Majdak, Patricia; Marzac, Christophe; Dubrulle, Sabine; Marjanovic, Zora; Legrand, Ollivier; Marie, Jean-Pierre

    2006-03-01

    Semisynthetic homoharringtonine (ssHHT) is now being evaluated in phase II clinical trials for the treatment of chronic myelogenous leukemia and acute myelogenous leukemia patients. Here, we examined the mechanism of the apoptosis induced by ssHHT in myeloid leukemia cells. First, we have shown that ssHHT induces apoptosis in HL60 and HL60/MRP cell lines in a time- and dose-dependent manner, and independently of the expression of Bax. The decrease of mitochondrial membrane potential and the release of cytochrome c were observed in the apoptotic cells induced by ssHHT. To unveil the relationship between ssHHT and the mitochondrial disruption, we have shown that ssHHT decreased myeloid cell leukemia-1 (Mcl-1) expression and induced Bcl-2 cleavage in HL60 and HL60/MRP cell lines. The Bcl-2 cleavage could be inhibited by the Z-VAD.fmk caspase inhibitor. However, Mcl-1 turnover was very rapid and occurred before caspase activation. The Mcl-1 turnover was only induced by ssHHT and cycloheximide, but not by daunorubicin and cytosine arabinoside, and could be restored by proteasome inhibitors. Second, we confirmed that ssHHT rapidly induced massive apoptosis in acute myelogenous leukemia patient cells. We have also confirmed the release of cytochrome c and a rapid turnover of Mcl-1 in these patient cells, taking place only in apoptotic cells induced by ssHHT but not in cells undergoing spontaneous apoptosis. Finally, we have shown that ssHHT inhibits protein synthesis in both cell line and patient cells. We suggest that the inhibition of protein synthesis and resulting Mcl-1 turnover play a key role in the apoptosis induced by ssHHT. Our results encourage further clinical trials for the use of ssHHT in acute myelogenous leukemia.

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

    NASA Astrophysics Data System (ADS)

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

    2015-05-01

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

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

    SciTech Connect

    Tashiro, Haruko; Mizutani-Noguchi, Mitsuho; Shirasaki, Ryosuke

    2010-01-01

    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.

  12. Pediatric donor cell leukemia after allogeneic hematopoietic stem cell transplantation in AML patient from related donor.

    PubMed

    Bobadilla-Morales, Lucina; Pimentel-Gutiérrez, Helia J; Gallegos-Castorena, Sergio; Paniagua-Padilla, Jenny A; Ortega-de-la-Torre, Citlalli; Sánchez-Zubieta, Fernando; Silva-Cruz, Rocio; Corona-Rivera, Jorge R; Zepeda-Moreno, Abraham; González-Ramella, Oscar; Corona-Rivera, Alfredo

    2015-01-01

    Here we present a male patient with acute myeloid leukemia (AML) initially diagnosed as M5 and with karyotype 46,XY. After induction therapy, he underwent a HLA-matched allogeneic hematopoietic stem cell transplantation, and six years later he relapsed as AML M1 with an abnormal karyotype //47,XX,+10[2]/47,XX,+11[3]/48,XX,+10,+11[2]/46,XX[13]. Based on this, we tested the possibility of donor cell origin by FISH and molecular STR analysis. We found no evidence of Y chromosome presence by FISH and STR analysis consistent with the success of the allogeneic hematopoietic stem cell transplantation from the female donor. FISH studies confirmed trisomies and no evidence of MLL translocation either p53 or ATM deletion. Additionally 28 fusion common leukemia transcripts were evaluated by multiplex reverse transcriptase-polymerase chain reaction assay and were not rearranged. STR analysis showed a complete donor chimerism. Thus, donor cell leukemia (DCL) was concluded, being essential the use of cytological and molecular approaches. Pediatric DCL is uncommon, our patient seems to be the sixth case and additionally it presented a late donor cell leukemia appearance. Different extrinsic and intrinsic mechanisms have been considered to explain this uncommon finding as well as the implications to the patient.

  13. Enhancement of anti-leukemia activity of NK cells in vitro and in vivo by inhibition of leukemia cell-induced NK cell damage

    PubMed Central

    Arriga, Roberto; Caratelli, Sara; Coppola, Andrea; Spagnoli, Giulio Cesare; Venditti, Adriano; Amadori, Sergio; Lanzilli, Giulia; Lauro, Davide; Palomba, Patrizia; Sconocchia, Tommaso; Del Principe, Maria Ilaria; Maurillo, Luca; Buccisano, Francesco; Capuani, Barbara; Ferrone, Soldano; Sconocchia, Giuseppe

    2016-01-01

    Acute myeloid leukemia (AML) cells induce, in vitro, NK cell abnormalities (NKCAs) including apoptosis and activating receptor down-regulation. The potential negative impact of AML cells on the therapeutic efficacy of NK cell-based strategies prompted us to analyze the mechanisms underlying NKCAs and to develop approaches to protect NK cells from NKCAs. NKCA induction by the AML leukemia cells target a subpopulation of peripheral blood NK cells and is interleukin-2 independent but is abrogated by a long-term culture of NK (LTNK) cells at 37°C. LTNK cells displayed a significantly enhanced ability to damage AML cells in vitro and inhibited the subcutaneous growth of ML-2 cells grafted into CB17 SCID mice. Actinomycin D restored the susceptibility of LTNK cells to NKCAs while TAPI-0, a functional analog of the tissue inhibitor of metalloproteinase (TIMP) 3, inhibits ML-2 cell-induced NKCAs suggesting that the generation of NK cell resistance to NKCAs involves RNA transcription and metalloproteinase (MPP) inactivation. This conclusion is supported by the reduced susceptibility to AML cell-induced NKCAs of LTNK cells in which TIMP3 gene and protein are over-expressed. This information may contribute to the rational design of targeted strategies to enhance the efficacy of NK cell-based-immunotherapy of AML with haploidentical NK cells. PMID:26655503

  14. Enhancement of anti-leukemia activity of NK cells in vitro and in vivo by inhibition of leukemia cell-induced NK cell damage.

    PubMed

    Arriga, Roberto; Caratelli, Sara; Coppola, Andrea; Spagnoli, Giulio Cesare; Venditti, Adriano; Amadori, Sergio; Lanzilli, Giulia; Lauro, Davide; Palomba, Patrizia; Sconocchia, Tommaso; Del Principe, Maria Ilaria; Maurillo, Luca; Buccisano, Francesco; Capuani, Barbara; Ferrone, Soldano; Sconocchia, Giuseppe

    2016-01-12

    Acute myeloid leukemia (AML) cells induce, in vitro, NK cell abnormalities (NKCAs) including apoptosis and activating receptor down-regulation. The potential negative impact of AML cells on the therapeutic efficacy of NK cell-based strategies prompted us to analyze the mechanisms underlying NKCAs and to develop approaches to protect NK cells from NKCAs. NKCA induction by the AML leukemia cells target a subpopulation of peripheral blood NK cells and is interleukin-2 independent but is abrogated by a long-term culture of NK (LTNK) cells at 37°C. LTNK cells displayed a significantly enhanced ability to damage AML cells in vitro and inhibited the subcutaneous growth of ML-2 cells grafted into CB17 SCID mice. Actinomycin D restored the susceptibility of LTNK cells to NKCAs while TAPI-0, a functional analog of the tissue inhibitor of metalloproteinase (TIMP) 3, inhibits ML-2 cell-induced NKCAs suggesting that the generation of NK cell resistance to NKCAs involves RNA transcription and metalloproteinase (MPP) inactivation. This conclusion is supported by the reduced susceptibility to AML cell-induced NKCAs of LTNK cells in which TIMP3 gene and protein are over-expressed. This information may contribute to the rational design of targeted strategies to enhance the efficacy of NK cell-based-immunotherapy of AML with haploidentical NK cells.

  15. Fludarabine Phosphate and Total-Body Radiation Followed by Donor Peripheral Blood Stem Cell Transplant and Immunosuppression in Treating Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2016-11-28

    Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; Waldenström Macroglobulinemia

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

    PubMed Central

    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. PMID:27458532

  17. huJCAR014 CAR-T Cells in Treating Adult Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2017-03-31

    Adult B Acute Lymphoblastic Leukemia; CD19 Positive; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Adult Acute Lymphoblastic Leukemia; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

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

    ClinicalTrials.gov

    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)

  19. Leukemia patient-derived lymphoblastoid cell lines exhibit increased induction of leukemia-associated transcripts following high-dose irradiation.

    PubMed

    Spencer, A; Granter, N

    1999-09-01

    Improvement in diagnostic cytogenetic techniques has led to the recognition of an increasing number of leukemia-associated chromosomal translocations and inversions. These genetic lesions frequently are associated with the disruption of putative transcription factors and the production of hybrid transcripts that are implicated in leukemogenesis. Epidemiologic evidence suggests that some, but not all, individuals with a history of gamma-irradiation exposure are at increased risk of developing chronic myeloid leukemia (CML). CML is characterized by the Philadelphia chromosome and transcription of the resulting hybrid BCR-ABL gene. Utilizing the leukemia-associated BCR-ABL p210 transcript as a marker, we sought differences in the induction of illegitimate genetic recombination following high-dose gamma-irradiation of karyotypically normal lymphoblastoid cell lines (LCL) derived from individuals with and without a history of myeloid leukemias. Six LCL [4 leukemia patient derived [2 acute myeloid leukemia and 2 CML] and 2 from normal individuals were analyzed with reverse transcriptase polymerase chain reaction for BCR-ABL under stringent conditions following exposure to 0, 50, or 100 Gy of LET gamma-irradiation delivered via a Varian linear accelerator at 4 MV. Transcripts identical to disease-associated b2a2 and b3a2 transcripts were detected both spontaneously (background illegitimate genetic recombination) and following gamma-irradiation. Background BCR-ABL positivity was demonstrable in 4 of the 6 LCL, with no significant difference in detection between leukemic- and nonleukemic-derived LCL. Overall, increasing gamma-irradiation dose resulted in an increased frequency of BCR-ABL transcript detection (0 Gy vs 50 Gy vs 100 Gy,p = 0.0023, Chi-square test). Within the leukemic- but not the nonleukemic-derived LCL there was significantly greater BCR-ABL positivity after gamma-irradiation compared to unirradiated equivalents. Furthermore, the BCR-ABL positivity of both

  20. Flow cytometric analysis of cell-surface and intracellular antigens in the diagnosis of acute leukemia.

    PubMed

    Paredes-Aguilera, R; Romero-Guzman, L; Lopez-Santiago, N; Burbano-Ceron, L; Camacho-Del Monte, O; Nieto-Martinez, S

    2001-10-01

    To evaluate the usefulness of flow cytometric detection of intracellular antigens (Ags) in establishing proper lineage affiliation and its contribution to the diagnosis of acute leukemia, we studied 100 consecutive patients in whom acute leukemia was diagnosed between January 1997 and July 1998. Immunological classification was assessed using a three-line panel of monoclonal antibodies for phenotypic characterization of leukemic blast cells as proposed at the First Latin American Consensus Conference for Flow Cytometric Immunophenotyping of Leukemia. We found 74 cases of B-cell lineage acute lymphoblastic leukemia (ALL), seven cases of T-cell ALL, and 19 cases of acute myeloid leukemia (AML). In this study cytoplasmic (cy) CD79a, cyCD22, cyCD3, and cyMPO were highly sensitive, specific B, T, and myeloid markers that were expressed in virtually all cases of B and T cell ALL and in all subtypes of AML. Applied in combination with immunophenotyping this knowledge led to improvement in diagnostic precision and refinement of immunological classification, ensuring the selection of the most appropriate therapy for the patients studied. In conclusion, intracellular Ags detection was of utmost importance in establishing correct lineage affiliation in cases lacking expression of B, T, or myeloid surface Ags or disclosing equivocal or ambiguous immunophenotypic features and in identifying biphenotypic acute leukemia. In combination with FAB morphology and immunophenotyping, we were able to reliably classify all patients with acute leukemia in this study.

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

    SciTech Connect

    Marrero, Maria Teresa; Estevez, Sara; Negrin, Gledy; Quintana, Jose; Leon, Francisco; Estevez, Francisco

    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.

  2. Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells*

    PubMed Central

    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.

    2013-01-01

    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

  3. Synergistic Interactions between HDAC and Sirtuin Inhibitors in Human Leukemia Cells

    PubMed Central

    Cea, Michele; Soncini, Debora; Fruscione, Floriana; Raffaghello, Lizzia; Garuti, Anna; Emionite, Laura; Moran, Eva; Magnone, Mirko; Zoppoli, Gabriele; Reverberi, Daniele; Caffa, Irene; Salis, Annalisa; Cagnetta, Antonia; Bergamaschi, Micaela; Casciaro, Salvatore; Pierri, Ivana; Damonte, Gianluca; Ansaldi, Filippo; Gobbi, Marco; Pistoia, Vito; Ballestrero, Alberto; Patrone, Franco

    2011-01-01

    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. PMID:21818379

  4. Remediation of textile azo dye acid red 114 by hairy roots of Ipomoea carnea Jacq. and assessment of degraded dye toxicity with human keratinocyte cell line.

    PubMed

    Jha, Pamela; Jobby, Renitta; Desai, N S

    2016-07-05

    Bioremediation has proven to be the most desirable and cost effective method to counter textile dye pollution. Hairy roots (HRs) of Ipomoea carnea J. were tested for decolourization of 25 textile azo dyes, out of which >90% decolourization was observed in 15 dyes. A diazo dye, Acid Red 114 was decolourized to >98% and hence, was chosen as the model dye. A significant increase in the activities of oxidoreductive enzymes was observed during decolourization of AR114. The phytodegradation of AR114 was confirmed by HPLC, UV-vis and FTIR spectroscopy. The possible metabolites were identified by GCMS as 4- aminobenzene sulfonic acid 2-methylaniline and 4- aminophenyl 4-ethyl benzene sulfonate and a probable pathway for the biodegradation of AR114 has been proposed. The nontoxic nature of the metabolites and toxicity of AR114 was confirmed by cytotoxicity tests on human keratinocyte cell line (HaCaT). When HaCaT cells were treated separately with 150 μg mL(-1) of AR114 and metabolites, MTT assay showed 50% and ≈100% viability respectively. Furthermore, flow cytometry data showed that, as compared to control, the cells in G2-M and death phase increased by 2.4 and 3.6 folds respectively on treatment with AR114 but remained unaltered in cells treated with metabolites.

  5. Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage III-IV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia

    ClinicalTrials.gov

    2016-10-24

    Childhood B Acute Lymphoblastic Leukemia; Childhood Burkitt Leukemia; Childhood Diffuse Large Cell Lymphoma; Mediastinal (Thymic) Large B-Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma

  6. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

    PubMed Central

    Samudio, Ismael; Harmancey, Romain; Fiegl, Michael; Kantarjian, Hagop; Konopleva, Marina; Korchin, Borys; Kaluarachchi, Kumar; Bornmann, William; Duvvuri, Seshagiri; Taegtmeyer, Heinrich; Andreeff, Michael

    2009-01-01

    The traditional view is that cancer cells predominately produce ATP by glycolysis, rather than by oxidation of energy-providing substrates. Mitochondrial uncoupling — the continuing reduction of oxygen without ATP synthesis — has recently been shown in leukemia cells to circumvent the ability of oxygen to inhibit glycolysis, and may promote the metabolic preference for glycolysis by shifting from pyruvate oxidation to fatty acid oxidation (FAO). Here we have demonstrated that pharmacologic inhibition of FAO with etomoxir or ranolazine inhibited proliferation and sensitized human leukemia cells — cultured alone or on bone marrow stromal cells — to apoptosis induction by ABT-737, a molecule that releases proapoptotic Bcl-2 proteins such as Bak from antiapoptotic family members. Likewise, treatment with the fatty acid synthase/lipolysis inhibitor orlistat also sensitized leukemia cells to ABT-737, which supports the notion that fatty acids promote cell survival. Mechanistically, we generated evidence suggesting that FAO regulates the activity of Bak-dependent mitochondrial permeability transition. Importantly, etomoxir decreased the number of quiescent leukemia progenitor cells in approximately 50% of primary human acute myeloid leukemia samples and, when combined with either ABT-737 or cytosine arabinoside, provided substantial therapeutic benefit in a murine model of leukemia. The results support the concept of FAO inhibitors as a therapeutic strategy in hematological malignancies. PMID:20038799

  7. Chronic Myeloid Leukemia

    MedlinePlus

    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. ...

  8. Chronic Lymphocytic Leukemia

    MedlinePlus

    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. ...

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

    ClinicalTrials.gov

    2017-02-20

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

  10. Successful Hematopoietic Cell Transplantation in a Patient With X-linked Agammaglobulinemia and Acute Myeloid Leukemia

    PubMed Central

    Abu-Arja, Rolla F.; Chernin, Leah R.; Abusin, Ghada; Auletta, Jeffery; Cabral, Linda; Egler, Rachel; Ochs, Hans D.; Torgerson, Troy R.; Lopez-Guisa, Jesus; Hostoffer, Robert W.; Tcheurekdjian, Haig; Cooke, Kenneth R.

    2016-01-01

    X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19+ B-cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patient’s leukemia. PMID:25900577

  11. B Cell Acute Lymphocytic Leukemia Presenting as a Bile Duct Stricture Diagnosed With Cholangioscopy

    PubMed Central

    Bartel, Michael J.; Jiang, Liuyan; Lukens, Frank

    2016-01-01

    Indeterminate biliary strictures represent a diagnostic challenge requiring further work-up, which encompasses a variety of diagnostic modalities. We report a very rare case of B-cell acute lymphocytic leukemia presenting as a biliary stricture following remission of acute myeloid leukemia, which was initially treated with allogenic stem cell transplant. After multiple diagnostic modalities were implemented with no success, the use of cholangioscopy-guided biopsies was the key for the final diagnosis. PMID:27807569

  12. Identification of Merkel Cell Polyomavirus from a Patient with Acute Myeloid Leukemia

    PubMed Central

    Song, Y.

    2017-01-01

    ABSTRACT Merkel cell polyomavirus (MCPyV) is an oncogenic virus associated with Merkel cell carcinoma, an aggressive form of skin cancer with a high (>30%) mortality rate. The virus has a high incidence in patients with immunosuppressed conditions, such as AIDS or leukemia, or following organ transplantation. Here, we report the complete genomic sequence of MCPyV identified from a blood sample from a patient with acute myeloid leukemia. PMID:28104648

  13. The quality and quantity of leukemia-derived dendritic cells from patients with acute myeloid leukemia and myelodysplastic syndrome are a predictive factor for the lytic potential of dendritic cells-primed leukemia-specific T cells.

    PubMed

    Grabrucker, Christine; Liepert, Anja; Dreyig, Julia; Kremser, Andreas; Kroell, Tanja; Freudenreich, Markus; Schmid, Christoph; Schweiger, Cornelia; Tischer, Johanna; Kolb, Hans-Jochen; Schmetzer, Helga

    2010-06-01

    Adoptive immunotherapy is an important therapy option to reduce relapse rates after stem-cell transplantation in patients suffering from acute myeloid leukemia and myelodysplastic syndromes. Myeloid leukemic cells can regularly be induced to differentiate into leukemia-derived dendritic cells (DC(leu)), regaining the stimulatory capacity of professional dendritic cells (DCs) while presenting the known/unknown leukemic antigen repertoire. So far, induced antileukemic T-cell responses are variable or even mediate opposite effects. To further elicit DC/DC(leu)-induced T-cell-response patterns, we generated DC from 17 Acute myeloid leukemia (AML) and 2 myelodysplastic syndrome cases and carried out flowcytometry and (functional) nonradioactive fluorolysis assays before/after mixed lymphocyte cultures of matched (allogeneic) donor T cells (n=6), T cells prepared at relapse after stem-cell transplantation (n=4) or (autologous) patients' T cells (n=7) with blast containing mononuclear cells ("MNC") or DC(leu) ("DC"). Compared with "MNC", "DC" were better mediators of antileukemic-activity, although not in every case effective. We could define DC subtypes and cut-off proportions of DC subtypes/qualities (mature DC/DC(leu)) after "DC" priming, which were predictive for an antileukemic activity of primed T cells and the clinical course of the disease after immunotherapy (allogeneic stem-cell transplantation/donor lymphocytes infusion/therapy). In summary, our data show that the composition and quality of DC after a mixed lymphocyte culture-priming phase is predictive for a successful ex vivo antileukemic response, especially with respect to proportions of mature and leukemia-derived DC. These data contribute not only to predict DC-mediated functions or the clinical course of the diseases but also to develop and refine DC-vaccination strategies that may pave the way to develop and modify adoptive immunotherapy, especially for patients at relapse after allogeneic stem-cell

  14. Cancerous inhibitor of protein phosphatase 2A determines bortezomib-induced apoptosis in leukemia cells

    PubMed Central

    Liu, Chun-Yu; Shiau, Chung-Wai; Kuo, Hsin-Yu; Huang, Hsiang-Po; Chen, Ming-Huang; Tzeng, Cheng-Hwai; Chen, Kuen-Feng

    2013-01-01

    The multiple cellular targets affected by proteasome inhibition implicate a potential role for bortezomib, a first-in-class proteasome inhibitor, in enhancing antitumor activities in hematologic malignancies. Here, we examined the antitumor activity and drug targets of bortezomib in leukemia cells. Human leukemia cell lines were used for in vitro studies. Drug efficacy was evaluated by apoptosis assays and associated molecular events assessed by Western Blot. Gene silencing was performed by small interference RNA. Drug was tested in vivo in xenograft models of human leukemia cell lines and in primary leukemia cells. Clinical samples were assessed by immunohistochemical staining. Bortezomib differentially induced apoptosis in leukemia cells that was independent of its proteasome inhibition. Cancerous inhibitor of protein phosphatase 2A, a cellular inhibitor of protein phosphatase 2A, mediated the apoptotic effect of bortezomib. Bortezomib increased protein phosphatase 2A activity in sensitive leukemia cells (HL-60 and KG-1), but not in resistant cells (MOLT-3 and K562). Bortezomib’s downregulation of cancerous inhibitor of protein phosphatase 2A and phospho-Akt correlated with its drug sensitivity. Furthermore, cancerous inhibitor of protein phosphatase 2A negatively regulated protein phosphatase 2A activity. Ectopic expression of CIP2A up-regulated phospho-Akt and protected HL-60 cells from bortezomib-induced apoptosis, whereas silencing CIP2A overcame the resistance to bortezomib-induced apoptosis in MOLT3 and K562 cells. Importantly, bortezomib exerted in vivo antitumor activity in HL-60 xenografted tumors and induced cell death in some primary leukemic cells. Cancerous inhibitor of protein phosphatase 2A was expressed in leukemic blasts from bone marrow samples. Cancerous inhibitor of protein phosphatase 2A plays a major role in mediating bortezomib-induced apoptosis in leukemia cells. PMID:22983581

  15. Intracellular localization of the Epstein-Barr virus BFRF1 gene product in lymphoid cell lines and oral hairy leukoplakia lesions.

    PubMed

    Farina, Antonella; Cardinali, Giorgia; Santarelli, Roberta; Gonnella, Roberta; Webster-Cyriaque, Jennifer; Bei, Roberto; Muraro, Raffaella; Frati, Luigi; Angeloni, Antonio; Torrisi, Maria Rosaria; Faggioni, Alberto

    2004-01-01

    A novel protein encoded by the BFRF1 gene of the Epstein-Barr virus was identified recently [Farina et al. (2000) J Virol 74:3235-3244], which is antigenic "in vivo" and expressed early in the viral replicative cycle. In the present study, its subcellular localization was examined in greater detail comparing Epstein-Barr virus (EBV) induced producing and nonproducing cell lines by immunofluorescence: in 12-0-tetradecanoyl phorbol-13-acetate (TPA)-induced Raji and B95-8 cells, as well as in anti-IgG-stimulated Akata cells, the protein appeared to be localized over the cell nuclear membrane. A similar nuclear membrane localization was observed in epithelial cells of oral hairy leukoplakia, a pathological manifestation of permissive EBV infection. In contrast, upon transfection of BFRF1 in the EBV-negative Burkitt's lymphoma cell line DG75, the protein was localized predominantly over the plasma membrane. The membrane localization was abolished when DG75 cells were transfected with a C-terminal deletion mutant of BFRF1 lacking the transmembrane domain. Because induced Raji cells do not produce virus, the above observations indicate that the nuclear membrane localization is not associated with viral production, but requires the expression of EBV genes, and suggest that additional proteins, expressed early during viral lytic infection, might be necessary to target the protein to the nuclear membrane. Immunogold electron microscopy on ultrathin cryosections of induced B95-8 cells showed that BFRF1 on the nuclear membranes was concentrated over multilayered domains representing areas of active viral replication or at the sites of viral budding, suggesting that BFRF1 is involved in the process of viral assembly.

  16. The cytotoxic effect of 2-acylated-1,4-naphthohydroquinones on leukemia/lymphoma cells.

    PubMed

    Pedroza, Diego A; De Leon, Fernando; Varela-Ramirez, Armando; Lema, Carolina; Aguilera, Renato J; Mito, Shizue

    2014-01-15

    Here, we tested seven 2-acylated-1,4-hydronaphthoquinones for their cytotoxic effects on a panel of cancer lymphoma/leukemia cells and compared to a non-cancer origin cell line. Several naphthohydroquinones exhibited selective cytotoxic effects on lymphoma/leukemia cells with lowest activity on non-cancer cells. The mode of cell death induced by an acylated naphthohydroquinone, which has a long alkyl chain, was found to be via apoptosis. Furthermore, the naphthohydroquinone provoked mitochondria depolarization and activation of its downstream effector, caspase-3, thus implicating the intrinsic apoptotic pathway as its mechanism to exert cell death.

  17. The cytotoxic effect of 2-acylated-1,4-naphthohydroquinones on leukemia/lymphoma cells

    PubMed Central

    Pedroza, Diego A.; De Leon, Fernando; Varela-Ramirez, Armando; Lema, Carolina; Aguilera, Renato J.; Mito, Shizue

    2014-01-01

    Here, we tested seven 2-acylated-1,4-hydronaphthoquinones for their cytotoxic effects on a panel of cancer lymphoma/leukemia cells and compared to a non-cancer origin cell line. Several naphthohydroquinones exhibited selective cytotoxic effects on lymphoma/leukemia cells with lowest activity on non-cancer cells. The mode of cell death induced by an acylated naphthohydroquinone, which has a long alkyl chain, was found to be via apoptosis. Furthermore, the naphthohydroquinone provoked mitochondria depolarization and activation of its downstream effector, caspase-3, thus implicating the intrinsic apoptotic pathway as its mechanism to exert cell death. PMID:24368029

  18. Elevated expression of pleiotrophin in lymphocytic leukemia CD19+ B cells.

    PubMed

    Du, Chun-Xian; Wang, Lan; Li, Yan; Xiao, Wei; Guo, Qin-Lian; Chen, Fei; Tan, Xin-Ti

    2014-10-01

    Pleiotrophin (PTN) has been demonstrated to be strongly expressed in many fetal tissues, but seldom in healthy adult tissues. While PTN has been reported to be expressed in many types of tumors as well as at high serum concentrations in patients with many types of cancer, to date, there has been no report that PTN is expressed in leukemia, especially in lymphocytic leukemia. We isolated the CD19(+) subset of B cells from peripheral blood from healthy adults, B-cell acute lymphocytic leukemia (B-ALL) patients, and B-cell chronic lymphocytic leukemia (B-CLL) patients and examined these cells for PTN mRNA and protein expression. We used immunocytochemistry, western blotting, and enzyme-linked immunosorbent assay to show that PTN protein is highly expressed in CD19(+) B cells from B-ALL and B-CLL patients, but barely expressed in B cells from healthy adults. We also examined PTN expression at the nucleic acid level using reverse transcription polymerase chain reaction (RT-PCR) and northern blotting and detected a high levels of PTN transcripts in the CD19(+) B cells from both groups of leukemia patients, but very few in the CD19(+) B cells from the healthy controls. Interestingly, the quantity of the PTN transcripts correlated with the severity of disease. Moreover, suppression of PTN activity with an anti-PTN antibody promoted apoptosis of cells from leukemia patients and cell lines SMS-SB and JVM-2. This effect of the anti-PTN antibody suggests that PTN may be a new target for the treatment of lymphocytic leukemia.

  19. The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia.

    PubMed

    Durinck, Kaat; Wallaert, Annelynn; Van de Walle, Inge; Van Loocke, Wouter; Volders, Pieter-Jan; Vanhauwaert, Suzanne; Geerdens, Ellen; Benoit, Yves; Van Roy, Nadine; Poppe, Bruce; Soulier, Jean; Cools, Jan; Mestdagh, Pieter; Vandesompele, Jo; Rondou, Pieter; Van Vlierberghe, Pieter; Taghon, Tom; Speleman, Frank

    2014-12-01

    Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting a role as an essential driver for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34(+) thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from ex vivo isolated Notch active CD34(+) and Notch inactive CD4(+)CD8(+) thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publicly available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T cells. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way for the development of novel therapeutic strategies that target hyperactive Notch signaling in human T-cell acute lymphoblastic leukemia.

  20. Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib.

    PubMed

    Burger, Jan A; Li, Kelvin W; Keating, Michael J; Sivina, Mariela; Amer, Ahmed M; Garg, Naveen; Ferrajoli, Alessandra; Huang, Xuelin; Kantarjian, Hagop; Wierda, William G; O'Brien, Susan; Hellerstein, Marc K; Turner, Scott M; Emson, Claire L; Chen, Shih-Shih; Yan, Xiao-Jie; Wodarz, Dominik; Chiorazzi, Nicholas

    2017-01-26

    BACKGROUND. Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. METHODS. We used stable isotopic labeling with deuterated water ((2)H2O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL. RESULTS. The measured average CLL cell proliferation ("birth") rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%-1.04%); this decreased to 0.05% per day (range 0%-0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%-0.7%) prior to treatment to 1.5% per day (range 0%-3.0%) during ibrutinib therapy, and they were even higher in tissue compartments. CONCLUSIONS. This study provides the first direct in vivo measurements to our knowledge of ibrutinib's antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death. TRIAL REGISTRATION. This trial was registered at clinicaltrials.gov (NCT01752426). FUNDING. This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson's Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company.

  1. Anti-Leukemia Activity of In Vitro-Expanded Human Gamma Delta T Cells in a Xenogeneic Ph+ Leukemia Model

    PubMed Central

    Siegers, Gabrielle M.; Felizardo, Tania C.; Mathieson, A. Mark; Kosaka, Yoko; Wang, Xing-Hua; Medin, Jeffrey A.; Keating, Armand

    2011-01-01

    Gamma delta T cells (GDTc) lyse a variety of hematological and solid tumour cells in vitro and in vivo, and are thus promising candidates for cellular immunotherapy. We have developed a protocol to expand human GDTc in vitro, yielding highly cytotoxic Vgamma9/Vdelta2 CD27/CD45RA double negative effector memory cells. These cells express CD16, CD45RO, CD56, CD95 and NKG2D. Flow cytometric, clonogenic, and chromium release assays confirmed their specific cytotoxicity against Ph+ cell lines in vitro. We have generated a fluorescent and bioluminescent Ph+ cell line, EM-2eGFPluc, and established a novel xenogeneic leukemia model. Intravenous injection of EM-2eGFPluc into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice resulted in significant dose-dependent bone marrow engraftment; lower levels engrafted in blood, lung, liver and spleen. In vitro-expanded human GDTc injected intraperitoneally were found at higher levels in blood and organs compared to those injected intravenously; GDTc survived at least 33 days post-injection. In therapy experiments, we documented decreased bone marrow leukemia burden in mice treated with GDTc. Live GDTc were found in spleen and bone marrow at endpoint, suggesting the potential usefulness of this therapy. PMID:21304898

  2. Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib

    PubMed Central

    Li, Kelvin W.; Keating, Michael J.; Sivina, Mariela; Ferrajoli, Alessandra; Kantarjian, Hagop; Wierda, William G.; O’Brien, Susan; Hellerstein, Marc K.; Turner, Scott M.; Emson, Claire L.; Wodarz, Dominik; Chiorazzi, Nicholas

    2017-01-01

    BACKGROUND. Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton’s tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. METHODS. We used stable isotopic labeling with deuterated water (2H2O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL. RESULTS. The measured average CLL cell proliferation (“birth”) rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%–1.04%); this decreased to 0.05% per day (range 0%–0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%–0.7%) prior to treatment to 1.5% per day (range 0%–3.0%) during ibrutinib therapy, and they were even higher in tissue compartments. CONCLUSIONS. This study provides the first direct in vivo measurements to our knowledge of ibrutinib’s antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death. TRIAL REGISTRATION. This trial was registered at clinicaltrials.gov (NCT01752426). FUNDING. This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson’s Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company. PMID:28138560

  3. Differentially expressed cytosolic proteins in human leukemia and lymphoma cell lines correlate with lineages and functions.

    PubMed

    Gez, Swetlana; Crossett, Ben; Christopherson, Richard I

    2007-09-01

    Identification of cytosolic proteins differentially expressed between types of leukemia and lymphoma may provide a molecular basis for classification and understanding their cellular properties. Two-dimensional fluorescence difference gel electrophoresis (DIGE) and mass spectrometry have been used to identify proteins that are differentially expressed in cytosolic extracts from four human leukemia and lymphoma cell lines: HL-60 (acute promyelocytic leukemia), MEC1 (B-cell chronic lymphocytic leukemia), CCRF-CEM (T-cell acute lymphoblastic leukemia) and Raji (B-cell Burkitt's lymphoma). A total of 247 differentially expressed proteins were identified between the four cell lines. Analysis of the data by principal component analysis identified 22 protein spots (17 different protein species) differentially expressed at more than a 95% variance level between these cell lines. Several of these proteins were differentially expressed in only one cell line: HL-60 (myeloperoxidase, phosphoprotein 32 family member A, ras related protein Rab-11B, protein disulfide-isomerase, ran-specific GTPase-activating protein, nucleophosmin and S-100 calcium binding protein A4), and Raji (ezrin). Several of these proteins were differentially expressed in two cell lines: Raji and MEC1 (C-1-tetrahydrofolate synthase, elongation factor 2, alpha- and beta-tubulin, transgelin-2 and stathmin). MEC1 and CCRF-CEM (gamma-enolase), HL-60 and CCRF-CEM (ubiquitin-conjugating enzyme E2 N). The differentially expressed proteins identified in these four cell lines correlate with cellular properties and provide insights into the molecular basis of these malignancies.

  4. Hairy root transformation using Agrobacterium rhizogenes as a tool for exploring cell type-specific gene expression and function using tomato as a model.

    PubMed

    Ron, Mily; Kajala, Kaisa; Pauluzzi, Germain; Wang, Dongxue; Reynoso, Mauricio A; Zumstein, Kristina; Garcha, Jasmine; Winte, Sonja; Masson, Helen; Inagaki, Soichi; Federici, Fernán; Sinha, Neelima; Deal, Roger B; Bailey-Serres, Julia; Brady, Siobhan M

    2014-10-01

    Agrobacterium rhizogenes (or Rhizobium rhizogenes) is able to transform plant genomes and induce the production of hairy roots. We describe the use of A. rhizogenes in tomato (Solanum spp.) to rapidly assess gene expression and function. Gene expression of reporters is indistinguishable in plants transformed by Agrobacterium tumefaciens as compared with A. rhizogenes. A root cell type- and tissue-specific promoter resource has been generated for domesticated and wild tomato (Solanum lycopersicum and Solanum pennellii, respectively) using these approaches. Imaging of tomato roots using A. rhizogenes coupled with laser scanning confocal microscopy is facilitated by the use of a membrane-tagged protein fused to a red fluorescent protein marker present in binary vectors. Tomato-optimized isolation of nuclei tagged in specific cell types and translating ribosome affinity purification binary vectors were generated and used to monitor associated messenger RNA abundance or chromatin modification. Finally, transcriptional reporters, translational reporters, and clustered regularly interspaced short palindromic repeats-associated nuclease9 genome editing demonstrate that SHORT-ROOT and SCARECROW gene function is conserved between Arabidopsis (Arabidopsis thaliana) and tomato.

  5. Black hairy tongue syndrome

    PubMed Central

    Gurvits, Grigoriy E; Tan, Amy

    2014-01-01

    Black hairy tongue (BHT) is a benign medical condition characterized by elongated filiform lingual papillae with typical carpet-like appearance of the dorsum of the tongue. Its prevalence varies geographically, typically ranging from 0.6% to 11.3%. Known predisposing factors include smoking, excessive coffee/black tea consumption, poor oral hygiene, trigeminal neuralgia, general debilitation, xerostomia, and medication use. Clinical presentation varies but is typically asymptomatic, although aesthetic concerns are common. Differential diagnosis includes pseudo-BHT, acanthosis nigricans, oral hairy leukoplakia, pigmented fungiform papillae of the tongue, and congenital melanocytic/melanotic nevi/macules. Clinical diagnosis relies on visual observation, detailed history taking, and occasionally microscopic evaluation. Treatment involves identification and discontinuation of the offending agent, modifications of chronic predisposing factors, patient’s re-assurance to the benign nature of the condition, and maintenance of adequate oral hygiene with gentle debridement to promote desquamation. Complications of BHT (burning mouth syndrome, halitosis, nausea, gagging, dysgeusia) typically respond to therapy. Prognosis is excellent with treatment of underlying medical conditions. BHT remains an important medical condition which may result in additional burden on the patient and health care system and requires appropriate prevention, recognition and treatment. PMID:25152586

  6. Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia

    PubMed Central

    Maude, Shannon L.; Frey, Noelle; Shaw, Pamela A.; Aplenc, Richard; Barrett, David M.; Bunin, Nancy J.; Chew, Anne; Gonzalez, Vanessa E.; Zheng, Zhaohui; Lacey, Simon F.; Mahnke, Yolanda D.; Melenhorst, Jan J.; Rheingold, Susan R.; Shen, Angela; Teachey, David T.; Levine, Bruce L.; June, Carl H.; Porter, David L.; Grupp, Stephan A.

    2014-01-01

    BACKGROUND Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor–modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. METHODS We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×106 to 20.6×106 CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. RESULTS A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti–interleukin-6 receptor antibody tocilizumab. CONCLUSIONS Chimeric antigen receptor–modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by

  7. Acute Myeloid Leukemia

    MedlinePlus

    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 ...

  8. Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation.

    PubMed

    Roth, Michael; Will, Britta; Simkin, Guillermo; Narayanagari, Swathi; Barreyro, Laura; Bartholdy, Boris; Tamari, Roni; Mitsiades, Constantine S; Verma, Amit; Steidl, Ulrich

    2012-07-12

    Eltrombopag (EP) is a small-molecule, nonpeptide thrombopoietin receptor (TPO-R) agonist that has been approved recently for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura. Prior studies have shown that EP stimulates megakaryopoiesis in BM cells from patients with acute myeloid leukemia and myelodysplastic syndrome, and the results also suggested that it may inhibit leukemia cell growth. In the present study, we studied the effects of EP on leukemia cell proliferation and the mechanism of its antiproliferative effects. We found that EP leads to a decreased cell division rate, a block in G(1) phase of cell cycle, and increased differentiation in human and murine leukemia cells. Because EP is species specific in that it can only bind TPO-R in human and primate cells, these findings further suggested that the antileukemic effect is independent of TPO-R. We found that treatment with EP leads to a reduction in free intracellular iron in leukemic cells in a dose-dependent manner. Experimental increase of intracellular iron abrogated the antiproliferative and differentiation-inducing effects of EP, demonstrating that its antileukemic effects are mediated through modulation of intracellular iron content. Finally, determination of EP's antileukemic activity in vivo demonstrated its ability to prolong survival in 2 mouse models of leukemia.

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

    SciTech Connect

    Wang, Houcai; Yu, Jing; Zhang, Lixia; Xiong, Yuanyuan; Chen, Shuying; Xing, Haiyan; Tian, Zheng; Tang, Kejing; Wei, Hui; Rao, Qing; Wang, Min; Wang, Jianxiang

    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.

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

    PubMed Central

    Chen, Yu-Jen; Fang, Li-Wen; Su, Wen-Chi; Hsu, Wen-Yi; Yang, Kai-Chien; Huang, Huey-Lan

    2016-01-01

    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 macrophagic differentiation in AML U937 cells by lapatinib. We also noted the synergistic effects of the use of lapatinib and cytotoxic drugs in U937 leukemia cells. These results indicate that lapatinib may have potential for development as a novel antileukemia agent. PMID:27499639

  11. Nanomechanical measurement of adhesion and migration of leukemia cells with phorbol 12-myristate 13-acetate treatment.

    PubMed

    Zhou, Zhuo Long; Ma, Jing; Tong, Ming-Hui; Chan, Barbara Pui; Wong, Alice Sze Tsai; Ngan, Alfonso Hing Wan

    The adhesion and traction behavior of leukemia cells in their microenvironment is directly linked to their migration, which is a prime issue affecting the release of cancer cells from the bone marrow and hence metastasis. In assessing the effectiveness of phorbol 12-myristate 13-acetate (PMA) treatment, the conventional batch-cell transwell-migration assay may not indicate the intrinsic effect of the treatment on migration, since the treatment may also affect other cellular behavior, such as proliferation or death. In this study, the pN-level adhesion and traction forces between single leukemia cells and their microenvironment were directly measured using optical tweezers and traction-force microscopy. The effects of PMA on K562 and THP1 leukemia cells were studied, and the results showed that PMA treatment significantly increased cell adhesion with extracellular matrix proteins, bone marrow stromal cells, and human fibroblasts. PMA treatment also significantly increased the traction of THP1 cells on bovine serum albumin proteins, although the effect on K562 cells was insignificant. Western blots showed an increased expression of E-cadherin and vimentin proteins after the leukemia cells were treated with PMA. The study suggests that PMA upregulates adhesion and thus suppresses the migration of both K562 and THP1 cells in their microenvironment. The ability of optical tweezers and traction-force microscopy to measure directly pN-level cell-protein or cell-cell contact was also demonstrated.

  12. Leukemia-derived immature dendritic cells differentiate into functionally competent mature dendritic cells that efficiently stimulate T cell responses.

    PubMed

    Cignetti, Alessandro; Vallario, Antonella; Roato, Ilaria; Circosta, Paola; Allione, Bernardino; Casorzo, Laura; Ghia, Paolo; Caligaris-Cappio, Federico

    2004-08-15

    Primary acute myeloid leukemia cells can be induced to differentiate into dendritic cells (DC). In the presence of GM-CSF, TNF-alpha, and/or IL-4, leukemia-derived DC are obtained that display features of immature DC (i-DC). The aim of this study was to determine whether i-DC of leukemic origin could be further differentiated into mature DC (m-DC) and to evaluate the possibility that leukemic m-DC could be effective in vivo as a tumor vaccine. Using CD40L as maturating agent, we show that leukemic i-DC can differentiate into cells that fulfill the phenotypic criteria of m-DC and, compared with normal counterparts, are functionally competent in vitro in terms of: 1) production of cytokines that support T cell activation and proliferation and drive Th1 polarization; 2) generation of autologous CD8(+) CTLs and CD4(+) T cells that are MHC-restricted and leukemia-specific; 3) migration from tissues to lymph nodes; 4) amplification of Ag presentation by monocyte attraction; 5) attraction of naive/resting and activated T cells. Irradiation of leukemic i-DC after CD40L stimulation did not affect their differentiating and functional capacity. Our data indicate that acute myeloid leukemia cells can fully differentiate into functionally competent m-DC and lay the ground for testing their efficacy as a tumor vaccine.

  13. Long-term durable remission by cladribine followed by rituximab in patients with hairy cell leukaemia: update of a phase II trial.

    PubMed

    Chihara, Dai; Kantarjian, Hagop; O'Brien, Susan; Jorgensen, Jeffrey; Pierce, Sherry; Faderl, Stefan; Ferrajoli, Alessandra; Poku, Rebecca; Jain, Preetesh; Thompson, Phillip; Brandt, Mark; Luthra, Rajyalakshmi; Burger, Jan; Keating, Michael; Ravandi, Farhad

    2016-09-01

    Nucleoside analogues are highly active in patients with hairy cell leukaemia (HCL); however, patients continue to relapse. This phase II study evaluated the efficacy and safety of cladribine followed by rituximab in patients with untreated HCL (N = 59), relapsed HCL (N = 14) and HCL variant (HCLv, N = 7). Cladribine 5·6 mg/m(2) was given intravenously (IV) daily for 5 d and was followed approximately 1 month later with rituximab 375 mg/m(2) IV weekly for 8 weeks. Complete response rate in patients with untreated HCL, relapsed HCL and HCLv was 100%, 100% and 86%, respectively. With a median follow up of 60 months, 5-year failure-free survival (FFS) in patients with untreated HCL, relapsed HCL and HCLv was 95%, 100% and 64%, respectively. Median duration of response to the cladribine followed by rituximab was significantly longer than the first-line cladribine single agent in patients who received this treatment as second-line treatment (72 months vs not reached, P = 0·004). Almost all patients (94%) achieved negative minimal residual disease (MRD) after the treatment. Positive MRD during the follow up did not necessarily result in clinically relevant relapse. Cladribine followed by rituximab is highly effective even in patients with relapsed disease and HCLv, and can achieve durable remission.

  14. Monoclonal Antibody Therapy in Treating Patients With Ovarian Epithelial Cancer, Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-09

    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); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer

  15. Simultaneous occurrence of B-cell chronic lymphocytic leukemia and chronic myeloid leukemia with further evolution to lymphoid blast crisis.

    PubMed

    Esteve, J; Cervantes, F; Rives, S; Rozman, M; Zarco, M A; Montserrat, E

    1997-01-01

    The coexistence of chronic myeloid leukemia (CML) and B-cell chronic lymphocytic leukemia (CLL) in the same patient is rare. A 71-year-old woman developed a B-lineage lymphoid blast crisis at 18 months after diagnosis of Ph-positive CML. At this time, a lymphoid cell population with morphologic and immunophenotypic features of CLL was demonstrated. The retrospective review of the tests performed at diagnosis and thereafter disclosed the presence of lymphoid nodules in the initial bone marrow biopsy in the absence of lymphocytosis. Subsequently, there was an appearance of moderate lymphocytosis in the following months. Therefore, diagnosis of CML and coexistent CLL was established. Although a transient remission of blast crisis was achieved, blast cells reappeared two months later and the patient died shortly afterwards. Molecular studies of the immunoglobulin heavy chain gene (IH) rearrangement pattern point to the origin of the diseases in two different cell clones. In addition, previously published cases of simultaneous CLL and CML are reviewed.

  16. Aspects of hairy black holes

    SciTech Connect

    Anabalón, Andrés; Astefanesei, Dumitru

    2015-03-26

    We review the existence of exact hairy black holes in asymptotically flat, anti-de Sitter and de Sitter space-times. We briefly discuss the issue of stability and the charging of the black holes with a Maxwell field.

  17. Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-09-09

    Adult Acute Lymphoblastic Leukemia in Remission; Adult B Acute Lymphoblastic Leukemia; Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1; Adult L1 Acute Lymphoblastic Leukemia; Adult L2 Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

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

    SciTech Connect

    Nonaka, Mizuho; Uota, Shin; Saitoh, Yasunori; Takahashi, Mayumi; Sugimoto, Haruyo; Amet, Tohti; Arai, Ayako; Miura, Osamu; Yamamoto, Naoki; Yamaoka, Shoji

    2009-01-15

    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.

  19. Unusual configurations of endoplasmic reticulum in cells of acute promyelocytic leukemia.

    PubMed

    Parkin, J L; Brunning, R D

    1978-08-01

    An ultrastructural study of leukemia cells from 8 patients with acute promyelocytic leukemia revealed several features that have not previously been emphasized: prominent dilated rough endoplasmic reticulum and two unusual configurations of endoplasmic reticulum (ER). The two membrane structures, multilaminar ER and complex stellate arrangements of ER, appeared to be morphogenetically related. The multilaminar ER was observed in every mitotic cell and less frequently in interphase cells. The stellate ER complex was observed only in interphase cells. Ultrastructural evidence is presented to support the possible evolution of the stellate ER complex from the multilaminar ER.

  20. Hollow core photonic crystal fiber for monitoring leukemia cells using surface enhanced Raman scattering (SERS)

    PubMed Central

    Khetani, Altaf; Momenpour, Ali; Alarcon, Emilio I.; Anis, Hanan

    2015-01-01

    The present paper demonstrates an antibody-free, robust, fast, and portable platform for detection of leukemia cells using Raman spectroscopy with a 785-nm laser diode coupled to a hollow core photonic crystal (HC-PCF) containing silver nanoparticles. Acute myeloid leukemia is one of the most common bone marrow cancers in children and youths. Clinical studies suggest that early diagnosis and remission evaluation of myoblasts in the bone marrow are pivotal for improving patient survival. However, the current protocols for leukemic cells detection involve the use of expensive antibodies and flow cytometers. Thus, we have developed a new technology for detection of leukemia cells up to 300 cells/ml using a compact fiber HC-PCF, which offers a novel alternative to existing clinical standards. Furthermore, we were also able to accurately distinguish live, apoptotic and necrotic leukemic cells. PMID:26601021

  1. Hollow core photonic crystal fiber for monitoring leukemia cells using surface enhanced Raman scattering (SERS).

    PubMed

    Khetani, Altaf; Momenpour, Ali; Alarcon, Emilio I; Anis, Hanan

    2015-11-01

    The present paper demonstrates an antibody-free, robust, fast, and portable platform for detection of leukemia cells using Raman spectroscopy with a 785-nm laser diode coupled to a hollow core photonic crystal (HC-PCF) containing silver nanoparticles. Acute myeloid leukemia is one of the most common bone marrow cancers in children and youths. Clinical studies suggest that early diagnosis and remission evaluation of myoblasts in the bone marrow are pivotal for improving patient survival. However, the current protocols for leukemic cells detection involve the use of expensive antibodies and flow cytometers. Thus, we have developed a new technology for detection of leukemia cells up to 300 cells/ml using a compact fiber HC-PCF, which offers a novel alternative to existing clinical standards. Furthermore, we were also able to accurately distinguish live, apoptotic and necrotic leukemic cells.

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

    PubMed Central

    Niewiesk, Stefan

    2016-01-01

    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

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

    PubMed

    Niewiesk, Stefan

    2016-01-01

    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.

  4. Haploidentical stem cell transplantation for the treatment of leukemia: current status.

    PubMed

    Chang, Ying-Jun; Wang, Yu; Huang, Xiao-Jun

    2014-10-01

    Haploidentical stem cell transplantation (haplo-SCT), either with T-cell depletion or T-cell replete, has been a reliable source of stem cells for patients with high-risk leukemia who do not have matched donors because it provides comparable outcomes to human leukocyte antigen-matched sibling donor transplantation, unrelated donor transplantation and umbilical cord blood transplantation. Factors, such as the Hematopoietic Cell Transplantation-Specific Comorbidity Index, associated with transplant outcomes may help us design risk-stratification-directed intervention to improve the prognosis of leukemia patients. Preliminary results of novel protocols, including co-transplant of haploidentical allografts and cord blood, as well as human leukocyte antigen-mismatched stem cell microtransplantation, for leukemia have shown that these approaches are feasible. Several strategies for enhancing the graft-versus-leukemia effects significantly decreased the relapse rate after haplo-SCT. Future direction of research will focus on perfecting available haplo-SCT protocols and determining the optimal time of haplo-SCT for leukemia and 'fit' haploidentical transplant candidates.

  5. Nanomechanical measurement of adhesion and migration of leukemia cells with phorbol 12-myristate 13-acetate treatment

    PubMed Central

    Zhou, Zhuo Long; Ma, Jing; Tong, Ming-Hui; Chan, Barbara Pui; Wong, Alice Sze Tsai; Ngan, Alfonso Hing Wan

    2016-01-01

    The adhesion and traction behavior of leukemia cells in their microenvironment is directly linked to their migration, which is a prime issue affecting the release of cancer cells from the bone marrow and hence metastasis. In assessing the effectiveness of phorbol 12-myristate 13-acetate (PMA) treatment, the conventional batch-cell transwell-migration assay may not indicate the intrinsic effect of the treatment on migration, since the treatment may also affect other cellular behavior, such as proliferation or death. In this study, the pN-level adhesion and traction forces between single leukemia cells and their microenvironment were directly measured using optical tweezers and traction-force microscopy. The effects of PMA on K562 and THP1 leukemia cells were studied, and the results showed that PMA treatment significantly increased cell adhesion with extracellular matrix proteins, bone marrow stromal cells, and human fibroblasts. PMA treatment also significantly increased the traction of THP1 cells on bovine serum albumin proteins, although the effect on K562 cells was insignificant. Western blots showed an increased expression of E-cadherin and vimentin proteins after the leukemia cells were treated with PMA. The study suggests that PMA upregulates adhesion and thus suppresses the migration of both K562 and THP1 cells in their microenvironment. The ability of optical tweezers and traction-force microscopy to measure directly pN-level cell–protein or cell–cell contact was also demonstrated. PMID:27994457

  6. Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia.

    PubMed

    Jost, Tanja Rezzonico; Borga, Chiara; Radaelli, Enrico; Romagnani, Andrea; Perruzza, Lisa; Omodho, Lorna; Cazzaniga, Giovanni; Biondi, Andrea; Indraccolo, Stefano; Thelen, Marcus; Te Kronnie, Geertruy; Grassi, Fabio

    2016-06-01

    Infiltration of the central nervous system is a severe trait of T cell acute lymphoblastic leukemia. Inhibition of CXC chemokine receptor 4 significantly ameliorates T cell acute lymphoblastic leukemia in murine models of the disease; however, signaling by CXC chemokine receptor 4 is important in limiting the divagation of peripheral blood mononuclear cells out of the perivascular space into the central nervous system parenchyma. Therefore, Inhibition of CXC chemokine receptor 4 potentially may untangle T cell acute lymphoblastic leukemia cells from retention outside the brain. Here, we show that leukemic lymphoblasts massively infiltrate cranial bone marrow, with diffusion to the meninges without invasion of the brain parenchyma, in mice that underwent xenotransplantation with human T cell acute lymphoblastic leukemia cells or that developed leukemia from transformed hematopoietic progenitors. We tested the hypothesis that T cell acute lymphoblastic leukemia neuropathology results from meningeal infiltration through CXC chemokine receptor 4-mediated bone marrow colonization. Inhibition of leukemia engraftment in the bone marrow by pharmacologic CXC chemokine receptor 4 antagonism significantly ameliorated neuropathologic aspects of the disease. Genetic deletion of CXCR4 in murine hematopoietic progenitors abrogated leukemogenesis induced by constitutively active Notch1, whereas lack of CCR6 and CCR7, which have been shown to be involved in T cell and leukemia extravasation into the central nervous system, respectively, did not influence T cell acute lymphoblastic leukemia development. We hypothesize that lymphoblastic meningeal infiltration as a result of bone marrow colonization is responsible for the degenerative alterations of the neuroparenchyma as well as the alteration of cerebrospinal fluid drainage in T cell acute lymphoblastic leukemia xenografts. Therefore, CXC chemokine receptor 4 may constitute a pharmacologic target for T cell acute lymphoblastic

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

    SciTech Connect

    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.

  8. 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

    ClinicalTrials.gov

    2017-03-14

    Acute Biphenotypic Leukemia; Acute Erythroid Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Megakaryoblastic Leukemia; 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; Myelodysplastic Syndrome With Excess Blasts; Pancytopenia; Refractory Anemia; Secondary Acute Myeloid Leukemia

  9. Articulatin-D induces apoptosis via activation of caspase-8 in acute T-cell leukemia cell line.

    PubMed

    Mishra, Ruchi; Das, Mrinal K; Singh, Savita; Sharma, Radhey Shyam; Sharma, Sadhna; Mishra, Vandana

    2017-02-01

    Leukemia is among the most aggressive and prevalent human malignant carcinoma. Chemotherapy is the preferred therapeutic strategy; however, recurrence of cancer and non-selective cytotoxicity are the major concerns. Unlike synthetic chemotherapeutic agents, mistletoe ribosome-inactivating protein (RIP) displays anti-tumor function in various types of cancers. However, its effect on leukemia cells is little explored. In this study, we assessed the impact of Viscum articulatum RIP (Articulatin-D) on the survival of acute T-cell leukemia cells and the involved molecular and cellular mechanisms. Cell proliferation assay showed that Articulatin-D suppressed the viability of leukemia cells selectively. We further confirmed that the elevation of mitochondrial membrane potential and exposure of phosphatidylserine are the early events of apoptosis induction in Articulatin-D-treated Jurkat cells. Subsequently, we found that Articulatin-D treatment induces apoptosis in Jurkat cells in a time- and concentration-dependent manner. In conclusion, we provided evidence that Articulatin-D efficiently activates caspase-8 involved in extrinsic pathway of apoptosis induction, which ultimately results in caspase-3-dependent DNA fragmentation of Jurkat cells. Further evaluation of Articulatin-D in cell culture and animal models may provide novel information on selective cytotoxicity to acute T-cell leukemia and its involvement in targeting tumor cell survival pathways.

  10. The effects of thymoquinone and Doxorubicin on leukemia and cardiomyocyte cell lines.

    PubMed

    Brown, R Keith; Wilson, Gerri; Tucci, Michelle A; Benghuzzi, Hamed A

    2014-01-01

    Acute Lymphoblastic Leukemia remains the most common cancer for children, and if left untreated is rapidly fatal. The gold standard for treatment of ALL in children is with a class of drugs known as the antracyclines. Long term outcomes following treatment of leukemia with antracylines can result in cardiac abnormalities including arrhythmias, congestive heart failure, myocardial infarction, hypertension and left ventricular failure. Thymoquinone is a natural product that has demonstrated anti-proliferative, anti-inflammatory, anti-cancer, and chemo-protective effects in control trials as well as a reduction in cardiotoxicity in antracyline treated rats. The aims of the study were to determine if thymoqunione could be used to reduce leukemia cell viability without injuring primary cardiomyocyte, and to determine its effects if used in conjunction with a known chemotherapeutic agent. Cellular viability and morphological changes were observed in the, RAW leukemia cells and cardiac myocytes following treatment with thymoquinone, antracyline (doxorubicin), alone and in combination for 24, 48 and 72 hours. The results suggest that thymoquinone treatment in RAW leukemia cells reduced the cell number without altering the morphology, while doxorubicin reduced cell number and induced spindle cell formation and increased cellular damage. Findings also suggest RAW cell apoptosis increased in combination therapy with thymoquinone and doxorubicin. Thymoquinone administered to cardiomyocytes showed similar morphological changes as control over time in culture; whereas doxorubicin treated cells showed evidence of loss of connectivity and disruption of cell membranes. Combination treatment with doxorubicin and thymoquinone demonstrated significant cardiac myocyte survival at concentrations when used alone were able to reduce the leukemia cells. Overall, the data is promising and may provide a treatment regime to protect the heart tissue. Additional work is warrant to understand

  11. Dasatinib-loaded albumin nanoparticles possess diminished endothelial cell barrier disruption and retain potent anti-leukemia cell activity

    PubMed Central

    Li, Zhenyu; Shetty, Sreerama; Fu, Jian

    2016-01-01

    Dasatinib (DAS), a second-generation tyrosine kinase inhibitor, is highly effective in treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, its clinical use is limited due to serious adverse effects. DAS can disrupt endothelial barrier integrity and increase endothelial permeability which may cause peripheral edema and pleural effusion. Albumin nanoparticles (NPs) as a drug carrier may serve as a useful tool for cell-selective drug delivery to reduce DAS-induced endothelial hyperpermeability and maintain endothelial barrier integrity. In this study, we reported that DAS-loaded NPs exhibited potent anti-leukemia efficacy as DAS alone. Importantly, albumin NPs as a drug carrier markedly reduced DAS-induced endothelial hyperpermeability by restraining the inhibition of Lyn kinase signaling pathway in endothelial cells. Therefore, albumin NPs could be a potential tool to improve anti-leukemia efficacy of DAS through its cell-selective effects. PMID:27391073

  12. Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphoplasmacytic Lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), and Splenic Marginal Zone Lymphoma (SMZL)

    ClinicalTrials.gov

    2017-03-10

    B-Cell Chronic Lymphocytic Leukemia; Monoclonal B-Cell Lymphocytosis; Lymhoma, Small Lymphocytic; Chronic Lymphocytic Leukemia; Lymphoplasmacytic Lymphoma; Waldenstrom Macroglobulinemia; Splenic Marginal Zone Lymphoma

  13. [Induction of polyploid in hairy roots of Nicotiana tabacum and its plant regeneration].

    PubMed

    Hou, Lili; Shi, Heping; Yu, Wu; Tsang, Po Keung Eric; Chow, Cheuk Fai Stephen

    2014-04-01

    By genetic transformation with Agrobacterum rhizogenes and artificial chromosome doubling techniques, we studied the induction of hairy roots and their polyploidization, and subsequent plant regeneration and nicotine determination to enhance the content of nicotine in Nicotiana tabacum. The results show that hairy roots could be induced from the basal surface of leaf explants of N. tabacum 8 days after inoculation with Agrobacterium rhizogenes ATCC15834. The percentage of the rooting leaf explants was 100% 15 days after inoculation. The hairy roots could grow rapidly and autonomously on solid or liquid phytohormones-free MS medium. The transformation was confirmed by PCR amplification of rol gene of Ri plasmid and paper electrophoresis of opines from N. tabacum hairy roots. The highest rate of polyploidy induction, more than 64.71%, was obtained after treatment of hairy roots with 0.1% colchicine for 36 h. The optimum medium for plant regeneration from polyploid hairy roots was MS+2.0 mg/L 6-BA +0.2 mg/L NAA. Compared with the control diploid plants, the hairy roots-regenerated plants had weak apical dominance, more axillary buds and more narrow leaves; whereas the polyploid hairy root-regenerated plants had thicker stems, shorter internodes and the colour, width and thickness of leaves were significantly higher than that of the control. Observation of the number of chromosomes in their root tip cells reveals that the obtained polyploid regenerated plants were tetraploidy, with 96 (4n = 96) chromosomes. Pot-grown experiments showed compared to the control, the flowering was delayed by 21 days in diploid hairy roots-regenerated plants and polyploid hairy root-regenerated plants. GC-MS detection shows that the content of nicotine in polyploid plants was about 6.90 and 4.57 times the control and the diploid hairy roots-regenerated plants, respectively.

  14. Hairy and Groucho mediate the action of juvenile hormone receptor Methoprene-tolerant in gene repression

    PubMed Central

    Saha, Tusar T.; Shin, Sang Woon; Dou, Wei; Roy, Sourav; Zhao, Bo; Hou, Yuan; Wang, Xue-Li; Zou, Zhen; Girke, Thomas; Raikhel, Alexander S.

    2016-01-01

    The arthropod-specific juvenile hormone (JH) controls numerous essential functions. Its involvement in gene activation is known to be mediated by the transcription factor Methoprene-tolerant (Met), which turns on JH-controlled genes by directly binding to E-box–like motifs in their regulatory regions. However, it remains unclear how JH represses genes. We used the Aedes aegypti female mosquito, in which JH is necessary for reproductive maturation, to show that a repressor, Hairy, is required for the gene-repressive action of JH and Met. The RNA interference (RNAi) screen for Met and Hairy in the Aedes female fat body revealed a large cohort of Met- and Hairy-corepressed genes. Analysis of selected genes from this cohort demonstrated that they are repressed by JH, but RNAi of either Met or Hairy renders JH ineffective in repressing these genes in an in vitro fat-body culture assay. Moreover, this JH action was prevented by the addition of the translational inhibitor cycloheximide (CHX) to the culture, indicating the existence of an indirect regulatory hierarchy. The lack of Hairy protein in the CHX-treated tissue was verified using immunoblot analysis, and the upstream regions of Met/Hairy-corepressed genes were shown to contain common binding motifs that interact with Hairy. Groucho (gro) RNAi silencing phenocopied the effect of Hairy RNAi knockdown, indicating that it is involved in the JH/Met/Hairy hierarchy. Finally, the requirement of Hairy and Gro for gene repression was confirmed in a cell transfection assay. Thus, our study has established that Hairy and its cofactor Gro mediate the repressive function of JH and Met. PMID:26744312

  15. Mechanisms of pathogenesis induced by bovine leukemia virus as a model for human T-cell leukemia virus

    PubMed Central

    Aida, Yoko; Murakami, Hironobu; Takahashi, Masahiko; Takeshima, Shin-Nosuke

    2013-01-01

    Bovine leukemia virus (BLV) and human T-cell leukemia virus type 1 (HTLV-1) make up a unique retrovirus family. Both viruses induce chronic lymphoproliferative diseases with BLV affecting the B-cell lineage and HTLV-1 affecting the T-cell lineage. The pathologies of BLV- and HTLV-induced infections are notably similar, with an absence of chronic viraemia and a long latency period. These viruses encode at least two regulatory proteins, namely, Tax and Rex, in the pX region located between the env gene and the 3′ long terminal repeat. The Tax protein is a key contributor to the oncogenic potential of the virus, and is also the key protein involved in viral replication. However, BLV infection is not sufficient for leukemogenesis, and additional events such as gene mutations must take place. In this review, we first summarize the similarities between the two viruses in terms of genomic organization, virology, and pathology. We then describe the current knowledge of the BLV model, which may also be relevant for the understanding of leukemogenesis caused by HTLV-1. In addition, we address our improved understanding of Tax functions through the newly identified BLV Tax mutants, which have a substitution between amino acids 240 and 265. PMID:24265629

  16. Differential Effects of Polyphenols on Proliferation and Apoptosis in Human Myeloid and Lymphoid Leukemia Cell Lines

    PubMed Central

    Mahbub, Amani A; Le Maitre, Christine L.; Haywood-Small, Sarah L.; McDougall, Gordon J.; Cross, Neil A.; Jordan-Mahy, Nicola

    2013-01-01

    Background: Mortality rates for leukemia are high despite considerable improvements in treatment. Since polyphenols exert pro-apoptotic effects in solid tumors, our study investigated the effects of polyphenols in haematological malignancies. The effect of eight polyphenols (quercetin, chrysin, apigenin, emodin, aloe-emodin, rhein, cis-stilbene and trans-stilbene) were studied on cell proliferation, cell cycle and apoptosis in four lymphoid and four myeloid leukemic cells lines, together with normal haematopoietic control cells. Methods: Cellular proliferation was measured by CellTiter-Glo® luminescent assay; and cell cycle arrest was assessed using flow cytometry of propidium iodide stained cells. Apoptosis was investigated by caspase-3 activity assay using flow cytometry and apoptotic morphology was confirmed by Hoescht 33342 staining. Results: Emodin, quercetin, and cis-stilbene were the most effective polyphenols at decreasing cell viability (IC50 values of 5-22 µM, 8-33 µM, and 25-85 µM respectively) and inducing apoptosis (AP50 values (the concentration which 50% of cells undergo apoptosis) of 2-27 µM, 19-50 µM, and 8-50 µM respectively). Generally, lymphoid cell lines were more sensitive to polyphenol treatment compared to myeloid cell lines, however the most resistant myeloid (KG-1a and K562) cell lines were still found to respond to emodin and quercetin treatment at low micromolar levels. Non-tumor cells were less sensitive to all polyphenols compared to the leukemia cells. Conclusions: These findings suggest that polyphenols have anti-tumor activity against leukemia cells with differential effects. Importantly, the differential sensitivity of emodin, quercetin, and cis-stilbene between leukemia and normal cells suggests that polyphenols are potential therapeutic agents for leukemia. PMID:23796248

  17. Sequences responsible for erythroid and lymphoid leukemia in the long terminal repeats of Friend-mink cell focus-forming and Moloney murine leukemia viruses.

    PubMed Central

    Ishimoto, A; Takimoto, M; Adachi, A; Kakuyama, M; Kato, S; Kakimi, K; Fukuoka, K; Ogiu, T; Matsuyama, M

    1987-01-01

    Despite the high degree of homology (91%) between the nucleotide sequences of the Friend-mink cell focus-forming (MCF) and the Moloney murine leukemia virus (MuLV) genomic long terminal repeats (LTRs), the pathogenicities determined by the LTR sequences of the two viruses are quite different. Friend-MCF MuLV is an erythroid leukemia virus, and Moloney MuLV is a lymphoid leukemia virus. To map the LTR sequences responsible for the different disease specificities, we constructed nine viruses with LTRs recombinant between the Friend-MCF and Moloney MuLVs. Analysis of the leukemia induced with the recombinant viruses showed that a 195-base-pair nucleotide sequence, including a 75-base-pair nucleotide Moloney enhancer, is responsible for the tissue-specific leukemogenicity of Moloney MuLV. However, not only the enhancer but also its downstream sequences appear to be necessary. The Moloney virus enhancer and its downstream sequence exerted a dominant effect over that of the Friend-MCF virus, but the enhancer sequence alone did not. The results that three of the nine recombinant viruses induced both erythroid and lymphoid leukemias supported the hypothesis that multiple viral genetic determinants control both the ability to cause leukemia and the type of leukemia induced. PMID:3033317

  18. Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2017-03-28

    Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Secondary Myelofibrosis; Severe Combined Immunodeficiency; Severe Congenital Neutropenia; Shwachman-Diamond Syndrome; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Waldenstrom Macroglobulinemia; Wiskott-Aldrich Syndrome

  19. Ibrutinib in Treating Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma in Patients With HIV Infection

    ClinicalTrials.gov

    2015-08-18

    Adult B Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; HIV Infection; Intraocular Lymphoma; Multicentric Angiofollicular Lymphoid Hyperplasia; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Plasma Cell Myeloma; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  20. Biguanides sensitize leukemia cells to ABT-737-induced apoptosis by inhibiting mitochondrial electron transport.

    PubMed

    Velez, Juliana; Pan, Rongqing; Lee, Jason T C; Enciso, Leonardo; Suarez, Marta; Duque, Jorge Eduardo; Jaramillo, Daniel; Lopez, Catalina; Morales, Ludis; Bornmann, William; Konopleva, Marina; Krystal, Gerald; Andreeff, Michael; Samudio, Ismael

    2016-08-09

    Metformin displays antileukemic effects partly due to activation of AMPK and subsequent inhibition of mTOR signaling. Nevertheless, Metformin also inhibits mitochondrial electron transport at complex I in an AMPK-independent manner, Here we report that Metformin and rotenone inhibit mitochondrial electron transport and increase triglyceride levels in leukemia cell lines, suggesting impairment of fatty acid oxidation (FAO). We also report that, like other FAO inhibitors, both agents and the related biguanide, Phenformin, increase sensitivity to apoptosis induction by the bcl-2 inhibitor ABT-737 supporting the notion that electron transport antagonizes activation of the intrinsic apoptosis pathway in leukemia cells. Both biguanides and rotenone induce superoxide generation in leukemia cells, indicating that oxidative damage may sensitize toABT-737 induced apoptosis. In addition, we demonstrate that Metformin sensitizes leukemia cells to the oligomerization of Bak, suggesting that the observed synergy with ABT-737 is mediated, at least in part, by enhanced outer mitochondrial membrane permeabilization. Notably, Phenformin was at least 10-fold more potent than Metformin in abrogating electron transport and increasing sensitivity to ABT-737, suggesting that this agent may be better suited for targeting hematological malignancies. Taken together, our results suggest that inhibition of mitochondrial metabolism by Metformin or Phenformin is associated with increased leukemia cell susceptibility to induction of intrinsic apoptosis, and provide a rationale for clinical studies exploring the efficacy of combining biguanides with the orally bioavailable derivative of ABT-737, Venetoclax.

  1. Recognition of adult and pediatric acute lymphoblastic leukemia blasts by natural killer cells.

    PubMed

    Torelli, Giovanni F; Peragine, Nadia; Raponi, Sara; Pagliara, Daria; De Propris, Maria S; Vitale, Antonella; Bertaina, Alice; Barberi, Walter; Moretta, Lorenzo; Basso, Giuseppe; Santoni, Angela; Guarini, Anna; Locatelli, Franco; Foà, Robin

    2014-07-01

    In this study, we aimed to investigate the pathways of recognition of acute lymphoblastic leukemia blasts by natural killer cells and to verify whether differences in natural killer cell activating receptor ligand expression among groups defined by age of patients, or presence of cytogenetic/molecular aberrations correlate with the susceptibility to recognition and killing. We analyzed 103 newly diagnosed acute lymphoblastic leukemia patients: 46 adults and 57 children. Pediatric blasts showed a significantly higher expression of Nec-2 (P=0.03), ULBP-1 (P=0.01) and ULBP-3 (P=0.04) compared to adult cells. The differential expression of these ligands between adults and children was confined to B-lineage acute lymphoblastic leukemia with no known molecular alterations. Within molecularly defined subgroups of patients, a high surface expression of NKG2D and DNAM1 ligands was found on BCR-ABL(+) blasts, regardless of patient age. Accordingly, BCR-ABL(+) blasts proved to be significantly more susceptible to natural killer-dependent lysis than B-lineage blasts without molecular aberrations (P=0.03). Cytotoxic tests performed in the presence of neutralizing antibodies indicated a pathway of acute lymphoblastic leukemia cell recognition in the setting of the Nec-2/DNAM-1 interaction. These data provide a biological explanation of the different roles played by alloreactive natural killer cells in pediatric versus adult acute lymphoblastic leukemia and suggest that new natural killer-based strategies targeting specific subgroups of patients, particularly those BCR-ABL(+), are worth pursuing further.

  2. Biguanides sensitize leukemia cells to ABT-737-induced apoptosis by inhibiting mitochondrial electron transport

    PubMed Central

    Velez, Juliana; Pan, Rongqing; Lee, Jason T.C.; Enciso, Leonardo; Suarez, Marta; Duque, Jorge Eduardo; Jaramillo, Daniel; Lopez, Catalina; Morales, Ludis; Bornmann, William; Konopleva, Marina; Krystal, Gerald; Andreeff, Michael; Samudio, Ismael

    2016-01-01

    Metformin displays antileukemic effects partly due to activation of AMPK and subsequent inhibition of mTOR signaling. Nevertheless, Metformin also inhibits mitochondrial electron transport at complex I in an AMPK-independent manner, Here we report that Metformin and rotenone inhibit mitochondrial electron transport and increase triglyceride levels in leukemia cell lines, suggesting impairment of fatty acid oxidation (FAO). We also report that, like other FAO inhibitors, both agents and the related biguanide, Phenformin, increase sensitivity to apoptosis induction by the bcl-2 inhibitor ABT-737 supporting the notion that electron transport antagonizes activation of the intrinsic apoptosis pathway in leukemia cells. Both biguanides and rotenone induce superoxide generation in leukemia cells, indicating that oxidative damage may sensitize toABT-737 induced apoptosis. In addition, we demonstrate that Metformin sensitizes leukemia cells to the oligomerization of Bak, suggesting that the observed synergy with ABT-737 is mediated, at least in part, by enhanced outer mitochondrial membrane permeabilization. Notably, Phenformin was at least 10-fold more potent than Metformin in abrogating electron transport and increasing sensitivity to ABT-737, suggesting that this agent may be better suited for targeting hematological malignancies. Taken together, our results suggest that inhibition of mitochondrial metabolism by Metformin or Phenformin is associated with increased leukemia cell susceptibility to induction of intrinsic apoptosis, and provide a rationale for clinical studies exploring the efficacy of combining biguanides with the orally bioavailable derivative of ABT-737, Venetoclax. PMID:27283492

  3. Occupational exposure to formaldehyde, hematotoxicity and leukemia-specific chromosome changes in cultured myeloid progenitor cells

    PubMed Central

    Zhang, Luoping; Tang, Xiaojiang; Rothman, Nathaniel; Vermeulen, Roel; Ji, Zhiying; Shen, Min; Qiu, Chuangyi; Guo, Weihong; Liu, Songwang; Reiss, Boris; Laura Beane, Freeman; Ge, Yichen; Hubbard, Alan E.; Hua, Ming; Blair, Aaron; Galvan, Noe; Ruan, Xiaolin; Alter, Blanche P.; Xin, Kerry X.; Li, Senhua; Moore, Lee E.; Kim, Sungkyoon; Xie, Yuxuan; Hayes, Richard B.; Azuma, Mariko; Hauptmann, Michael; Xiong, Jun; Stewart, Patricia; Li, Laiyu; Rappaport, Stephen M.; Huang, Hanlin; Fraumeni, Joseph F.; Smith, Martyn T.; Lan, Qing

    2010-01-01

    There are concerns about the health effects of formaldehyde exposure, including carcinogenicity, in light of elevated indoor air levels in new homes and occupational exposures experienced by workers in health care, embalming, manufacturing and other industries. Epidemiological studies suggest that formaldehyde exposure is associated with an increased risk of leukemia. However, the biological plausibility of these findings has been questioned because limited information is available on formaldehyde’s ability to disrupt hematopoietic function. Our objective was to determine if formaldehyde exposure disrupts hematopoietic function and produces leukemia-related chromosome changes in exposed humans. We examined the ability of formaldehyde to disrupt hematopoiesis in a study of 94 workers in China (43 exposed to formaldehyde and 51 frequency-matched controls) by measuring complete blood counts and peripheral stem/progenitor cell colony formation. Further, myeloid progenitor cells, the target for leukemogenesis, were cultured from the workers to quantify the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in metaphase spreads of these cells. Among exposed workers, peripheral blood cell counts were significantly lowered in a manner consistent with toxic effects on the bone marrow and leukemia-specific chromosome changes were significantly elevated in myeloid blood progenitor cells. These findings suggest that formaldehyde exposure can have an adverse impact on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible, which heightens concerns about its leukemogenic potential from occupational and environmental exposures. PMID:20056626

  4. Differential mechanisms of cell death induction via delivery of therapeutic nanoliposomal ceramide in leukemias

    NASA Astrophysics Data System (ADS)

    Ryland, Lindsay K.

    Large granular lymphocyte (LGL) leukemia is a rare lymphoproliferative malignancy that involves blood, bone marrow and spleen infiltration. Clinically, LGL leukemia can manifest as a chronic lymphocytosis or as an aggressive leukemia that is fatal within a short period of time. A segment of LGL leukemia patients are unresponsive to immunosuppressive therapy and currently there is no known curative treatment for this disease. Another hematological malignancy, chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults in Western countries and accounts for approximately 30% of all diagnosed leukemia cases. Around 95% of all CLL cases involve clonal expansion and abnormal proliferation of neoplastic B lymphocytes in lymphoid organs, bone marrow and peripheral blood. Similar to LGL leukemia, CLL is also incurable with current therapies. Therefore, this represents a need for new therapeutic approaches for treatment of these diseases. Recent advances in nanotechnology have illustrated the feasibility of generating nanoliposomes that encapsulate hydrophobic compounds, like ceramide, to facilitate treatment of LGL leukemia and CLL. Ceramide is an anti-proliferative sphingolipid metabolite that has been shown to selectively induce cell death in cancer cells. However, the use of ceramide as a chemotherapeutic agent is limited due to hydrophobicity. While it is understood how nanoliposomal ceramide induces cell death in several types of cancers and hematological malignancies, the effect of nanoliposomal ceramide treatment in LGL leukemia and CLL remains unclear. In this study, we investigate the differential mechanisms of cell death induction following nanoliposomal C6-ceramide treatment in both LGL leukemia and CLL. We show that nanoliposomal C6-ceramide displays minimal cytotoxicity in normal donors. peripheral blood mononuclear cells (PBMCs) and is a well-tolerated therapy during in vivo treatment in these leukemia models. To further examine this mechanism

  5. All-trans retinoic acid inhibits HOXA7 expression in leukemia cell NB4.

    PubMed

    Guo, Q; Jiang, Q; Liu, W; Bai, Y

    2016-01-22

    Leukemia is a malignant proliferative disease of blood system, which is caused by hyperplasia of white blood cells and infiltration into other tissues and organs with blood flow, leading to a series of clinical manifestations. In this study, we detected the expression of HOXA7 gene in human acute promyelocytic leukemia cell line NB4. The expression level of HOXA7 decreased in the presence of ATRA, which was able to inhibit the proliferation of NB4 cells. Furthermore, ATRA altered the morphology of NB4 cells. The study suggested that HOXA7 might be a new gene candidate that influences the maturation of acute myeloid leukemia, and provided the molecular basis for the treatment for acute promyelocyticleukemia.

  6. Donor T Cells After Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2016-07-20

    Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

  7. Enhancement of fludarabine sensitivity by all-trans-retinoic acid in chronic lymphocytic leukemia cells

    PubMed Central

    Fernández-Calotti, Paula X.; Lopez-Guerra, Mónica; Colomer, Dolors; Pastor-Anglada, Marçal

    2012-01-01

    Background A subset of patients with fludarabine-resistant chronic lymphocytic leukemia has previously been shown to express elevated intracellular levels of the concentrative high-affinity fludarabine transporter hCNT3, without any detectable related activity. We have recently shown that all-trans-retinoic acid is capable of inducing hCNT3 trafficking to plasma membrane in the MEC1 cell line. We, therefore, evaluated the effect of all-trans-retinoic acid on hCNT3 in primary chronic lymphocytic leukemia cells as a suitable mechanism to improve fludarabine-based therapy of chronic lymphocytic leukemia. Design and Methods Cells from 23 chronic lymphocytic leukemia patients wild-type for P53 were analyzed for ex vivo sensitivity to fludarabine. hCNT3 activity in chronic lymphocytic leukemia cell samples was evaluated by measuring the uptake of [8-3H]-fludarabine. The amounts of transforming growth factor-β1 and hCNT3 messenger RNA were analyzed by real-time polymerase chain reaction. The effect of all-trans-retinoic acid on hCNT3 subcellular localization was analyzed by confocal microscopy and its effect on fludarabine-induced apoptosis was evaluated by flow cytometry analysis using annexin V staining. Results Chronic lymphocytic leukemia cases showing higher ex vivo basal sensitivity to fludarabine also had a greater basal hCNT3-associated fludarabine uptake capacity compared to the subset of patients showing ex vivo resistance to the drug. hCNT3 transporter activity in chronic lymphocytic leukemia cells from the latter patients was either negligible or absent. Treatment of the fludarabine-resistant subset of chronic lymphocytic leukemia cells with all-trans-retinoic acid induced increased fludarabine transport via hCNT3 which was associated with a significant increase in fludarabine sensitivity. Conclusions Improvement of ex vivo fludarabine sensitivity in chronic lymphocytic leukemia cells is associated with increased hCNT3 activity after all-trans-retinoic acid

  8. General Approach to Treatment of Chronic Myelomonocytic Leukemia

    MedlinePlus

    ... Leukemia General Approach to Treatment of Chronic Myelomonocytic Leukemia Stem cell transplant (SCT) is the only way ... of Chronic Myelomonocytic Leukemia More In Chronic Myelomonocytic Leukemia About Chronic Myelomonocytic Leukemia Causes, Risk Factors, and ...

  9. Induction of differentiation of myelogenous leukemia cells by humulone, a bitter in the hop.

    PubMed

    Honma, Y; Tobe, H; Makishima, M; Yokoyama, A; Okabe-Kado, J

    1998-07-01

    The active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (VD3), inhibits proliferation and induces differentiation of myelomonocytic leukemia cells, but its clinical use is limited by the adverse effect of hypercalcemia. VD3 mobilizes calcium stores from bone by inducing the dissolution of bone mineral and matrix. We have recently found that humulone, a bitter in the hop extract for beer brewing, effectively inhibits bone resorption. In this study we examined the effect of humulone on the differentiation of human myelogenous leukemia cells. Humulone alone inhibited the growth of monoblastic leukemia U937 cells while only slightly increasing differentiation markers such as nitroblue tetrazolium (NBT)-reducing and lysozyme activities. Humulone effectively enhanced the differentiation-inducing action of VD3. Other myelomonocytic leukemia cells were induced to differentiate by VD3 and this was also enhanced by humulone. Since humulone is a less-toxic inhibitor of bone resorption, the combination of humulone and VD3 may be useful in differentiation therapy of myelomonocytic leukemia.

  10. Rare aggressive natural killer cell leukemia presented with bone marrow fibrosis - a diagnostic challenge.

    PubMed

    Soliman, Dina S; Sabbagh, Ahmad Al; Omri, Halima El; Ibrahim, Firyal A; Amer, Aliaa M; Otazu, Ivone B

    2014-01-01

    Aggressive natural killer cell leukemia is an extraordinary rare aggressive malignant neoplasm of natural killer cells. Although its first recognition as a specific entity was approximately 20 years ago, this leukemia has not yet been satisfactorily characterized as fewer than 200 cases have been reported in the literature and up to our knowledge, this is the first case report in Qatar. Reaching a diagnosis of aggressive natural killer leukemia was a challenging experience, because in addition to being a rare entity, the relative scarcity of circulating neoplastic cells, failure to obtain an adequate aspirate sample sufficient to perform flow cytometric analysis, together with the absence of applicable method to prove NK clonality (as it lack specific clonal marker); our case had atypical confusing presentation of striking increase in bone marrow fibrosis that was misleading and complicated the case further. The bone marrow fibrosis encountered may be related to the neoplastic natural killer cells' chemokine profile and it may raise the awareness for considering aggressive natural killer leukemia within the differential diagnosis of leukemia with heightened marrow fibrosis.

  11. The establishment of a cell line from an acute megakaryoblastic leukemia with evidence of emperipolesis

    SciTech Connect

    Zheng, C.Y.; Pabello, P.; Skinnider, L.F.

    1994-09-01

    Acute megakaryoblstic leukemia is uncommon and comprises about 5% of acute non-lymphoid leukemia in the Franco-American-British (FAB) classification. Cell lines from such leukemias are relatively rare with only 6 reported in the literature. We have established a cell line from a case of acute megakaryoblastic leukemia arising in a 2-year-old child. Surface marker studies of the cells confirm their megakaryoblastic nature with 54.1% of the cells being CD61-positive. The cells have a doubling time of 72 hours. Morphologically they appear blast-like with Wright Giemsa stain and electron microscopy and some have small cytoplasmic blebs. Emperipolesis of one blast into another large one is occasionally seen and review of the original bone marrow specimen also showed emperipolesis of neutrophils into the megakaryoblasts (emperipolesis is a phenomenon in which a cell, usually a lymphocyte or neutrophil, enters another cell, moves about and leaves without undergoing phagocytosis). Karyotyping of the cells showed 45,XX + marker chromosome. The marker chromosome is apparently chromosome 16 with a small segment of a chromosome translocated to the terminal portion of chromosome 16. The origin of the translocated material will be elucidated using fluorescence in situ hybridization (FISH). This cell line may be useful in studying factors that contribute to the phenomenon of emperipolesis.

  12. Antiproliferative activity and apoptosis induction by 3',4'-dibenzyloxyflavonol on human leukemia cells.

    PubMed

    Said, Mercedes; Brouard, Ignacio; Quintana, José; Estévez, Francisco

    2017-02-21

    In this study, we investigated the effects of synthetic 3',4'-dibenzyloxyflavonol on viabilities of eight human tumor cells. It was cytotoxic against leukemia cells (HL-60, U-937, MOLT-3, K-562, NALM-6, Raji), with significant effects against P-glycoprotein-overexpressing K-562/ADR and Bcl-2-overexpressing U-937/Bcl-2 cells, but had no significant cytotoxic effects against quiescent or proliferating human peripheral blood mononuclear cells. The IC50 value for the leukemia HL-60 cells was 0.8 ± 0.1 μM. This indicates a 60-fold greater toxicity than the naturally occurring flavonol quercetin. Synthetic 3',4'-dibenzyloxyflavonol induced S phase cell cycle arrest and was a potent apoptotic inducer in human leukemia cells. Cell death was (i) mediated by the activation and the cleavage of initiator and executioner caspases; (ii) prevented by the pan-caspase inhibitor z-VAD-fmk; (iii) associated with the release of cytochrome c and with the phosphorylation of members of the mitogen activated protein kinases including p38(MAPK), JNK/SAPK and ERK, and (iv) independent of the generation of reactive oxygen species. The synthetic 3',4'-dibenzyloxyflavonol is a potent cytotoxic compound against several human leukemia cells and might be useful in the development of new strategies in the fight against cancer.

  13. AZD1775 sensitizes T cell acute lymphoblastic leukemia cells to cytarabine by promoting apoptosis over DNA repair.

    PubMed

    Ford, James B; Baturin, Dmitry; Burleson, Tamara M; Van Linden, Annemie A; Kim, Yong-Mi; Porter, Christopher C

    2015-09-29

    While some children with acute lymphoblastic leukemia (ALL) have excellent prognoses, the prognosis for adults and children with T cell ALL is more guarded. Treatment for T-ALL is heavily dependent upon antimetabolite chemotherapeutics, including cytarabine. Targeted inhibition of WEE1 with AZD1775 has emerged as a strategy to sensitize cancer cells to cytarabine and other chemotherapeutics. We sought to determine if this strategy would be effective for T-ALL with clinically relevant anti-leukemia agents. We found that AZD1775 sensitizes T-ALL cells to several traditional anti-leukemia agents, acting synergistically with cytarabine by enhancing DNA damage and apoptosis. In addition to increased phosphorylation of H2AX at serine 139 (γH2AX), AZD1775 led to increased phosphorylation of H2AX at tyrosine 142, a signaling event associated with promotion of apoptosis over DNA repair. In a xenograft model of T-ALL, the addition of AZD1775 to cytarabine slowed leukemia progression and prolonged survival. Inhibition of WEE1 with AZD1775 sensitizes T-ALL to several anti-leukemia agents, particularly cytarabine and that mechanistically, AZD1775 promotes apoptosis over DNA repair in cells treated with cytarabine. These data support the development of clinical trials including AZD1775 in combination with conventional chemotherapy for acute leukemia.

  14. Treosulfan, Fludarabine Phosphate, and Total-Body Irradiation Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2017-04-05

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  15. CD44, Hyaluronan, the Hematopoietic Stem Cell, and Leukemia-Initiating Cells

    PubMed Central

    Zöller, Margot

    2015-01-01

    CD44 is an adhesion molecule that varies in size due to glycosylation and insertion of so-called variant exon products. The CD44 standard isoform (CD44s) is highly expressed in many cells and most abundantly in cells of the hematopoietic system, whereas expression of CD44 variant isoforms (CD44v) is more restricted. CD44s and CD44v are known as stem cell markers, first described for hematopoietic stem cells and later on confirmed for cancer- and leukemia-initiating cells. Importantly, both abundantly expressed CD44s as well as CD44v actively contribute to the maintenance of stem cell features, like generating and embedding in a niche, homing into the niche, maintenance of quiescence, and relative apoptosis resistance. This is surprising, as CD44 is not a master stem cell gene. I here will discuss that the functional contribution of CD44 relies on its particular communication skills with neighboring molecules, adjacent cells and, last not least, the surrounding matrix. In fact, it is the interaction of the hyaluronan receptor CD44 with its prime ligand, which strongly assists stem cells to fulfill their special and demanding tasks. Recent fundamental progress in support of this “old” hypothesis, which may soon pave the way for most promising new therapeutics, is presented for both hematopoietic stem cell and leukemia-initiating cell. The contribution of CD44 to the generation of a stem cell niche, to homing of stem cells in their niche, to stem cell quiescence and apoptosis resistance will be in focus. PMID:26074915

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

    SciTech Connect

    Sumi, Daigo; Shinkai, Yasuhiro; Kumagai, Yoshito

    2010-05-01

    Arsenic trioxide (As{sub 2}O{sub 3}) is widely used to treat acute promyelocytic leukemia (APL). Several lines of evidence have indicated that As{sub 2}O{sub 3} 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 As{sub 2}O{sub 3} 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 As{sub 2}O{sub 3} exposure in leukemia cells.

  17. [Analysis of Flt-3 expression and Flt-3/ITD mutation in acute myeloid leukemia cells].

    PubMed

    Wang, Ya-Lun; Wang, Tong; Xu, Feng; Gang, Yan; Wang, Jie

    2006-06-01

    This study was aimed to explore the relationship between Flt-3 expression, Flt-3/ITD mutation in acute leukemia (AL) cell line and pathogenesis of AL, especially AML. The Flt-3 expression and Flt-3/ITD mutation were detected by RT-PCR and sequencing method in 82 leukemia cell lines including 20 AML, 57 ALL and 5 CML cell lines. The results indicated that positive results of Flt-3 expression were obtained in 48 out of 77 AL cell line, the positive rate was 62%; 12 cell lines were positive in 20 AML cell lines, the positive rate was 60%; 33 cell lines was positive in 57 ALL cell lines, the positive rate was 58%; 3 cell lines were positive in 5 CML cell lines, the positive rate was 60%. There was abnormal gene product in 1 AMOL cell line out of 12 AML cell lines with Flt-3 positive expression (positive rate 8.3%). DNA sequencing of abnormal gene product showed two coding duplication sequence with 29 bp long. The positive rate of Flt-3 expression in undifferentiated cell line was prominently higher than that in mature B cell ALL (P < 0.05). It is concluded that the Flt-3 expression is different in various leukemia cells. Flt-3/ITD duplication was found in one AML cell line. The detection of Flt-3 gene and Flt-3/ITD mutation may contribute to the diagnosis of ALL, especially to AML.

  18. Fludarabine Phosphate, Low-Dose Total-Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine, Mycophenolate Mofetil, Donor Lymphocyte Infusion in Treating Patients With Hematopoietic Cancer

    ClinicalTrials.gov

    2016-08-01

    ; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Renal Cell Cancer; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

  19. Activated Ca2+/calmodulin-dependent protein kinase IIgamma is a critical regulator of myeloid leukemia cell proliferation.

    PubMed

    Si, Jutong; Collins, Steven J

    2008-05-15

    Ca(2+) signaling is an important component of signal transduction pathways regulating B and T lymphocyte proliferation, but the functional role of Ca(2+) signaling in regulating myeloid leukemia cell proliferation has been largely unexplored. We observe that the activated (autophosphorylated) Ca(2+)/calmodulin-dependent protein kinase IIgamma (CaMKIIgamma) is invariably present in myeloid leukemia cell lines as well as in the majority of primary acute myelogenous leukemia patient samples. In contrast, myeloid leukemia cells induced to terminally differentiate or undergo growth arrest display a marked reduction in this CaMKIIgamma autophosphorylation. In cells harboring the bcr-abl oncogene, the activation (autophosphorylation) of CaMKIIgamma is regulated by this oncogene. Moreover, inhibition of CaMKIIgamma activity with pharmacologic agents, dominant-negative constructs, or short hairpin RNAs inhibits the proliferation of myeloid leukemia cells, and this is associated with the inactivation/down-regulation of multiple critical signal transduction networks involving the mitogen-activated protein kinase, Janus-activated kinase/signal transducers and activators of transcription (Jak/Stat), and glycogen synthase kinase (GSK3beta)/beta-catenin pathways. In myeloid leukemia cells, CaMKIIgamma directly phosphorylates Stat3 and enhances its transcriptional activity. Thus, CaMKIIgamma is a critical regulator of multiple signaling networks regulating the proliferation of myeloid leukemia cells. Inhibiting CaMKIIgamma may represent a novel approach in the targeted therapy of myeloid leukemia.

  20. Preclinical validation: LV/IL-12 transduction of patient leukemia cells for immunotherapy of AML

    PubMed Central

    Huang, Ju; Liu, Yuanfeng; Au, Bryan C; Barber, Dwayne L; Arruda, Andrea; Schambach, Axel; Rothe, Michael; Minden, Mark D; Paige, Christopher J; Medin, Jeffrey A

    2016-01-01

    Interleukin-12 (IL-12) is a potent cytokine that may be harnessed to treat cancer. To date, nearly 100 IL-12-based clinical trials have been initiated worldwide. Yet systemic administration of IL-12 is toxic. Different strategies are being developed to reduce such toxicities by restricting IL-12 distribution. Our previous studies employed lentivector-mediated expression of murine IL-12 in tumor cells and demonstrated effective protection in both mouse leukemia and solid tumor challenge models. In this study, we carried out preclinical validation studies using a novel lentivector to engineer expression of human IL-12 in acute myeloid leukemia blast cells isolated from 21 patients. Acute myeloid leukemia cells were transduced with a bicistronic lentivector that encodes the human IL-12 cDNA as a fusion, as well as a LNGFR (ΔLNGFR)/mutant thymidylate kinase cassette as a marking and cell-fate control element. A range of 20–70% functional transduction efficiencies was achieved. Transduced acute myeloid leukemia cells produced bioactive IL-12 protein and displayed dose-dependent sensitivity to the prodrug 3′-azido-3′-deoxythymidine. In vitro immortalization assays using transduced mouse hematopoietic stem cells demonstrated minimal genotoxic risk from our IL-12 vector. Scale-up transduction and cell processing was subsequently validated in a GMP facility to support our (now approved) Clinical Trial Application (CTA). PMID:27933304

  1. Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenes.

    PubMed

    Tremblay, Mathieu; Tremblay, Cédric S; Herblot, Sabine; Aplan, Peter D; Hébert, Josée; Perreault, Claude; Hoang, Trang

    2010-06-01

    Deciphering molecular events required for full transformation of normal cells into cancer cells remains a challenge. In T-cell acute lymphoblastic leukemia (T-ALL), the genes encoding the TAL1/SCL and LMO1/2 transcription factors are recurring targets of chromosomal translocations, whereas NOTCH1 is activated in >50% of samples. Here we show that the SCL and LMO1 oncogenes collaborate to expand primitive thymocyte progenitors and inhibit later stages of differentiation. Together with pre-T-cell antigen receptor (pre-TCR) signaling, these oncogenes provide a favorable context for the acquisition of activating Notch1 mutations and the emergence of self-renewing leukemia-initiating cells in T-ALL. All tumor cells harness identical and specific Notch1 mutations and Tcrbeta clonal signature, indicative of clonal dominance and concurring with the observation that Notch1 gain of function confers a selective advantage to SCL-LMO1 transgenic thymocytes. Accordingly, a hyperactive Notch1 allele accelerates leukemia onset induced by SCL-LMO1 and bypasses the requirement for pre-TCR signaling. Finally, the time to leukemia induced by the three transgenes corresponds to the time required for clonal expansion from a single leukemic stem cell, suggesting that SCL, LMO1, and Notch1 gain of function, together with an active pre-TCR, might represent the minimum set of complementing events for the transformation of susceptible thymocytes.

  2. Enkephalins stimulate leukemia cell migration and surface expression of CD9.

    PubMed Central

    Heagy, W; Duca, K; Finberg, R W

    1995-01-01

    Opioid peptides have been implicated in the regulation of tumor growth and biology; however, little attention has been given to the mechanisms that are involved. In this study we show that physiological concentrations of the endogenous opioid neuropeptide methionine-enkephalin (MET-ENK) and the synthetic enkephalins D-Ala2, Me-Phe4, Gly(ol)5 and D-Ala2, D-Leu5 are stimulants for the in vitro migration of pre-B acute lymphoblastoid leukemia (ALL) cells. Activation of the human pre-B ALL cell lines NALM 6 and LAZ 221 with MET-ENK resulted in both an increase in their migration and an augmentation in the surface expression of the leukemia cell marker CD9. The opiate receptor antagonist naloxone reversed these enkephalin-induced effects on the leukemia cells. When the pre-B ALL cells were preincubated with an anti-CD9 mAb before challenge with MET-ENK their migration to the enkephalin was markedly reduced. These studies show that endogenous and synthetic opioid peptides are stimulants for pre-B ALL cell migration and suggest that CD9 is important in the regulation of leukemia cell motility. Images PMID:7657811

  3. Neuroimmunological aspects of human T cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis.

    PubMed

    Saito, Mineki

    2014-04-01

    Human T cell leukemia virus type 1 (HTLV-1) is a human retrovirus etiologically associated with adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Only approximately 0.25-4 % of infected individuals develop HAM/TSP; the majority of infected individuals remain lifelong asymptomatic carriers. Recent data suggest that immunological aspects of host-virus interactions might play an important role in the development and pathogenesis of HAM/TSP. This review outlines and discusses the current understanding, ongoing developments, and future perspectives of HAM/TSP research.

  4. In vitro effect of imatinib mesylate loaded on polybutylcyanoacrylate nanoparticles on leukemia cell line K562.

    PubMed

    Hasandoost, Leyla; Akbarzadeh, Azim; Attar, Hossein; Heydarinasab, Amir

    2017-05-01

    The study aimed to prepare imatinib mesylate-loaded polybutylcyanoacrylate (PBCA) nanoparticles and evaluate their efficacy on leukemia cell line K562. The formulation was prepared by miniemulsion polymerization technique. Nanoparticles were characterized by dynamic light scattering (DLS), spectrophotometry, Fourier transform infrared spectroscopy (FTIR), dialysis membrane, and 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) techniques. Nanoscale particles with high encapsulation efficiency (86%) and physical entrapment of drug were observed. In addition, nanoparticles showed suitable drug retention capability and potentiate the cytotoxicity effects of imatinib mesylate. Findings of study suggested PBCA nanoparticles are promising carrier for imatinib mesylate delivery to leukemia cell line K562.

  5. Disruption of Annexin II /p11 Interaction Suppresses Leukemia Cell Binding, Homing and Engraftment, and Sensitizes the Leukemia Cells to Chemotherapy

    PubMed Central

    Gopalakrishnapillai, Anilkumar; Kolb, E. Anders; Dhanan, Priyanka; Mason, Robert W.; Napper, Andrew; Barwe, Sonali P.

    2015-01-01

    The bone marrow microenvironment plays an important role in acute lymphoblastic leukemia (ALL) cell proliferation, maintenance, and resistance to chemotherapy. Annexin II (ANX2) is abundantly expressed on bone marrow cells and complexes with p11 to form ANX2/p11-hetero-tetramer (ANX2T). We present evidence that p11 is upregulated in refractory ALL cell lines and patient samples. A small molecule inhibitor that disrupts ANX2/p11 interaction (ANX2T inhibitor), an anti-ANX2 antibody, and knockdown of p11, abrogated ALL cell adhesion to osteoblasts, indicating that ANX2/p11 interaction facilitates binding and retention of ALL cells in the bone marrow. Furthermore, ANX2T inhibitor increased the sensitivity of primary ALL cells co-cultured with osteoblasts to dexamethasone and vincristine induced cell death. Finally, in an orthotopic leukemia xenograft mouse model, the number of ALL cells homing to the bone marrow was reduced by 40–50% in mice injected with anti-ANX2 antibody, anti-p11 antibody or ANX2T inhibitor compared to respective controls. In a long-term engraftment assay, the percentage of ALL cells in mouse blood, bone marrow and spleen was reduced in mice treated with agents that disrupt ANX2/p11 interaction. These data show that disruption of ANX2/p11 interaction results in reduced ALL cell adhesion to osteoblasts, increased ALL cell sensitization to chemotherapy, and suppression of ALL cell homing and engraftment. PMID:26465153

  6. T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells

    PubMed Central

    Witkover, Aviva; Tanaka, Yuetsu; Fields, Paul; Bangham, Charles R. M.

    2016-01-01

    There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL) responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL), human T lymphotropic virus type-1 (HTLV-1), contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1) to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease. PMID:27893842

  7. T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells.

    PubMed

    Rowan, Aileen G; Witkover, Aviva; Melamed, Anat; Tanaka, Yuetsu; Cook, Lucy B M; Fields, Paul; Taylor, Graham P; Bangham, Charles R M

    2016-11-01

    There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL) responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL), human T lymphotropic virus type-1 (HTLV-1), contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1) to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease.

  8. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents.

    PubMed

    Yu, Yan; Xie, Yangchun; Cao, Lizhi; Yang, Liangchun; Yang, Minghua; Lotze, Michael T; Zeh, Herbert J; Kang, Rui; Tang, Daolin

    2015-01-01

    Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Development of resistance to chemotherapeutic agents is a major hurdle in the effective treatment of patients with AML. The quinazolinone derivative erastin was originally identified in a screen for small molecules that exhibit synthetic lethality with expression of the RAS oncogene. This lethality was subsequently shown to occur by induction of a novel form of cell death termed ferroptosis. In this study we demonstrate that erastin enhances the sensitivity of AML cells to chemotherapeutic agents in an RAS-independent manner. Erastin dose-dependently induced mixed types of cell death associated with ferroptosis, apoptosis, necroptosis, and autophagy in HL-60 cells (AML, NRAS_Q61L), but not Jurkat (acute T-cell leukemia, RAS wild type), THP-1 (AML, NRAS_G12D), K562 (chronic myelogenous leukemia, RAS wild type), or NB-4 (acute promyelocytic leukemia M3, KRAS_A18D) cells. Treatment with ferrostatin-1 (a potent ferroptosis inhibitor) or necrostatin-1 (a potent necroptosis inhibitor), but not with Z-VAD-FMK (a general caspase inhibitor) or chloroquine (a potent autophagy inhibitor), prevented erastin-induced growth inhibition in HL-60 cells. Moreover, inhibition of c-JUN N-terminal kinase and p38, but not of extracellular signal-regulated kinase activation, induced resistance to erastin in HL-60 cells. Importantly, low-dose erastin significantly enhanced the anticancer activity of 2 first-line chemotherapeutic drugs (cytarabine/ara-C and doxorubicin/adriamycin) in HL-60 cells. Collectively, the induction of ferroptosis and necroptosis contributed to erastin-induced growth inhibition and overcame drug resistance in AML cells.

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

    SciTech Connect

    Halanay, A.; Cândea, D.; Rădulescu, R.

    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.

  10. Extensive nuclear lobulation in the cells of a patient with acute myelomonocytic leukemia. The role of electron microscopy for establishment of a correct diagnosis.

    PubMed

    Djaldetti, M; Cohen, A; Gardyn, J; Bendayan, D

    1990-07-01

    Extensive nuclear convolution and lobulation was found in the peripheral blood cells of a patient with acute leukemia. While the morphology of the cells, such as observed with the light microscope, was compatible with the diagnosis of acute myeloid leukemia, the finding of Sezary-like cells with the electron microscope helped to establish the diagnosis of acute myelomonocytic leukemia. This report emphasizes the importance of the electron microscope for the correct diagnosis of leukemias.

  11. LMO2 Oncoprotein Stability in T-Cell Leukemia Requires Direct LDB1 Binding

    PubMed Central

    Layer, Justin H.; Alford, Catherine E.; McDonald, W. Hayes

    2015-01-01

    LMO2 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study, we systematically dissected the LMO2/LDB1-binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif, R320LITR, required for LMO2 binding. Most strikingly, coexpression of full-length, wild-type LDB1 increased LMO2 steady-state abundance, whereas coexpression of mutant proteins deficient in LMO2 binding compromised LMO2 stability. These mutant LDB1 proteins also exerted dominant negative effects on growth and transcription in diverse leukemic cell lines. Mass spectrometric analysis of LDB1 binding partners in leukemic lines supports the notion that LMO2/LDB1 function in leukemia occurs in the context of multisubunit complexes, which also protect the LMO2 oncoprotein from degradation. Collectively, these data suggest that the assembly of LMO2 into complexes, via direct LDB1 interaction, is a potential molecular target that could be exploited in LMO2-driven leukemias resistant to existing chemotherapy regimens. PMID:26598604

  12. Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia

    PubMed Central

    Yuan, Na; Song, Lin; Zhang, Suping; Lin, Weiwei; Cao, Yan; Xu, Fei; Fang, Yixuan; Wang, Zhen; Zhang, Han; Li, Xin; Wang, Zhijian; Cai, Jinyang; Wang, Jian; Zhang, Yi; Mao, Xinliang; Zhao, Wenli; Hu, Shaoyan; Chen, Suning; Wang, Jianrong

    2015-01-01

    B-cell acute lymphoblastic leukemia is the most common type of pediatric leukemia. Despite improved remission rates, current treatment regimens for pediatric B-cell acute lymphoblastic leukemia are often associated with adverse effects and central nervous system relapse, necessitating more effective and safer agents. Bafilomycin A1 is an inhibitor of vacuolar H+-ATPase that is frequently used at high concentration to block late-phase autophagy. Here, we show that bafilomycin A1 at a low concentration (1 nM) effectively and specifically inhibited and killed pediatric B-cell acute lymphoblastic leukemia cells. It targeted both early and late stages of the autophagy pathway by activating mammalian target of rapamycin signaling and by disassociating the Beclin 1-Vps34 complex, as well as by inhibiting the formation of autolysosomes, all of which attenuated functional autophagy. Bafilomycin A1 also targeted mitochondria and induced caspase-independent apoptosis by inducing the translocation of apoptosis-inducing factor from mitochondria to the nucleus. Moreover, bafilomycin A1 induced the binding of Beclin 1 to Bcl-2, which further inhibited autophagy and promoted apoptotic cell death. In primary cells from pediatric patients with B-cell acute lymphoblastic leukemia and a xenograft model, bafilomycin A1 specifically targeted leukemia cells while sparing normal cells. An in vivo mouse toxicity assay confirmed that bafilomycin A1 is safe. Our data thus suggest that bafilomycin A1 is a promising candidate drug for the treatment of pediatric B-cell acute lymphoblastic leukemia. PMID:25512644

  13. Differences in vanadocene dichloride and cisplatin effect on MOLT-4 leukemia and human peripheral blood mononuclear cells.

    PubMed

    Havelek, Radim; Siman, Pavel; Cmielova, Jana; Stoklasova, Alena; Vavrova, Jirina; Vinklarek, Jaromir; Knizek, Jiri; Rezacova, Martina

    2012-07-01

    Modern chemotherapy is interested in developing new agents with high efficiency of treatment in low-dose medication strategies, lower side toxicity and stronger specificity to the tumor cells. Vanadocene dichloride (VDC) belongs to the group of the most promising metallocene antitumor agents; however, its mechanism of action and cytotoxicity profile are not fully understood. In this paper we assess cytotoxic effects of VDC in comparison to cisplatin using opposite prototype of cells; human peripheral blood mononuclear (PBMCs) cells and human acute lymphoblastic leukemia cell line (MOLT-4). Our findings showed cytotoxic effect of VDC on leukemia cells, but unfortunately on human peripheral blood mononuclear cells as well. VDC induces apoptosis in leukemia cells; the induction is, however, lower than that of cisplatin, and in contrary to cisplatin, VDC does not induce p53 up-regulation. Cytotoxic effect of VDC on leukemia cells is less pronounced than that of cisplatin and more pronounced in PBMCs than in MOLT-4 cells.

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

    PubMed Central

    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

  15. Air entrainment in hairy surfaces

    NASA Astrophysics Data System (ADS)

    Nasto, Alice; Regli, Marianne; Brun, P.-T.; Alvarado, José; Clanet, Christophe; Hosoi, A. E.

    2016-07-01

    Motivated by diving semiaquatic mammals, we investigate the mechanism of dynamic air entrainment in hairy surfaces submerged in liquid. Hairy surfaces are cast out of polydimethylsiloxane elastomer and plunged into a fluid bath at different velocities. Experimentally, we find that the amount of air entrained is greater than what is expected for smooth surfaces. Theoretically, we show that the hairy surface can be considered as a porous medium and we describe the air entrainment via a competition between the hydrostatic forcing and the viscous resistance in the pores. A phase diagram that includes data from our experiments and biological data from diving semiaquatic mammals is included to place the model system in a biological context and predict the regime for which the animal is protected by a plastron of air.

  16. Clonal analysis of childhood acute lymphoblastic leukemia with "cytogenetically independent" cell populations.

    PubMed Central

    Pui, C H; Raskind, W H; Kitchingman, G R; Raimondi, S C; Behm, F G; Murphy, S B; Crist, W M; Fialkow, P J; Williams, D L

    1989-01-01

    Acute lymphoblastic leukemia (ALL) is generally regarded as a clonal disease in which a single abnormal progenitor cell gives rise to neoplastic progeny. Five of 463 cases of childhood ALL with adequately banded leukemic cells were found to have two cytogenetically independent cell populations. In addition, two of the four cases tested had more than two rearranged immunoglobulin genes and (or) T cell receptor genes. To investigate the clonality of these unusual leukemias, we examined the neoplastic cells for X-linked markers extrinsic to the disease. Leukemic cells from each of the three patients heterozygous for an X-linked, restriction fragment length polymorphism showed a single active parental allele, suggesting that both apparently independent cell populations developed from a common progenitor. These cases provide evidence that leukemogenesis involves a multistep process of mutation and suggest that karyotypic abnormalities may be a late event of malignant transformation. Images PMID:2566623

  17. Transplantability of human lymphoid cell line, lymphoma, and leukemia in splenectomized and/or irradiated nude mice

    SciTech Connect

    Watanabe, S.; Shimosato, Y.; Kuroki, M.; Sato, Y.; Nakajima, T.

    1980-07-01

    The effects of splenectomy and/or whole-body irradiation of nude mice before xenotransplantation of lymphoid cell lines, lymphoma, and leukemia were studied. Transplantation after whole-body irradiation resulted in the increased ''take'' rate of three cultured cell lines (two of T-cell-derived acute lymphocytic leukemia and one of B-cell derived acute lymphocytic leukemia) and in the tumorous growth of Burkitt-derived Raji and spontaneously transformed lymphoblastoid cell lines. With splenectomy plus irradiation as a pretreatment, tumorous growth occurred in four other cell lines which were not transplantable after irradiation only (two cell lines of Epstein-Barr virus-transformed cord blood cells and one each of null acute lymphocytic leukemia and nodular lymphoma-derived cell lines). Direct transplantation of leukemia and lymphoma cells into the pretreated mice was successful in 7 of 24 cases (29%). B-cell-derived diffuse large lymphoid lymphoma was transplantable in three of seven cases (43%). However, lymphoma and leukemia of peripheral T-cell origin was difficult to transplant even with pretreatment, and only one pleomorphic T-cell lymphoma grew to a significant size (2 cm). One tumor each of B-cell-derived diffuse large lymphoid and T-cell diffuse lymphoblastic lymphoma became transplantable.

  18. Frequency of monoclonal B-cell lymphocytosis in relatives of patients with chronic lymphocytic leukemia

    PubMed Central

    Franco Alzate, Catalina; Rendón Henao, Javier; Torres Hernández, José Domingo; Jaramillo Arbelaez, Patricia Elena

    2016-01-01

    Introduction: Monoclonal B-cell lymphocytosis is a symptom free condition characterized by the circulation of small clonal population of B lymphocytes in peripheral blood (less than 5x109/L) expressing an immunophenotype similar to chronic lymphocytic leukemia. Different studies based on big hospital series have manifested a higher risk in subjects with monoclonal B-cell lymphocytosis to progress to a chronic lymphocytic leukemia. The behavior of this hematologic entity is unknown therefore its frequency in sporadic chronic lymphocytic leukemia patient relatives was determined. Methods: Transversal descriptive study, 8 color flow cytometry was performed using two of the tubes of the Euro Flow recommended panel, with modifications, for the diagnose of chronic lymphoproliferative disorders of B lymphocytes; besides, a fluorescence in situ hybridization was performed. univariate and bivariate analyses of the information were performed. Results: Monoclonal B-cell lymphocytosis frequency found in 51 analyzed relatives was 2%, it was a female participant, 59 years old, with a total leukocyte count of 7.7x109/L and a B lymphocyte count of 0.124x109/L; from these, 0.04x109/L were clonal cells with restrictions of the kappa light chain. Rearrangements of the IGH gene (14q32) were found. Conclusion: Monoclonal B-cell lymphocytosis was detected in one relative of a patient with sporadic chronic lymphocytic leukemia in a frequency similar to the one reported in general population. PMID:27546929

  19. Wilms tumor 1 peptide vaccination after hematopoietic stem cell transplant in leukemia patients

    PubMed Central

    Maeda, Tetsuo; Hashii, Yoshiko; Tsuboi, Akihiro; Nishida, Sumiyuki; Nakata, Jun; Oji, Yusuke; Oka, Yoshihiro; Sugiyama, Haruo

    2016-01-01

    Although the prognosis of leukemia patients after allogeneic hematopoietic stem cell transplantation (HSCT) has greatly improved, relapse is still a major cause of death after HSCT. Cancer vaccines may have the potential to enhance the graft-versus-leukemia (GVL) effect. The post–allogeneic HSCT period provides a unique platform for vaccination, because (I) tumor burden is minimal, (II) lymphopenia allows for rapid expansion of cytotoxic T cells (CTLs), (III) donor-derived CTLs are not exhausted, (IV) inflammation is caused by alloreactions, and (V) the abundance of regulatory T cells is low due to their late recovery. Tumor cell lysates, dendritic cells (DCs), and peptides derived from leukemia-associated antigens (LAAs) have been used as vaccines. Clinical trials with several types of vaccines for post-HSCT patients revealed that the vaccination induced an immunological response and might benefit patients with minimal residual disease; however, the efficacy of this approach must be examined in randomized studies. In addition, it is important to consider the combination of cancer vaccine with checkpoint antibodies, recently shown to be useful in treating leukemia relapse after HSCT. PMID:28078270

  20. Factors associated with improved outcomes after second allogeneic hematopoietic cell transplantation for relapsed pediatric leukemia.

    PubMed

    Menon, Neethu N; Jenkins, Lydia M; Cui, Haiyan; Jenkins, Craig; Anwer, Faiz; Yeager, Andrew M; Katsanis, Emmanuel

    2016-03-01

    A second allogeneic (allo) hematopoietic cell transplant (HCT) is an important therapeutic consideration for patients relapsing after their first. We conducted a retrospective review of 41 pediatric patients with leukemia that underwent a second allo-HCT at our institution. Overall, 53.7 and 43.9 % of patients were alive and disease-free at 1 and 5 years, respectively, after the second allo-HCT. The factors affecting outcome by both univariate and multivariate analysis were interval between transplants and the use of a myeloablative conditioning (MAC) regimen prior to second transplant. Outcomes were inferior in patients who received their second transplant <6 months from their first HCT when compared to patients in whom the interval between HCTs was 6-12 or more than 12 months. Interval between HCTs was also significant when each type of leukemia (acute lymphoblastic leukemia (ALL) n = 21, acute myelogenous leukemia (AML) n = 11, and chronic myelogenous leukemia (CML) n = 7) was analyzed separately. In univariate analysis, use of the same donor and use of a matched sibling donor resulted in significant improved outcome. There was not a significant association between disease-free survival (DFS) and age, remission status, use of total body irradiation (TBI) before second HCT, or type of leukemia. Second allogeneic HCT can be a curative therapeutic option for leukemia patients relapsing after their first transplant. As more targeted therapies have become available, patients that relapse after first HCT are more likely to achieve remission. Therefore, it is anticipated that there will be more candidates for second HCT with improved performance and remission status, ultimately leading to a better outcome with the second HCT.

  1. A cationic amphiphilic peptide ABP-CM4 exhibits selective cytotoxicity against leukemia cells.

    PubMed

    Chen, Yu Qing; Min, Cui; Sang, Ming; Han, Yang Yang; Ma, Xiao; Xue, Xiao Qing; Zhang, Shuang Quan

    2010-08-01

    Some cationic antibacterial peptides exhibit a broad spectrum of cytotoxic activity against cancer cells, which could provide a new class of anticancer drugs. In the present study, the anticancer activity of ABP-CM4, an antibacterial peptide from Bombyx mori, against leukemic cell lines THP-1, K562 and U937 was evaluated, and the cytotoxicity compared with the effects on non-cancerous mammalian cells, including peripheral blood mononuclear cells (PBMCs), HEK-293 and erythrocytes. ABP-CM4 reduced the number of viable cells of the leukemic cell lines after exposure for 24h. The reduction was concentration dependent, and the IC50 values ranged from 14 to 18 microM. Conversely, ABP-CM4, even at 120 microM, exhibited no cytotoxicity toward HEK-293 or PBMCs, indicating that there was no significant effect on these two types of non-cancer cells. ABP-CM4 at a concentration of 200 microM had no hemolytic activity on mammalian erythrocytes. Together, these results suggested a selective cytotoxicity in leukemia cells. Flow cytometry demonstrated that the binding activity of ABP-CM4 to leukemia cells was much higher than that to HEK-293 or PBMCs, and there was almost no binding to erythrocytes. FITC-labeled ABP-CM4 molecules were examined under a confocal microscope and found to be concentrated at the surface of leukemia cells and changes of the cell membrane were determined by a cell permeability assay, which led us to the conclusion that ABP-CM4 could act at the cell membrane for its anticancer activity on leukemia cells. Collectively, our results indicated that ABP-CM4 has the potential for development as a novel antileukemic agent.

  2. Lenalidomide Induces Immunomodulation in Chronic Lymphocytic Leukemia and Enhances Antitumor Immune Responses Mediated by NK and CD4 T Cells

    PubMed Central

    Acebes-Huerta, Andrea; Huergo-Zapico, Leticia; Gonzalez-Rodriguez, Ana Pilar; Fernandez-Guizan, Azahara; Payer, Angel R.; Gonzalez, Segundo

    2014-01-01

    Lenalidomide is an immunomodulatory drug with therapeutic activity in chronic lymphocytic leukemia (CLL). However, it has pleiotropic effects, and the mechanism of action responsible for its therapeutic activity has not been well defined yet. Herein, we show that lenalidomide treatment does not have an effect on the proliferation of leukemia cells, but it increases the proliferation of B cells from healthy donors. Lenalidomide did not exert a direct effect on the apoptosis of leukemia cells obtained from CLL patients, although it indirectly induced their apoptosis through the activation of nonmalignant immune cells. Thus, lenalidomide markedly increased the proliferation of NK and CD4 T cells. The effect of lenalidomide on NK cells was secondary to the induction of IL-2 production by CD4 T cells. Accordingly, depletion of T cells or blockade of IL-2 activity completely abrogated the proliferation of NK cells. Additionally, lenalidomide enhanced NK and NKT-like cell-mediated natural cytotoxicity against leukemia cells from CLL patients. Lenalidomide also upregulated CD20 expression on leukemia cells and, accordingly, it had a synergistic effect with rituximab on promoting antibody-dependent cell-mediated cytotoxicity against primary leukemia cells. Overall, these observations provide a support for combining lenalidomide with rituximab as a treatment in CLL. PMID:25313353

  3. IRF4 is a suppressor of c-Myc induced B cell leukemia.

    PubMed

    Pathak, Simanta; Ma, Shibin; Trinh, Long; Eudy, James; Wagner, Kay-Uwe; Joshi, Shantaram S; Lu, Runqing

    2011-01-01

    Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B cell development and function. We have previously shown that IRF4, together with IRF8, orchestrates pre-B cell development by limiting pre-B cell expansion and by promoting pre-B cell differentiation. Here, we report that IRF4 suppresses c-Myc induced leukemia in EμMyc mice. Our results show that c-Myc induced leukemia was greatly accelerated in the IRF4 heterozygous mice (IRF4(+/-)Myc); the average age of mortality in the IRF4(+/-)Myc mice was only 7 to 8 weeks but was 20 weeks in the control mice. Our results show that IRF4(+/-)Myc leukemic cells were derived from large pre-B cells and were hyperproliferative and resistant to apoptosis. Further analysis revealed that the majority of IRF4(+/-)Myc leukemic cells inactivated the wild-type IRF4 allele and contained defects in Arf-p53 tumor suppressor pathway. p27(kip) is part of the molecular circuitry that controls pre-B cell expansion. Our results show that expression of p27(kip) was lost in the IRF4(+/-)Myc leukemic cells and reconstitution of IRF4 expression in those cells induced p27(kip) and inhibited their expansion. Thus, IRF4 functions as a classical tumor suppressor to inhibit c-Myc induced B cell leukemia in EμMyc mice.

  4. Donor Stem Cell Transplant in Treating Patients With High Risk Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-08-29

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myeloid Leukemia in Remission; Childhood Acute Myelomonocytic Leukemia (M4); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  5. Lenalidomide in Treating Older Patients With Acute Myeloid Leukemia Who Have Undergone Stem Cell Transplant

    ClinicalTrials.gov

    2015-03-02

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia

  6. Molecular Targeting of the Oncoprotein PLK1 in Pediatric Acute Myeloid Leukemia: RO3280, a Novel PLK1 Inhibitor, Induces Apoptosis in Leukemia Cells

    PubMed Central

    Wang, Na-Na; Li, Zhi-Heng; Zhao, He; Tao, Yan-Fang; Xu, Li-Xiao; Lu, Jun; Cao, Lan; Du, Xiao-Juan; Sun, Li-Chao; Zhao, Wen-Li; Xiao, Pei-Fang; Fang, Fang; Su, Guang-Hao; Li, Yan-Hong; Li, Gang; Li, Yi-Ping; Xu, Yun-Yun; Zhou, Hui-Ting; Wu, Yi; Jin, Mei-Fang; Liu, Lin; Ni, Jian; Wang, Jian; Hu, Shao-Yan; Zhu, Xue-Ming; Feng, Xing; Pan, Jian

    2015-01-01

    Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor; however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35; p < 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy; however, the underlying mechanisms remain to be determined. PMID:25574601

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

    PubMed Central

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

    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. PMID:19887046

  8. Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations.

    PubMed

    Emadi, Ashkan; Jun, Sung Ah; Tsukamoto, Takashi; Fathi, Amir T; Minden, Mark D; Dang, Chi V

    2014-04-01

    The incidence of mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) in de novo acute myeloid leukemia (AML) is approximately 20%. These mutations result in distinct metabolic characteristics including dependency of cancer cells on glutamine as the main source for α-ketoglutarate, which is consumed by leukemia cells to produce a cancer-derived metabolite, 2-hydroxyglutarate. We sought to exploit this glutamine addiction therapeutically in mutant IDH primary AML cells from patients by measuring cell growth after exposure to a small molecule glutaminase inhibitor, BPTES. We found that BPTES only suppressed the growth of AML cells expressing mutant IDH compared with those expressing wild type IDH. This study lays the groundwork for strategies to target a specific subtype of AML metabolically with IDH mutations with a unique reprogramming of intermediary metabolism that culminates in glutamine dependency of cancer cells for survival.

  9. Acute Lymphocytic Leukemia

    MedlinePlus

    ... hard for blood to do its work. In acute lymphocytic leukemia (ALL), also called acute lymphoblastic leukemia, there are too ... of white blood cells called lymphocytes or lymphoblasts. ALL is the most common type of cancer in ...

  10. Triptolide induced cell death through apoptosis and autophagy in murine leukemia WEHI-3 cells in vitro and promoting immune responses in WEHI-3 generated leukemia mice in vivo.

    PubMed

    Chan, Shih-Feng; Chen, Ya-Yin; Lin, Jen-Jyh; Liao, Ching-Lung; Ko, Yang-Ching; Tang, Nou-Ying; Kuo, Chao-Lin; Liu, Kuo-Ching; Chung, Jing-Gung

    2017-02-01

    Triptolide, a traditional Chinese medicine, obtained from Tripterygium wilfordii Hook F, has anti-inflammatory, antiproliferative, and proapoptotic properties. We investigated the potential efficacy of triptolide on murine leukemia by measuring the triptolide-induced cytotoxicity in murine leukemia WEHI-3 cells in vitro. Results indicated that triptolide induced cell morphological changes and induced cytotoxic effects through G0/G1 phase arrest, induction of apoptosis. Flow cytometric assays showed that triptolide increased the production of reactive oxygen species, Ca(2+) release and mitochondrial membrane potential (ΔΨm ), and activations of caspase-8, -9, and -3. Triptolide increased protein levels of Fas, Fas-L, Bax, cytochrome c, caspase-9, Endo G, Apaf-1, PARP, caspase-3 but reduced levels of AIF, ATF6α, ATF6β, and GRP78 in WEHI-3 cells. Triptolide stimulated autophagy based on an increase in acidic vacuoles, monodansylcadaverine staining for LC-3 expression and increased protein levels of ATG 5, ATG 7, and ATG 12. The in vitro data suggest that the cytotoxic effects of triptolide may involve cross-talk between cross-interaction of apoptosis and autophagy. Normal BALB/c mice were i.p. injected with WEHI-3 cells to generate leukemia and were oral treatment with triptolide at 0, 0.02, and 0.2 mg/kg for 3 weeks then animals were weighted and blood, liver, spleen samples were collected. Results indicated that triptolide did not significantly affect the weights of animal body, spleen and liver of leukemia mice, however, triptolide significant increased the cell populations of T cells (CD3), B cells (CD19), monocytes (CD11b), and macrophage (Mac-3). Furthermore, triptolide increased the phagocytosis of macrophage from peripheral blood mononuclear cells (PBMC) but not effects from peritoneum. Triptolide promoted T and B cell proliferation at 0.02 and 0.2 mg/kg treatment when cells were pretreated with Con A and LPS stimulation, respectively; however, triptolide

  11. Alisertib in Combination With Vorinostat in Treating Patients With Relapsed or Recurrent Hodgkin Lymphoma, B-Cell Non-Hodgkin Lymphoma, or Peripheral T-Cell Lymphoma

    ClinicalTrials.gov

    2016-12-26

    Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; T-Cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  12. Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains.

    PubMed

    Trowbridge, Jennifer J; Sinha, Amit U; Zhu, Nan; Li, Mingjie; Armstrong, Scott A; Orkin, Stuart H

    2012-02-15

    Epigenetic mechanisms regulating leukemia stem cells (LSCs) are an attractive target for therapy of blood cancers. Here, we report that conditional knockout of the DNA methyltransferase Dnmt1 blocked development of leukemia, and haploinsufficiency of Dnmt1 was sufficient to delay progression of leukemogenesis and impair LSC self-renewal without altering normal hematopoiesis. Haploinsufficiency of Dnmt1 resulted in tumor suppressor gene derepression associated with reduced DNA methylation and bivalent chromatin marks. These results suggest that LSCs depend on not only active expression of leukemogenic programs, but also DNA methylation-mediated silencing of bivalent domains to enforce transcriptional repression.

  13. In vitro cellular uptake and cytotoxic effect of functionalized nickel nanoparticles on leukemia cancer cells.

    PubMed

    Guo, Dadong; Wu, Chunhui; Li, Xiaomao; Jiang, Hui; Wang, Xuemei; Chen, Baoan

    2008-05-01

    Nickel nanoparticles (Ni NPs) have been applied in a wide range of areas because of their unique structure and properties such as catalysts, high-density magnetic recording media and others. However, little effort has been paid to their biological application and the concrete effect of Ni NPs on biological systems is still unknown. In this study, the possibility of the utilization of the magnetic Ni NPs in cancer cell studies was explored and the effects of the Ni NPs capped with positively charged tetraheptylammonium on leukemia K562 cells in vitro were investigated. Our observations of optical microscopy, atomic force microscopy (AFM) and scanning electron microscopy (SEM) studies indicate that the morphological changes of cancer cells induced by Ni NPs could be apparently observed. The results of 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) assay, DNA fragmentation and flow cytometry studies demonstrate that the Ni NPs could exert cytotoxicity to leukemia K562 cells at high concentration, and subsequently induce both apoptosis and necrosis of target cancer cells, whilst it had little impact on target cells when at low concentration. Meanwhile, functionalized Ni NPs with positively charged groups could enhance the permeability of cell membrane and facilitate the cellular uptake of outer target molecules into cancer cells. These findings reveal the potential mechanism of Ni NPs to target cancer cells which could induce the cytotoxicity to leukemia cancer cells and suggest the possibility for applications of the Ni NPs in related clinical and biomedical areas.

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

    PubMed

    do Valle, A C; Galhardo, M C; Leite, A C; Araújo, A Q; Cuzzi-Maya, T; Maceira, J P; de Ameida Dobbin, J

    2001-01-01

    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.

  15. T-cell lymphoma of the tympanic bulla in a feline leukemia virus-negative cat.

    PubMed

    de Lorimier, Louis-Philippe; Alexander, Suzanne D; Fan, Timothy M

    2003-12-01

    This report constitutes the first description of a T-cell lymphoma of the tympanic bulla in a cat. This feline leukemia virus (FeLV)-negative cat originally presented with signs referable to middle ear disease; it deteriorated rapidly after definitive diagnosis. Lymphoma of the middle ear is extremely rare in all species.

  16. T-Cell Large Granular Lymphocyte Leukemia in the Lower Eyelid.

    PubMed

    Sia, Paul Ikgan; Figueira, Edwin; Kuss, Bryone; Craig, James; Selva, Dinesh

    The authors describe a case of T-cell large granular lymphocytic leukemia nodular lesion of the eyelid. To their knowledge, this has not been reported previously to occur in the eyelids. They have also reviewed previous literature reports on similar skin lesions in areas elsewhere.

  17. Favorable response to aggressive chemotherapy in a patient with primary plasma cell leukemia.

    PubMed

    Lishner, M; Lang, R; Jutrin, I; Ravid, M

    1985-01-01

    Primary plasma cell leukemia was diagnosed in a previously healthy 58-year-old man. The unusual presentation with concomitant multiple osteolytic lesions and hepatosplenomegaly, the favorable response to aggressive chemotherapy with COAP, and the relatively long survival of 22 months prompted this report. This and several other cases recently reported should encourage an aggressive therapeutic approach to this disease.

  18. Metastatic Calcinosis Cutis: A Case in a Child with Acute Pre-B Cell Lymphoblastic Leukemia

    PubMed Central

    Castanedo-Cázares, Juan Pablo; Reyes-Herrera, Amalia; Hernández-Blanco, Diana; Oros-Ovalle, Cuauhtémoc; Torres-Álvarez, Bertha

    2015-01-01

    Hypercalcemia in children with malignancy is an uncommon condition. It has been described in leukemia patients with impaired renal excretion of calcium or osteolytic lesions. Metastatic calcinosis cutis (MCC) may develop if hypercalcemia persists. We report the case of a 5-year-old girl with an atypical dermatosis and unspecific gastrointestinal symptoms. Considered clinical diagnoses were xanthomas, histiocytosis, molluscum contagiosum, and nongenital warts. Cutaneous histological analysis showed amorphous basophilic deposits in the dermis suggestive of calcium deposits. Laboratory tests confirmed serum hypercalcemia. Extensive investigations such as bone marrow biopsy established the diagnosis of an acute pre-B cell lymphoblastic leukemia. Hypercalcemia in hematopoietic malignancies is unusual, especially as initial manifestation of the disease. Careful review of the literature fails to reveal previous reports of these peculiar cutaneous lesions of MCC in children with leukemia. PMID:26346120

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

    SciTech Connect

    Agris, P.F.; Campbell, I.D.

    1982-06-18

    Proton nuclear magnetic resonance of intact Friend leukemia cells was used to analyze their erythroid-like differentiation. The technique, which requires only 10/sup 8/ to 10/sup 9/ 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.

  20. Phagocytosis by macrophages and endothelial cells inhibits procoagulant and fibrinolytic activity of acute promyelocytic leukemia cells.

    PubMed

    Xie, Rui; Gao, Chunyan; Li, Wen; Zhu, Jiuxin; Novakovic, Valerie; Wang, Jing; Ma, Ruishuang; Zhou, Jin; Gilbert, Gary E; Shi, Jialan

    2012-03-08

    The coagulopathy of acute promyelocytic leukemia (APL) is mainly related to procoagulant substances and fibrinolytic activators of APL blasts, but the fate of these leukemic cells is unknown. The aim of this study was to investigate the removal of APL blasts by macrophages and endothelial cells in vitro and consequent procoagulant and fibrinolytic activity of APL cells. We found that human umbilical vein endothelial cells as well as THP-1 and monocyte-derived macrophages bound, engulfed, and subsequently degraded immortalized APL cell line NB4 and primary APL cells. Lactadherin promoted phagocytosis of APL cells in a time-dependent fashion. Furthermore, factor Xa and prothrombinase activity of phosphatidylserine-exposed target APL cells was time-dependently decreased after incubation with phagocytes (THP-1-derived macrophages or HUVECs). Thrombin production on target APL cells was reduced by 40%-45% after 2 hours of coincubation with phagocytes and 80% by a combination of lactadherin and phagocytes. Moreover, plasmin generation of target APL cells was inhibited 30% by 2 hours of phagocytosis and ∼ 50% by lactadherin-mediated engulfment. These results suggest that engulfment by macrophages and endothelial cells reduce procoagulant and fibrinolytic activity of APL blasts. Lactadherin and phagocytosis could cooperatively ameliorate the clotting disorders in APL.

  1. Sensitization of acute lymphoblastic leukemia cells for LCL161-induced cell death by targeting redox homeostasis.

    PubMed

    Haß, Christina; Belz, Katharina; Schoeneberger, Hannah; Fulda, Simone

    2016-04-01

    Disturbed redox homeostasis with both elevated reactive oxygen species (ROS) levels and antioxidant defense mechanisms has been reported in acute lymphoblastic leukemia (ALL). We therefore hypothesized that inhibition of pathways responsible for ROS detoxification renders ALL cells more susceptible for cell death. Here, we report that pharmacological inhibitors of key pathways for the elimination of ROS, i.e. Erastin, buthionine sulfoximine (BSO) and Auranofin, sensitize ALL cells for cell death upon treatment with the Smac mimetic LCL161 that antagonizes Inhibitor of Apoptosis (IAP) proteins. Erastin, BSO or Auranofin significantly increase LCL161-induced cell death and also act in concert with LCL161 to profoundly suppress long-term clonogenic survival in several ALL cell lines. Erastin or BSO cooperates with LCL161 to stimulate ROS production and lipid peroxidation prior to cell death. ROS production and lipid peroxidation are required for this cotreatment-induced cell death, since ROS scavengers or pharmacological inhibition of lipid peroxidation provides significant protection against cell death. These results emphasize that inhibition of antioxidant defense mechanisms can serve as a potent approach to prime ALL cells for LCL161-induced cell death.

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

    ClinicalTrials.gov

    2016-11-21

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

  3. SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome

    PubMed Central

    Alachkar, Houda; Santhanam, Ramasamy; Maharry, Kati; Metzeler, Klaus H.; Huang, Xiaomeng; Kohlschmidt, Jessica; Mendler, Jason H.; Benito, Juliana M.; Hickey, Christopher; Neviani, Paolo; Dorrance, Adrienne M.; Anghelina, Mirela; Khalife, Jihane; Tarighat, Somayeh S.; Volinia, Stefano; Whitman, Susan P.; Paschka, Peter; Hoellerbauer, Pia; Wu, Yue-Zhong; Han, Lina; Bolon, Brad N.; Blum, William; Mrózek, Krzysztof; Carroll, Andrew J.; Perrotti, Danilo; Andreeff, Michael; Caligiuri, Michael A.; Konopleva, Marina; Garzon, Ramiro; Bloomfield, Clara D.; Marcucci, Guido

    2014-01-01

    Aberrant expression of the secreted protein, acidic, cysteine-rich (osteonectin) (SPARC) gene, which encodes a matricellular protein that participates in normal tissue remodeling, is associated with a variety of diseases including cancer, but the contribution of SPARC to malignant growth remains controversial. We previously reported that SPARC was among the most upregulated genes in cytogenetically normal acute myeloid leukemia (CN-AML) patients with gene-expression profiles predictive of unfavorable outcome, such as mutations in isocitrate dehydrogenase 2 (IDH2-R172) and overexpression of the oncogenes brain and acute leukemia, cytoplasmic (BAALC) and v-ets erythroblastosis virus E26 oncogene homolog (ERG). In contrast, SPARC was downregulated in CN-AML patients harboring mutations in nucleophosmin (NPM1) that are associated with favorable prognosis. Based on these observations, we hypothesized that SPARC expression is clinically relevant in AML. Here, we found that SPARC overexpression is associated with adverse outcome in CN-AML patients and promotes aggressive leukemia growth in murine models of AML. In leukemia cells, SPARC expression was mediated by the SP1/NF-κB transactivation complex. Furthermore, secreted SPARC activated the integrin-linked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent β-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-κB complex resulted in SPARC downregulation and leukemia growth inhibition. Together, our data indicate that evaluation of SPARC expression has prognosticative value and SPARC is a potential therapeutic target for AML. PMID:24590286

  4. p53 causes butein-mediated apoptosis of chronic myeloid leukemia cells

    PubMed Central

    WOO, SANG-MI; CHOI, YOUN KYNUG; KIM, AH JEONG; CHO, SUNG-GOOK; KO, SEONG-GYU

    2016-01-01

    Progression of chronic myeloid leukemia, marked by the oncogenic Bcr-Abl mutation, is tightly associated with an alteration of the p53 pathway. It is known that butein extracted from various plants represses cancer growth. Although the anticancer effects of butein are widely accepted, the mechanisms by which butein induces apoptosis of chronic myeloid leukemia cells remains to be elucidated. The present study demonstrated that butein-induced apoptosis was mediated by p53. KBM5 chronic myeloid leukemia (CML) cells expressing wild-type p53 were more sensitive to butein compared with p53-null K562 CML cells in terms of apoptotic cell death. In addition, butein arrested KBM5 cells at S-phase and altered the expression levels of certain cyclins and the p53-downstream targets, MDM2 and p21. In addition, while butein reduced the protein expression of MDM2 in the KBM5 and K562 cells, it resulted in proteasome-independent MDM2 degradation in p53-expressing KBM5 cells, however, not in p53-null K562 cells. Therefore, the present study suggested that p53 causes the butein-mediated apoptosis of leukemic cells. PMID:26676515

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

    NASA Astrophysics Data System (ADS)

    Tormoen, Garth W.; Recht, Olivia; Gruber, András; Levine, Ross L.; McCarty, Owen J. T.

    2013-10-01

    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.

  6. The roles of reactive oxygen species (ROS) and autophagy in the survival and death of leukemia cells.

    PubMed

    Chen, Yong-Feng; Liu, Hao; Luo, Xin-Jing; Zhao, Zhiqiang; Zou, Zhen-You; Li, Jing; Lin, Xiao-Jing; Liang, Yong

    2017-04-01

    As a clonal disease of hematopoietic stem cells (HSCs), the etiology and pathogenesis of leukemia is not fully understood. Recent studies suggest that cellular homeostasis plays an essential role in maintaining the function of HSCs because dysregulation of cellular homeostasis is one of the major factors underlying the malignant transformation of HSCs. Reactive oxygen species (ROS) and autophagy, key factors regulating cellular homeostasis, are commonly observed in the human body. Autophagy can be induced by ROS through a variety of signaling pathways, and conversely inhibits ROS-induced damage to cells and tissues. ROS and autophagy coordinate to maintain cellular homeostasis. Previous studies have demonstrated that both of ROS and autophagy play important roles in the development of leukemia and are closely involved in drug resistance in leukemia. Interference with cellular homeostasis by promoting programmed leukemia cell death via ROS and autophagy has been verified to be an efficient technique in the treatment of leukemia. However, the critical roles of ROS and autophagy in the development of leukemia are largely unknown. In this review, we summarize the roles of ROS and autophagy in the pathogenesis of leukemia, which may allow the identification of novel targets and drugs for the treatment of leukemia based on the regulation of HSCs homeostasis through ROS and autophagy.

  7. Stromal cell-dependent growth of leukemic cells from murine erythroblastic leukemia.

    PubMed

    Itoh, K; Sasaki, R; Ono, K; Tezuka, H; Sakoda, H; Sawada, H; Hitomi, K; Nakane, H; Uchiyama, T; Uchino, H

    1988-08-01

    Transplantable erythroblastic leukemia was induced by 300-rad irradiation of C3H mice. Conditions for in vitro growth of the leukemic cells were studied. None of interleukin-3, granulocyte/macrophage colony-stimulating factor and erythropoietin could support the growth of the cells in vitro. In contrast, the leukemic cells grew into a stroma-dependent cell line, ELM-D, in close contact with the stromal cell layer of 900-rad-irradiated long-term bone marrow culture. A stroma-independent cell line, termed ELM-I-1, was further established from the non-adherent population in the co-culture of the leukemic cells, ELM-D, with stromal cells. Reverse transcriptase activity was not detectable in ELM-D or ELM-I-1 cells. Studies on binding and cross-linking of 125I-erythropoietin showed that ELM-I-1 cells had erythropoietin receptors, and two major radiolabeled protein products with molecular weights of 120 kDa and 140 kDa were detected on sodium dodecyl sulfate/polyacrylamide gel electrophoresis under reducing conditions.

  8. CD93 marks a non-quiescent human leukemia stem cell population and is required for development of MLL-rearranged acute myeloid leukemia

    PubMed Central

    Iwasaki, Masayuki; Liedtke, Michaela; Gentles, Andrew J.; Cleary, Michael L.

    2015-01-01

    SUMMARY Leukemia stem cells (LSCs) are thought to share several properties with hematopoietic stem cells, including cell cycle quiescence and a capacity for self-renewal. These features are hypothesized to underlie leukemic initiation, progression, and relapse, and also complicate efforts to eradicate leukemia through therapeutic targeting of LSCs without adverse effects on HSCs. Here, we show that acute myeloid leukemias with genomic rearrangements of the MLL gene contain a non-quiescent LSC population. Although human CD34+CD38− LSCs are generally highly quiescent, the C-type lectin CD93 is expressed on a subset of actively cycling, non-quiescent AML cells enriched for LSC activity. CD93 expression is functionally required for engraftment of primary human AML LSCs and leukemogenesis, and regulates LSC self-renewal predominantly by silencing CDKN2B, a major tumor suppressor in AML. Thus, CD93 expression identifies a predominantly cycling, non-quiescent leukemia-initiating cell population in MLL-rearranged AML, providing opportunities for selective targeting and eradication of LSCs. PMID:26387756

  9. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells

    PubMed Central

    Guzman, Monica L.; Rossi, Randall M.; Neelakantan, Sundar; Li, Xiaojie; Corbett, Cheryl A.; Hassane, Duane C.; Becker, Michael W.; Bennett, John M.; Sullivan, Edmund; Lachowicz, Joshua L.; Vaughan, Andrew; Sweeney, Christopher J.; Matthews, William; Carroll, Martin; Liesveld, Jane L.; Crooks, Peter A.

    2007-01-01

    Leukemia stem cells (LSCs) are thought to play a central role in the pathogenesis of acute leukemia and likely contribute to both disease initiation and relapse. Therefore, identification of agents that target LSCs is an important consideration for the development of new therapies. To this end, we have previously demonstrated that the naturally occurring compound parthenolide (PTL) can induce death of human LSCs in vitro while sparing normal hematopoietic cells. However, PTL has relatively poor pharmacologic properties that limit its potential clinical use. Consequently, we generated a family of PTL analogs designed to improve solubility and bioavailability. These studies identified an analog, dimethylamino-parthenolide (DMAPT), which induces rapid death of primary human LSCs from both myeloid and lymphoid leukemias, and is also highly cytotoxic to bulk leukemic cell populations. Molecular studies indicate the prevalent activities of DMAPT include induction of oxidative stress responses, inhibition of NF-κB, and activation of p53. The compound has approximately 70% oral bioavailability, and pharmacologic studies using both mouse xenograft models and spontaneous acute canine leukemias demonstrate in vivo bioactivity as determined by functional assays and multiple biomarkers. Therefore, based on the collective preclinical data, we propose that the novel compound DMAPT has the potential to target human LSCs in vivo. PMID:17804695

  10. Autologous stem cell transplantation versus alternative allogeneic donor transplants in adult acute leukemias.

    PubMed

    Claude Gorin, Norbert

    2016-04-01

    The availability of alternative sources of stem cells including most recently T-replete haploidentical marrow or peripheral blood, and the increasing use of reduced-intensity conditioning (RIC), renders feasible an allogeneic transplant to almost all patients with acute leukemia up to 70 years of age. Autologous stem cell transplantation (ASCT) for consolidation of complete remission (CR), however, offers in some circumstances an alternative option. Although associated with a higher relapse rate, autologous transplant benefits from a lower non-relapse mortality, the absence of graft-versus-host disease (GVHD), and a better quality of life for long-term survivors. The recent use of intravenous busulfan (IVBU) with high-dose melphalan, better monitoring of minimal residual disease (MRD), and maintenance therapy post autografting bring new interest. Few retrospective studies compared the outcome following alternative donor versus autologous transplants for remission consolidation. Genoidentical and phenoidentical allogeneic stem cell transplantations are undisputed gold standards, but there are no data showing the superiority of alternative allogeneic donor over autologous transplantation, at the time of undetectable MRD, in patients with good- and intermediate-1 risk acute myelocytic leukemia (AML) in first complete remission (CR1), acute promyelocytic leukemia in second complete remission (CR2), and Philadelphia chromosome-positive (Ph(+)) acute lymphocytic leukemia (ALL).

  11. Successful cell-mediated cytokine-activated immunotherapy for relapsed acute myeloid leukemia after hematopoietic stem cell transplantation.

    PubMed

    Gesundheit, Benjamin; Shapira, Michael Y; Resnick, Igor B; Amar, Avraham; Kristt, Don; Dray, Lilianne; Budowski, Einat; Or, Reuven

    2009-03-01

    Acute myeloid leukemia (AML) is an extremely aggressive disease with a high relapse rate even after allogeneic hematopoietic stem cell transplantation (HSCT). We report the successful outcome of cell-mediated cytokine-activated immunotherapy in a high-risk pediatric AML patient who relapsed shortly after allogeneic HSCT. Donor lymphocyte infusion along with interferon induced a graft-versus-leukemia effect, presenting as a reversible episode of graft-versus-host disease, which led to stable complete donor chimerism and total eradication of AML for over 24 months, at the time of this report. The curative potential of immunotherapy in hematological malignancies is discussed.

  12. Establishment and characterization of 10 cell lines derived from patients with adult T-cell leukemia.

    PubMed Central

    Hoshino, H; Esumi, H; Miwa, M; Shimoyama, M; Minato, K; Tobinai, K; Hirose, M; Watanabe, S; Inada, N; Kinoshita, K; Kamihira, S; Ichimaru, M; Sugimura, T

    1983-01-01

    By using human T-cell growth factor (TCGF), 10 cell lines were established from tissue samples of 10 patients with adult T-cell leukemia (ATL). Three cell lines were adapted to growth in medium lacking TCGF. The surface markers of all cell lines were characteristic of inducer/helper T cells, i.e., OKT3+, OKT4+, OKT6-, OKT8-, OKIa1+, and human Lyt2+ and Lyt3+, except that one cell line was OKT3-. The expression of the viral antigen was examined during establishment of 8 of the 10 cell lines. The viral antigen was not expressed in leukemic cells before cultivation. In 5 lines, the viral antigen was detected by immunofluorescent staining after a short period of cultivation. However, 3 cell lines, ATL-6A, ATL-9Y, and ATL-1K did not express the viral antigen during short-term culture: the ATL-6A and ATL-9Y cell lines became positive for the viral antigen after 5 and 2 months of cultivation, respectively; the ATL-1K cell line remained antigen-negative throughout a culture period of 13 months. Southern blot hybridization assay showed that all of the cell lines, including the viral antigen-negative ATL-1K cell line, contained the viral genome. Thus, the retrovirus was associated with all 10 cell lines established from ATL patients, but there was a heterogeneity in the expression time of the retroviral antigen in leukemic cells maintained in vitro. Our findings suggested that the expression of the viral antigen was not required for maintenance of the leukemic state in vivo and for growth of leukemic cells in vitro. Images PMID:6193528

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

    SciTech Connect

    Sun, G.; Hajianpour, M.J.; Hajianpour, A.K.

    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.

  14. Alternative Splice Variants Modulates Dominant-Negative Function of Helios in T-Cell Leukemia

    PubMed Central

    Zhao, Shaorong; Liu, Wei; Li, Yinghui; Liu, Pengjiang; Li, Shufang; Dou, Daolei; Wang, Yue; Yang, Rongcun; Xiang, Rong; Liu, Feifei

    2016-01-01

    The molecular defects which lead to multistep incidences of human T-cell leukemia have yet to be identified. The DNA-binding protein Helios (known as IKZF2), a member of the Ikaros family of Krüppel-like zinc-finger proteins, functions pivotally in T-cell differentiation and activation. In this study, we identify three novel short Helios splice variants which are T-cell leukemic specific, and demonstrate their dominant-negative function. We then test the cellular localization of distinct Helios isoforms, as well as their capability to form heterodimer with Ikaros, and the association with complexes comprising histone deacetylase (HDAC). In addition, the ectopic expression of T-cell leukemic Helios isoforms interferes with T-cell proliferation and apoptosis. The gene expression profiling and pathway analysis indicated the enrichment of signaling pathways essential for gene expression, translation, cell cycle checkpoint, and response to DNA damage stimulus. These data indicate the molecular function of Helios to be involved in the leukemogenesis and phenotype of T-cell leukemia, and also reveal Helios deregulation as a novel marker for T-cell leukemia. PMID:27681508

  15. Methylenedioxy flavonoids: assessment of cytotoxic and anti-cancer potential in human leukemia cells.

    PubMed

    Orlikova, Barbora; Menezes, José C J M D S; Ji, Seungwon; Kamat, Shrivallabh P; Cavaleiro, José A S; Diederich, Marc

    2014-09-12

    A new series of chalcones, flavanones and flavones with methylenedioxy group at the 3',4' position in chalcone, 7,8 position in flavanones and flavones with mono-, di- and trimethoxy groups in the benzaldehyde ring have been assessed for their effect on proliferation, cytotoxic potential and apoptosis in human leukemia cells. Among the tested compounds, the chalcone series showed the best activity and chalcone 3 (mono methoxy group at the ortho position in A-ring) showed a significant effect on down-regulation of cancer cell proliferation and viability in three different leukemia cell lines (K562, Jurkat, U937). The executioner caspase cleavage analyses indicated that the cytotoxic effect mediated by chalcone 3 is due to induction of apoptotic cell death. Interestingly, the cytotoxic effect was cell type-specific and targeted preferentially cancer cells as peripheral blood mononuclear cells (PBMCs) from healthy donors were less affected by the treatment compared to K562, Jurkat and U937 leukemia cells. Altogether our results indicate a potential drug candidate with interesting differential toxicity obeying Lipinski's rule of five.

  16. Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia

    ClinicalTrials.gov

    2017-03-22

    Adult Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia in Remission; Myelodysplastic Syndrome; Secondary Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Therapy-Related Myelodysplastic Syndrome

  17. Idelalisib and caffeine reduce suppression of T cell responses mediated by activated chronic lymphocytic leukemia cells

    PubMed Central

    Hock, Barry D.; MacPherson, Sean A.; McKenzie, Judith L.

    2017-01-01

    Chronic lymphocytic leukemia (CLL) is associated with T cell dysfunction. Activated CLL cells are found within the lymphoid tumor micro-environment and overcoming immuno-suppression induced by these cells may improve anti-CLL immune responses. However, the mechanisms by which activated CLL cells inhibit T cell responses, and reagents targeting such mechanisms have not been identified. Here we demonstrate that the ability of in vitro activated CLL cells to suppress T cell proliferation is not reversed by the presence of ecto-nuclease inhibitors or blockade of IL-10, PD-1 and CTLA-4 pathways. Caffeine is both an adenosine receptor antagonist and a phosphatidylinositol-3-kinase, p110δ (PI3Kδ) inhibitor and, at physiologically relevant levels, significantly reversed suppression. Significant reversal of suppression was also observed with the PI3Kδ specific inhibitor Idelalisib but not with adenosine receptor specific antagonists. Furthermore, addition of caffeine or Idelalisib to activated CLL cells significantly inhibited phosphorylation of AKT, a downstream kinase of PI3K, but did not affect CLL viability. These results suggest that caffeine, in common with Idelalisib, reduces the immuno-suppressive activity of activated CLL cells by inhibiting PI3Kδ. These findings raise the possibility that these compounds may provide a useful therapeutic adjunct by reducing immuno-suppression within the tumor micro-environment of CLL. PMID:28257435

  18. Pterostilbene induces accumulation of autophagic vacuoles followed by cell death in HL60 human leukemia cells.

    PubMed

    Siedlecka-Kroplewska, K; Jozwik, A; Boguslawski, W; Wozniak, M; Zauszkiewicz-Pawlak, A; Spodnik, J H; Rychlowski, M; Kmiec, Z

    2013-10-01

    Pterostilbene, a naturally occurring structural analog of resveratrol, has been reported to exert antiproliferative and proapoptotic effects in various cancer types. Recently, it has been demonstrated to induce both autophagy and apoptosis in human bladder and breast cancer cell lines. The aim of this study was to evaluate the effects of pterostilbene on HL60 human leukemia cells. Cell morphology was examined using confocal and electron microscopy. Cell viability was determined by MTT, neutral red uptake and trypan blue exclusion assays. LC3 processing was studied based on Western blotting and immunofluorescence analyses. Flow cytometry was used to study cell cycle distribution, phosphatidylserine externalization, caspase activation, disruption of mitochondrial membrane potential and intracellular production of reactive oxygen species. DNA degradation was examined by gel electrophoresis. We found that treatment of HL60 cells with pterostilbene at the IC90 concentration resulted in the G0/G1 cell cycle arrest. Pterostilbene induced conversion of cytosolic LC3-I to membrane-bound LC3-II and accumulation of large LC3-positive vacuolar structures. Pterostilbene also led to phosphatidylserine externalization, internucleosomal DNA fragmentation, caspase activation and disruption of mitochondrial membrane potential. Moreover, it did not induce oxidative stress. Our results suggest that pterostilbene induces accumulation of autophagic vacuoles followed by cell death in HL60 cells.

  19. Enhancement of flavone levels through overexpression of chalcone isomerase in hairy root cultures of Scutellaria baicalensis.

    PubMed

    Park, Nam Il; Xu, Hui; Li, Xiaohua; Kim, Sun-Ju; Park, Sang Un

    2011-09-01

    A complementary DNA (cDNA) encoding Scutellaria baicalensis chalcone isomerase (SbCHI) was isolated using rapid amplification of cDNA ends polymerase chain reaction. After the treatment of wounding or methyl jasmonate, SbCHI transcripts were increased in S. baicalensis cell suspensions. SbCHI-overexpressed and SbCH-silenced transgenic hairy root lines were established by using an Agrobacterium rhizogenes-mediated system. SbCHI-overexpressed hairy root lines not only enhanced SbCHI gene expression but also produced more flavones (i.e., baicalin, baicalein, and wogonin) than the control hairy root line. In contrast, SbCHI-silenced hairy root lines reduced SbCHI transcripts and flavone production compared to those of the control hairy roots. In addition, the amount of wogonin in all hairy root cultures was increased compared to that of wild-type roots of S. baicalensis. Finally, this study showed the importance of CHI in flavone biosynthesis and the efficiency of metabolic engineering in S. baicalensis hairy roots.

  20. Differential expression of the ufo/axl oncogene in human leukemia-lymphoma cell lines.

    PubMed

    Challier, C; Uphoff, C C; Janssen, J W; Drexler, H G

    1996-05-01

    The ufo protein (also termed axl) is a member of a new family of receptor tyrosine kinases and is encoded by a transforming gene that was initially isolated from primary human myeloid leukemia cells by DNA-mediated transformation of NIH/3T3 cells. The ligand, Gas6, a protein S-related molecule lacking any known function yet, has recently been identified. We report the expression pattern of ufo mRNA in a panel of 76 human continuous leukemia-lymphoma cell lines. The gene was not expressed in cell lines derived from lymphoid malignancies (n=28), but transcription was seen in 3/11 myeloid, 0/6 monocytic, 9/13 erythroid and 11/18 megakaryocytic cell lines. Several cell lines were treated with phorbol ester leading to significant upregulation of the ufo message in constitutively positive cells. An apparent ufo mRNA overexpression was not found in any of the positive leukemia cell lines, but was identified in the drug-resistant subclones of the cervix carcinoma cell line HeLa. Southern blot analysis of restriction enzyme-digested genomic DNA did not provide evidence for gene amplification, but the HeLa subclones showed banding patterns suggestive of gene rearrangement. Two main ufo mRNA bands of 3.2 and 5.0 kb were identified; no differences in the half-lives (t1/2 = 2.5 h) of these two mRNA species could be identified. In summary, ufo, representing a novel type of receptor tyrosine kinase, is expressed solely in myeloid and erythro-megakaryocytic leukemias but not in lymphoid malignancies. These and previous data suggest an involvement of the ufo receptor tyrosine kinase in normal and malignant myelopoiesis; however, its exact role, if any, and mode of operation in leukemogenesis remains to be determined.

  1. Immortalization of human AE pre-leukemia cells by hTERT allows leukemic transformation

    PubMed Central

    Wunderlich, Mark; Chou, Fu-Sheng; Mulloy, James C.

    2016-01-01

    Human CD34+ hematopoietic stem and progenitor cells (HSPC) expressing fusion protein AML1-ETO (AE), generated by the t(8;21)(q22;q22) rearrangement, manifest enhanced self-renewal and dysregulated differentiation without leukemic transformation, representing a pre-leukemia stage. Enabling replicative immortalization via telomerase reactivation is a crucial step in cancer development. However, AE expression alone is not sufficient to maintain high telomerase activity to immortalize human HSPC cells, which may hamper transformation. Here, we investigated the cooperativity of telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, and AE in disease progression. Enforced expression of hTERT immortalized human AE pre-leukemia cells in a telomere-lengthening independent manner, and improved the pre-leukemia stem cell function by enhancing cell proliferation and survival. AE-hTERT cells retained cytokine dependency and multi-lineage differentiation potential similar to parental AE clones. Over the short-term, AE-hTERT cells did not show features of stepwise transformation, with no leukemogenecity evident upon initial injection into immunodeficient mice. Strikingly, after extended culture, we observed full transformation of one AE-hTERT clone, which recapitulated the disease evolution process in patients and emphasizes the importance of acquiring cooperating mutations in t(8;21) AML leukemogenesis. In summary, achieving unlimited proliferative potential via hTERT activation, and thereby allowing for acquisition of additional mutations, is a critical link for transition from pre-leukemia to overt disease in human cells. AE-hTERT cells represent a tractable model to study cooperating genetic lesions important for t(8;21) AML disease progression. PMID:27509060

  2. Adipocytes cause leukemia cell resistance to daunorubicin via oxidative stress response

    PubMed Central

    Sheng, Xia; Tucci, Jonathan; Parmentier, Jean-Hugues; Ji, Lingyun; Behan, James W.; Heisterkamp, Nora; Mittelman, Steven D.

    2016-01-01

    Adipocytes promote cancer progression and impair treatment, and have been shown to protect acute lymphoblastic leukemia (ALL) cells from chemotherapies. Here we investigate whether this protection is mediated by changes in oxidative stress. Co-culture experiments showed that adipocytes protect ALL cells from oxidative stress induced by drugs or irradiation. We demonstrated that ALL cells induce intracellular ROS and an oxidative stress response in adipocytes. This adipocyte oxidative stress response leads to the secretion of soluble factors which protect ALL cells from daunorubicin (DNR). Collectively, our investigation shows that ALL cells elicit an oxidative stress response in adipocytes, leading to adipocyte protection of ALL cells against DNR. PMID:27705905

  3. Upregulation of miR-99a is associated with poor prognosis of acute myeloid leukemia and promotes myeloid leukemia cell expansion

    PubMed Central

    Si, Xiaohui; Zhang, Xiaoyun; Hao, Xing; Li, Yunan; Chen, Zizhen; Ding, Yahui; Shi, Hui; Bai, Jie; Gao, Yingdai; Cheng, Tao; Yang, Feng-Chun; Zhou, Yuan

    2016-01-01

    Leukemia stem cells (LSCs) can resist available treatments that results in disease progression and/or relapse. To dissect the microRNA (miRNA) expression signature of relapse in acute myeloid leukemia (AML), miRNA array analysis was performed using enriched LSCs from paired bone marrow samples of an AML patient at different disease stages. We identified that miR-99a was significantly upregulated in the LSCs obtained at relapse compared to the LSCs collected at the time of initial diagnosis. We also found that miR-99a was upregulated in LSCs compared to non-LSCs in a larger cohort of AML patients, and higher expression levels of miR-99a were significantly correlated with worse overall survival and event-free survival in these AML patients. Ectopic expression of miR-99a led to increased colony forming ability and expansion in myeloid leukemia cells after exposure to chemotherapeutic drugs in vitro and in vivo, partially due to overcoming of chemotherapeutic agent-mediated cell cycle arrest. Gene profiling and bioinformatic analyses indicated that ectopic expression of miR-99a significantly upregulated genes that are critical for LSC maintenance, cell cycle, and downstream targets of E2F and MYC. This study suggests that miR-99a has a novel role and potential use as a biomarker in myeloid leukemia progression. PMID:27801668

  4. Sensitization of K562 Leukemia Cells to Doxorubicin by the Viscum album Extract.

    PubMed

    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.

  5. Further Electron Microscope Studies of a Mouse Leukemia Induced by Cell-Free Filtrates

    PubMed Central

    de Harven, Etienne; Friend, Charlotte

    1960-01-01

    Further electron microscope observations of tissues from Swiss and DBA/2 mice with leukemia transmissible by cell-free filtrates to the adult animals are presented. The cytological characteristics of the leukemic cells, the fine structure of the viruses, and the virus host-cell relationships have been examined. The leukemia virus has an external diameter averaging 870 A, and appears to be formed at the level of cell membranes by a budding process. The viruses are observed most frequently in intercellular spaces, but are also often found within cytoplasmic vacuoles of megakaryocytes. Lead hydroxide staining was applied to the study of the leukemic material. The viruses have been found to have a considerable affinity for this lead salt, only comparable in intensity to the affinity shown by RNP granules for the same chemical. PMID:13814781

  6. Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults

    PubMed Central

    Lee, Kum Ja; Chow, Vivian; Weissman, Ashley; Tulpule, Sunil; Aldoss, Ibrahim; Akhtari, Mojtaba

    2016-01-01

    Adults with relapsed or refractory B-cell acute lymphoblastic leukemia have a dismal prognosis with a short median overall survival that can be measured in months. Because most patients will have chemotherapy-resistant disease, allogeneic hematopoietic stem cell transplantation remains the only potentially curative treatment. Despite advances in current management, patients continue to have poor outcomes and lack of durable responses. Thus, new therapies with alternative modes of actions are currently being investigated. Blinatumomab is a novel bispecific T-cell engager that simultaneously binds CD3-positive cytotoxic T-cells and CD19-positive B-cells, resulting in selective lysis of tumor cells. It has shown promising results in patients with relapsed or refractory acute lymphoblastic leukemia or those achieving hematologic response with persistent minimum residual disease. Future clinical trials will answer questions regarding its optimal place in the treatment paradigm. Dose-limiting toxicities include immunological toxicities and cytokine release syndrome. However, most patients tolerate the therapy relatively well. This review will focus on the pharmacology, clinical efficacy, and safety of blinatumomab in the treatment of adult B-cell acute lymphoblastic leukemia while highlighting its unique drug warnings and toxicity management. PMID:27601914

  7. Inactivation of SAG E3 ubiquitin ligase blocks embryonic stem cell differentiation and sensitizes leukemia cells to retinoid acid.

    PubMed

    Tan, Mingjia; Li, Yun; Yang, Ruiguo; Xi, Ning; Sun, Yi

    2011-01-01

    Sensitive to Apoptosis Gene (SAG), also known as RBX2 (RING box protein-2), is the RING component of SCF (SKP1, Cullin, and F-box protein) E3 ubiquitin ligase. Our previous studies have demonstrated that SAG is an anti-apoptotic protein and an attractive anti-cancer target. We also found recently that Sag knockout sensitized mouse embryonic stem cells (mES) to radiation and blocked mES cells to undergo endothelial differentiation. Here, we reported that compared to wild-type mES cells, the Sag(-/-) mES cells were much more sensitive to all-trans retinoic acid (RA)-induced suppression of cell proliferation and survival. While wild-type mES cells underwent differentiation upon exposure to RA, Sag(-/-) mES cells were induced to death via apoptosis instead. The cell fate change, reflected by cellular stiffness, can be detected as early as 12 hrs post RA exposure by AFM (Atomic Force Microscopy). We then extended this novel finding to RA differentiation therapy of leukemia, in which the resistance often develops, by testing our hypothesis that SAG inhibition would sensitize leukemia to RA. Indeed, we found a direct correlation between SAG overexpression and RA resistance in multiple leukemia lines. By using MLN4924, a small molecule inhibitor of NEDD8-Activating Enzyme (NAE), that inactivates SAG-SCF E3 ligase by blocking cullin neddylation, we were able to sensitize two otherwise resistant leukemia cell lines, HL-60 and KG-1 to RA. Mechanistically, RA sensitization by MLN4924 was mediated via enhanced apoptosis, likely through accumulation of pro-apoptotic proteins NOXA and c-JUN, two well-known substrates of SAG-SCF E3 ligase. Taken together, our study provides the proof-of-concept evidence for effective treatment of leukemia patients by RA-MLN4924 combination.

  8. Segmentation and Classification of Bone Marrow Cells Images Using Contextual Information for Medical Diagnosis of Acute Leukemias

    PubMed Central

    Reta, Carolina; Altamirano, Leopoldo; Gonzalez, Jesus A.; Diaz-Hernandez, Raquel; Peregrina, Hayde; Olmos, Ivan; Alonso, Jose E.; Lobato, Ruben

    2015-01-01

    Morphological identification of acute leukemia is a powerful tool used by hematologists to determine the family of such a disease. In some cases, experienced physicians are even able to determine the leukemia subtype of the sample. However, the identification process may have error rates up to 40% (when classifying acute leukemia subtypes) depending on the physician’s experience and the sample quality. This problem raises the need to create automatic tools that provide hematologists with a second opinion during the classification process. Our research presents a contextual analysis methodology for the detection of acute leukemia subtypes from bone marrow cells images. We propose a cells separation algorithm to break up overlapped regions. In this phase, we achieved an average accuracy of 95% in the evaluation of the segmentation process. In a second phase, we extract descriptive features to the nucleus and cytoplasm obtained in the segmentation phase in order to classify leukemia families and subtypes. We finally created a decision algorithm that provides an automatic diagnosis for a patient. In our experiments, we achieved an overall accuracy of 92% in the supervised classification of acute leukemia families, 84% for the lymphoblastic subtypes, and 92% for the myeloblastic subtypes. Finally, we achieved accuracies of 95% in the diagnosis of leukemia families and 90% in the diagnosis of leukemia subtypes. PMID:26107374

  9. Segmentation and Classification of Bone Marrow Cells Images Using Contextual Information for Medical Diagnosis of Acute Leukemias.

    PubMed

    Reta, Carolina; Altamirano, Leopoldo; Gonzalez, Jesus A; Diaz-Hernandez, Raquel; Peregrina, Hayde; Olmos, Ivan; Alonso, Jose E; Lobato, Ruben

    2015-01-01

    Morphological identification of acute leukemia is a powerful tool used by hematologists to determine the family of such a disease. In some cases, experienced physicians are even able to determine the leukemia subtype of the sample. However, the identification process may have error rates up to 40% (when classifying acute leukemia subtypes) depending on the physician's experience and the sample quality. This problem raises the need to create automatic tools that provide hematologists with a second opinion during the classification process. Our research presents a contextual analysis methodology for the detection of acute leukemia subtypes from bone marrow cells images. We propose a cells separation algorithm to break up overlapped regions. In this phase, we achieved an average accuracy of 95% in the evaluation of the segmentation process. In a second phase, we extract descriptive features to the nucleus and cytoplasm obtained in the segmentation phase in order to classify leukemia families and subtypes. We finally created a decision algorithm that provides an automatic diagnosis for a patient. In our experiments, we achieved an overall accuracy of 92% in the supervised classification of acute leukemia families, 84% for the lymphoblastic subtypes, and 92% for the myeloblastic subtypes. Finally, we achieved accuracies of 95% in the diagnosis of leukemia families and 90% in the diagnosis of leukemia subtypes.

  10. Phospholipase A/sub 2/ stimulation during cell secretion in rat basophilic leukemia cells

    SciTech Connect

    Garcia-Gil, M.; Siraganian, R.P.

    1986-01-01

    The bridging of IgE receptors on rat basophilic leukemia cells (RBL-2H3) results in a number of biochemical events that accompany histamine secretion. Prominent among these is the release of arachidonic acid from cellular phospholipids, which could be due to the activation of phospholipase enzymes. In the present experiments they studied the intracellular activation of phospholipase A/sub 2/ (PLA/sub 2/) during histamine release. The enzyme in the homogenates was capable of cleaving arachidonic acid from different phospholipids. The production of lysophospholipids could play a critical role in histamine release from cells. These results demonstrate the activation of PLA/sub 2/ enzyme in cellular homogenates during the secretory process.

  11. ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival

    PubMed Central

    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 Ca2+ 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

  12. Cytoplasmic proliferating cell nuclear antigen connects glycolysis and cell survival in acute myeloid leukemia

    PubMed Central

    Ohayon, Delphine; De Chiara, Alessia; Chapuis, Nicolas; Candalh, Céline; Mocek, Julie; Ribeil, Jean-Antoine; Haddaoui, Lamya; Ifrah, Norbert; Hermine, Olivier; Bouillaud, Frédéric; Frachet, Philippe; Bouscary, Didier; Witko-Sarsat, Véronique

    2016-01-01

    Cytosolic proliferating cell nuclear antigen (PCNA), a scaffolding protein involved in DNA replication, has been described as a key element in survival of mature neutrophil granulocytes, which are non-proliferating cells. Herein, we demonstrated an active export of PCNA involved in cell survival and chemotherapy resistance. Notably, daunorubicin-resistant HL-60 cells (HL-60R) have a prominent cytosolic PCNA localization due to increased nuclear export compared to daunorubicin-sensitive HL-60 cells (HL-60S). By interacting with nicotinamide phosphoribosyltransferase (NAMPT), a protein involved in NAD biosynthesis, PCNA coordinates glycolysis and survival, especially in HL-60R cells. These cells showed a dramatic increase in intracellular NAD+ concentration as well as glycolysis including increased expression and activity of hexokinase 1 and increased lactate production. Furthermore, this functional activity of cytoplasmic PCNA was also demonstrated in patients with acute myeloid leukemia (AML). Our data uncover a novel pathway of nuclear export of PCNA that drives cell survival by increasing metabolism flux. PMID:27759041

  13. Cytotoxic effect of trans-cinnamaldehyde on human leukemia K562 cells

    PubMed Central

    Zhang, Jia-hua; Liu, Li-qiong; He, Yan-li; Kong, Wei-jia; Huang, Shi-ang

    2010-01-01

    Aim: To investigate the effects of trans-cinnamaldehyde (TCA) on the human leukemia K562 cell line and the cytotoxicity of cytokine-induced killer (CIK) cells against K562 cells. Methods: Apoptosis, Fas expression, and mitochondrial transmembrane potential in K652 cells were analyzed using flow cytometry. K562 cells were labeled with CFSE. The cytotoxic effect of expanded CIK cells on CFSE-labeled K562 cells was determined by FACS flow cytometry. Results: Treatment with TCA 180 μmol/L for 9 h induced apoptosis in 8.9%±1.23% of K562 cells. Treatment with 120 or 180 μmol/L TCA for 24 h significantly increased the apoptotic cells to 18.63%±1.42 % and 38.98%±2.74%, respectively. TCA significantly upregulates Fas expression and decreases mitochondrial transmembrane potential in K562 cells. TCA treatment at 120 and 180 μmol/L for 9 h enhanced the percentage of lysis of K562 cells by expanded CIK cells from 34.84%±2.13% to 48.21%±2.22 % and 64.81%±3.22% at the E:F ratio of 25:1 and from 49.26%±3.22% to 57.81%±5.13% and 73.36%±5.98% at E:F ratio of 50:1. Conclusion: TCA exerts cytotoxic effects on human leukemia K562 cells by inducing apoptosis and synergizing the cytotoxicity of CIK cells against K562 cells. These properties of TCA are beneficial to the treatment of leukemia, even in the patients who have received hematopoietic stem cells transplantation (HSCT). PMID:20581850

  14. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib

    PubMed Central

    Sharman, Jeff; Di Paolo, Julie

    2016-01-01

    The B-cell receptor signaling pathway has emerged as an important therapeutic target in chronic lymphocytic leukemia and other B-cell malignancies. Novel agents have been developed targeting the signaling enzymes spleen tyrosine kinase (SYK), Bruton’s tyrosine kinase, and phosphoinositide 3-kinase delta. This review discusses the rationale for targeting these enzymes, as well as the preclinical and clinical evidence supporting their role as therapeutic targets, with a particular focus on SYK inhibition with entospletinib. PMID:27247756

  15. Therapeutic potential and functional interaction of carfilzomib and vorinostat in T-cell leukemia/lymphoma.

    PubMed

    Gao, Minjie; Chen, Gege; Wang, Houcai; Xie, Bingqian; Hu, Liangning; Kong, Yuanyuan; Yang, Guang; Tao, Yi; Han, Ying; Wu, Xiaosong; Zhang, Yiwen; Dai, Bojie; Shi, Jumei

    2016-05-17

    We previously showed that the proteasome inhibitor carfilzomib and the histone deacetylase inhibitor (HDACI) vorinostat cooperated to induce cell apoptosis in one T-cell leukemia cell line in vitro, implying the possibility of the combination treatment of carfilzomib and vorinostat as a potential therapeutic strategy in human T-cell leukemia/lymphoma. Here we report that combination treatment of carfilzomib and vorinostat enhanced cell apoptosis and induced a marked increase in G2-M arrest, reactive oxygen species (ROS) generation, and activated the members of mitogen-activated protein kinases (MAPK) family, including the stress-activated kinases JNK, p38MAPK, and ERK1/2. Carfilzomib/vorinostat-mediated apoptosis was blocked by the ROS scavenger N-acetylcysteine (NAC). The JNK inhibitor SP600125 and the p38MAPK inhibitor SB203580 but not the MEK1/2 inhibitor U0126 significantly attenuated carfilzomib/vorinostat-induced apoptosis, suggesting that p38MAPK and JNK activation contribute to carfilzomib and vorinostat-induced apoptosis. This was further confirmed via short hairpin (shRNA) RNA knockdown of p38MAPK and JNK. Interestingly, the ROS scavenger NAC attenuated carfilzomib/vorinostat-mediated activation of p38MAPK and JNK. However, p38MAPK shRNA but not JNK shRNA diminished carfilzomib/vorinostat-mediated ROS generation. In contrast, overexpression of p38MAPK significantly increased carfilzomib/vorinostat-mediated ROS generation, suggesting that an amplification loop exists between ROS and p38MAPK pathway. Combination treatment of carfilzomib and vorinostat enhanced their individual antitumor activity in both a human xenograft model as well as human primary T-cell leukemia/lymphoma cells. These data suggest the potential clinical benefit and underlying molecular mechanism of combining carfilzomib with vorinostat in the treatment of human T-cell leukemia/lymphoma.

  16. Extracts from red muscadine and cabernet sauvignon wines induce cell death in MOLT-4 human leukemia cells.

    PubMed

    Mertens-Talcott, Susanne U; Percival, Susan S; Talcott, Stephen T

    2008-06-01

    Red wine contains a diversity of polyphenolic compounds that exert beneficial health effects including anti-cancer effects. This trial evaluated the anti-proliferative potential of red muscadine (Vitis rotundifolia) and red cabernet sauvignon (Vitis vinifera) wines in cell culture. Chemical properties of wines were determined by HPLC-PDA analysis and concentrated extracts of each wine were evaluated before and after glycosidic hydrolysis in MOLT-4 leukemia cells. Cell growth and the induction of apoptosis were evaluated after exposure to various extract dilutions. Wine extracts reduced cell viability up to 68% and cell numbers up to 50% after 48h with muscadine extracts being more effective than cabernet sauvignon. Caspase-3 activity was induced similarly by all extracts in a dose dependent manner. Cell cycle arrest in the G2/M phase was observed for both muscadine and the non-hydrolyzed cabernet sauvignon extract. Collectively, extracts from both wines exerted anti-cancer effects in leukemia cells.

  17. B-cell precursor acute lymphoblastic leukemia and stromal cells communicate through Galectin-3

    PubMed Central

    Fei, Fei; Joo, Eun Ji; Tarighat, Somayeh S.; Schiffer, Isabelle; Paz, Helicia; Fabbri, Muller; Abdel-Azim, Hisham; Groffen, John; Heisterkamp, Nora

    2015-01-01

    The molecular interactions between B-cell precursor acute lymphoblastic leukemia (pre-B ALL) cells and stromal cells in the bone marrow that provide microenvironmentally-mediated protection against therapeutic drugs are not well-defined. Galectin-3 (Lgals3) is a multifunctional galactose-binding lectin with reported location in the nucleus, cytoplasm and extracellular space in different cell types. We previously reported that ALL cells co-cultured with stroma contain high levels of Galectin-3. We here establish that, in contrast to more mature B-lineage cancers, Galectin-3 detected in and on the ALL cells originates from stromal cells, which express it on their surface, secrete it as soluble protein and also in exosomes. Soluble and stromal-bound Galectin-3 is internalized by ALL cells, transported to the nucleus and stimulates transcription of endogenous LGALS3 mRNA. When human and mouse ALL cells develop tolerance to different drugs while in contact with protective stromal cells, Galectin-3 protein levels are consistently increased. This correlates with induction of Galectin-3 transcription in the ALL cells. Thus Galectin-3 sourced from stroma becomes supplemented by endogenous Galectin-3 production in the pre-B ALL cells that are under continuous stress from drug treatment. Our data suggest that stromal Galectin-3 may protect ALL cells through auto-induction of Galectin-3 mRNA and tonic NFκB pathway activation. Since endogenously synthesized Galectin-3 protects pre-B ALL cells against drug treatment, we identify Galectin-3 as one possible target to counteract the protective effects of stroma. PMID:25869099

  18. AMD3100 disrupts the cross-talk between chronic lymphocytic leukemia cells and a mesenchymal stromal or nurse-like cell-based microenvironment: pre-clinical evidence for its association with chronic lymphocytic leukemia treatments

    PubMed Central

    Stamatopoulos, Basile; Meuleman, Nathalie; De Bruyn, Cécile; Pieters, Karlien; Mineur, Philippe; Le Roy, Christine; Saint-Georges, Stéphane; Varin-Blank, Nadine; Cymbalista, Florence; Bron, Dominique; Lagneaux, Laurence

    2012-01-01

    Background Interactions with the microenvironment, such as bone marrow mesenchymal stromal cells and nurse-like cells, protect chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis. This protection is partially mediated by the chemokine SDF-1α (CXCL12) and its receptor CXCR4 (CD184) present on the chronic lymphocytic leukemia cell surface. Design and Methods Here, we investigated the ability of AMD3100, a CXCR4 antagonist, to sensitize chronic lymphocytic leukemia cells to chemotherapy in a chronic lymphocytic leukemia/mesenchymal stromal cell based or nurse-like cell based microenvironment co-culture model. Results AMD3100 decreased CXCR4 expression signal (n=15, P=0.0078) and inhibited actin polymerization/migration in response to SDF-1α (n=8, P<0.01) and pseudoemperipolesis (n=10, P=0.0010), suggesting that AMD3100 interferes with chronic lymphocytic leukemia cell trafficking. AMD3100 did not have a direct effect on apoptosis when chronic lymphocytic leukemia cells were cultured alone (n=10, P=0.8812). However, when they were cultured with SDF-1α, mesenchymal stromal cells or nurse-like cells (protecting them from apoptosis, P<0.001), chronic lymphocytic leukemia cell pre-treatment with AMD3100 significantly inhibited these protective effects (n=8, P<0.01) and decreased the expression of the anti-apoptotic proteins MCL-1 and FLIP. Furthermore, combining AMD3100 with various drugs (fludarabine, cladribine, valproïc acid, bortezomib, flavopiridol, methylprednisolone) in our mesenchymal stromal cell co-culture model enhanced drug-induced apoptosis (n=8, P<0.05) indicating that AMD3100 could mobilize chronic lymphocytic leukemia cells away from their protective microenvironment, making them more accessible to conventional therapies. Conclusions Taken together, these data demonstrate that interfering with the SDF-1α/CXCR4 axis by using AMD3100 inhibited chronic lymphocytic leukemia cell trafficking and microenvironment

  19. Antitumor effects with apoptotic death in human promyelocytic leukemia HL-60 cells and suppression of leukemia xenograft tumor growth by irinotecan HCl.

    PubMed

    Chen, Yung-Liang; Chueh, Fu-Shin; Yang, Jai-Sing; Hsueh, Shu-Ching; Lu, Chi-Cheng; Chiang, Jo-Hua; Lee, Ching-Sung; Lu, Hsu-Feng; Chung, Jing-Gung

    2015-07-01

    Irinotecan HCl (CPT-11) is an anticancer prodrug, but there is no available information addressing CPT-11-inhibited leukemia cells in in vitro and in vivo studies. Therefore, we investigated the cytotoxic effects of CPT-11 in promyelocytic leukemia HL-60 cells and in vivo and tumor growth in a leukemia xenograft model. Effects of CPT-11 on HL-60 cells were determined using flow cytometry, immunofluorescence staining, comet assay, real-time PCR, and Western blotting. CPT-11 demonstrated a dose- and time-dependent inhibition of cell growth, induction of apoptosis, and cell-cycle arrest at G0/G1 phase in HL-60 cells. CPT-11 promoted the release of AIF from mitochondria and its translocation to the nucleus. Bid, Bax, Apaf-1, caspase-9, AIF, Endo G, caspase-12, ATF-6b, Grp78, CDK2, Chk2, and cyclin D were all significantly upregulated and Bcl-2 was down-regulated by CPT-11 in HL-60 cells. Induction of cell-cycle arrest by CPT-11 was associated with changes in expression of key cell-cycle regulators such as CDK2, Chk2, and cyclin D in HL-60 cells. To test whether CPT-11 could augment antitumor activity in vivo, athymic BALB/c(nu/nu) nude mice were inoculated with HL-60 cells, followed by treatment with either CPT-11. The treatments significantly inhibited tumor growth and reduced tumor weight and volume in the HL-60 xenograft mice. The present study demonstrates the schedule-dependent antileukemia effect of CPT-11 using both in vitro and in vivo models. CPT-11 could potentially be a promising agent for the treatment of promyelocytic leukemia and requires further investigation.

  20. Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells

    SciTech Connect

    Okabe, Seiichi 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.

  1. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    SciTech Connect

    Waters, Katrina M.; Sontag, Ryan L.; Weber, Thomas J.

    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.

  2. Asparaginase induces apoptosis and cytoprotective autophagy in chronic myeloid leukemia cells.

    PubMed

    Song, Ping; Ye, Li; Fan, Jiajun; Li, Yubin; Zeng, Xian; Wang, Ziyu; Wang, Shaofei; Zhang, Guoping; Yang, Ping; Cao, Zhonglian; Ju, Dianwen

    2015-02-28

    The antitumor enzyme asparaginase, which targets essential amino acid L-asparagine and catalyzes it to L-aspartic acid and ammonia, has been used for years in the treatment of acute lymphoblastic leukemia (ALL), subtypes of myeloid leukemia and T-cell lymphomas, whereas the anti-chronic myeloid leukemia (CML) effect of asparaginase and its underlying mechanism has not been completely elucidated. We have shown here that asparaginase induced significant growth inhibition and apoptosis in K562 and KU812 cells. Apart from induction of apoptosis, we reported for the first time that asparaginase induced autophagic response in K562 and KU812 cells as evidenced by the formation of autophagosome, microtubule-associated protein light chain 3 (LC3)-positive autophagy-like vacuoles, and the upregulation of LC3-II. Further study suggested that the Akt/mTOR (mammalian target of rapamycin) and Erk (extracellular signal-regulated kinase) signaling pathway were involved in asparaginase-induced autophagy in K562 cells. Moreover, blocking autophagy using pharmacological inhibitors LY294002, chloroquine (CQ) and quinacrine (QN) enhanced asparaginase-induced cell death and apoptosis, indicating the cytoprotective role of autophagy in asparaginase-treated K562 and KU812 cells. Together, these findings provide a rationale that combination of asparaginase anticancer activity and autophagic inhibition might be a promising new therapeutic strategy for CML.

  3. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia.

    PubMed

    Knoechel, Birgit; Roderick, Justine E; Williamson, Kaylyn E; Zhu, Jiang; Lohr, Jens G; Cotton, Matthew J; Gillespie, Shawn M; Fernandez, Daniel; Ku, Manching; Wang, Hongfang; Piccioni, Federica; Silver, Serena J; Jain, Mohit; Pearson, Daniel; Kluk, Michael J; Ott, Christopher J; Shultz, Leonard D; Brehm, Michael A; Greiner, Dale L; Gutierrez, Alejandro; Stegmaier, Kimberly; Kung, Andrew L; Root, David E; Bradner, James E; Aster, Jon C; Kelliher, Michelle A; Bernstein, Bradley E

    2014-04-01

    The identification of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL) led to clinical testing of γ-secretase inhibitors (GSIs) that prevent NOTCH1 activation. However, responses to these inhibitors have been transient, suggesting that resistance limits their clinical efficacy. Here we modeled T-ALL resistance, identifying GSI-tolerant 'persister' cells that expand in the absence of NOTCH1 signaling. Rare persisters are already present in naive T-ALL populations, and the reversibility of their phenotype suggests an epigenetic mechanism. Relative to GSI-sensitive cells, persister cells activate distinct signaling and transcriptional programs and exhibit chromatin compaction. A knockdown screen identified chromatin regulators essential for persister viability, including BRD4. BRD4 binds enhancers near critical T-ALL genes, including MYC and BCL2. The BRD4 inhibitor JQ1 downregulates expression of these targets and induces growth arrest and apoptosis in persister cells, at doses well tolerated by GSI-sensitive cells. Consistently, the GSI-JQ1 combination was found to be effective against primary human leukemias in vivo. Our findings establish a role for epigenetic heterogeneity in leukemia resistance that may be addressed by incorporating epigenetic modulators in combination therapy.

  4. Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation

    PubMed Central

    Kunz, Joachim B.; Rausch, Tobias; Bandapalli, Obul R.; Eilers, Juliane; Pechanska, Paulina; Schuessele, Stephanie; Assenov, Yassen; Stütz, Adrian M.; Kirschner-Schwabe, Renate; Hof, Jana; Eckert, Cornelia; von Stackelberg, Arend; Schrappe, Martin; Stanulla, Martin; Koehler, Rolf; Avigad, Smadar; Elitzur, Sarah; Handgretinger, Rupert; Benes, Vladimir; Weischenfeldt, Joachim; Korbel, Jan O.; Muckenthaler, Martina U.; Kulozik, Andreas E.

    2015-01-01

    Relapsed precursor T-cell acute lymphoblastic leukemia is characterized by resistance against chemotherapy and is frequently fatal. We aimed at understanding the molecular mechanisms resulting in relapse of T-cell acute lymphoblastic leukemia and analyzed 13 patients at first diagnosis, remission and relapse by whole exome sequencing, targeted ultra-deep sequencing, multiplex ligation dependent probe amplification and DNA methylation array. Compared to primary T-cell acute lymphoblastic leukemia, in relapse the number of single nucleotide variants and small insertions and deletions approximately doubled from 11.5 to 26. Targeted ultra-deep sequencing sensitively detected subclones that were selected for in relapse. The mutational pattern defined two types of relapses. While both are characterized by selection of subclones and acquisition of novel mutations, ‘type 1’ relapse derives from the primary leukemia whereas ‘type 2’ relapse originates from a common pre-leukemic ancestor. Relapse-specific changes included activation of the nucleotidase NT5C2 resulting in resistance to chemotherapy and mutations of epigenetic modulators, exemplified by SUZ12, WHSC1 and SMARCA4. While mutations present in primary leukemia and in relapse were enriched for known drivers of leukemia, relapse-specific changes revealed an association with general cancer-promoting mechanisms. This study thus identifies mechanisms that drive progression of pediatric T-cell acute lymphoblastic leukemia to relapse and may explain the characteristic treatment resistance of this condition. PMID:26294725

  5. Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation.

    PubMed

    Kunz, Joachim B; Rausch, Tobias; Bandapalli, Obul R; Eilers, Juliane; Pechanska, Paulina; Schuessele, Stephanie; Assenov, Yassen; Stütz, Adrian M; Kirschner-Schwabe, Renate; Hof, Jana; Eckert, Cornelia; von Stackelberg, Arend; Schrappe, Martin; Stanulla, Martin; Koehler, Rolf; Avigad, Smadar; Elitzur, Sarah; Handgretinger, Rupert; Benes, Vladimir; Weischenfeldt, Joachim; Korbel, Jan O; Muckenthaler, Martina U; Kulozik, Andreas E

    2015-11-01

    Relapsed precursor T-cell acute lymphoblastic leukemia is characterized by resistance against chemotherapy and is frequently fatal. We aimed at understanding the molecular mechanisms resulting in relapse of T-cell acute lymphoblastic leukemia and analyzed 13 patients at first diagnosis, remission and relapse by whole exome sequencing, targeted ultra-deep sequencing, multiplex ligation dependent probe amplification and DNA methylation array. Compared to primary T-cell acute lymphoblastic leukemia, in relapse the number of single nucleotide variants and small insertions and deletions approximately doubled from 11.5 to 26. Targeted ultra-deep sequencing sensitively detected subclones that were selected for in relapse. The mutational pattern defined two types of relapses. While both are characterized by selection of subclones and acquisition of novel mutations, 'type 1' relapse derives from the primary leukemia whereas 'type 2' relapse originates from a common pre-leukemic ancestor. Relapse-specific changes included activation of the nucleotidase NT5C2 resulting in resistance to chemotherapy and mutations of epigenetic modulators, exemplified by SUZ12, WHSC1 and SMARCA4. While mutations present in primary leukemia and in relapse were enriched for known drivers of leukemia, relapse-specific changes revealed an association with general cancer-promoting mechanisms. This study thus identifies mechanisms that drive progression of pediatric T-cell acute lymphoblastic leukemia to relapse and may explain the characteristic treatment resistance of this condition.

  6. PCFT/SLC46A1 promoter methylation and restoration of gene expression in human leukemia cells

    SciTech Connect

    Gonen, Nitzan; Bram, Eran E.; Assaraf, Yehuda G.

    2008-11-28

    The proton-coupled folate transporter (PCFT/SLC46A1) displays optimal and prominent folate and antifolate transport activity at acidic pH in human carcinoma cells but poor activity in leukemia cells. Consistently herein, human leukemia cell lines expressed poor PCFT transcript levels, whereas various carcinoma cell lines showed substantial PCFT gene expression. We identified a CpG island with high density at nucleotides -200 through +100 and explored its role in PCFT promoter silencing. Leukemia cells with barely detectable PCFT transcripts consistently harbored 85-100% methylation of this CpG island, whereas no methylation was found in carcinoma cells. Treatment with 5-Aza-2'-deoxycytidine which induced demethylation but not with the histone deacetylase inhibitor trichostatin A, restored 50-fold PCFT expression only in leukemia cells. These findings constitute the first demonstration of the dominant epigenetic silencing of the PCFT gene in leukemia cells. The potential translational implications of the restoration of PCFT expression in chemotherapy of leukemia are discussed.

  7. Killing of human myelomonocytic leukemia and lymphocytic cell lines by Actinobacillus actinomycetemcomitans leukotoxin.

    PubMed Central

    Simpson, D L; Berthold, P; Taichman, N S

    1988-01-01

    The purified leukotoxin of Actinobacillus actinomycetemcomitans kills human leukemic cell lines (e.g., HL-60, U937, and KG-1) and human T- and B-cell lines (e.g., JURKAT, MOLT-4, Daudi, and Raji) in a dose- and time-dependent manner. The 50% effective doses for these cell lines are similar to those established for human polymorphonuclear leukocytes and monocytes. In contrast, other human and nonhuman tumor cell lines are not susceptible to the leukotoxin. These human leukemia and lymphoid cell lines will serve as useful model systems with which to study the molecular specificity and mechanism(s) of action of the actinobacillus leukotoxin. Images PMID:3258584

  8. T-cell chronic lymphocytic leukemia in a double yellow-headed Amazon parrot (Amazona ochrocephala oratrix).

    PubMed

    Osofsky, Anna; Hawkins, Michelle G; Foreman, Oded; Kent, Michael S; Vernau, William; Lowenstine, Linda J

    2011-12-01

    An adult, male double yellow-headed Amazon parrot (Amazona ochrocephala oratrix) was diagnosed with chronic lymphocytic leukemia based on results of a complete blood cell count and cytologic examination of a bone marrow aspirate. Treatment with oral chlorambucil was attempted, but no response was evident after 40 days. The bird was euthanatized, and the diagnosis of chronic lymphocytic leukemia was confirmed on gross and microscopic examination of tissues. Neoplastic lymphocytes were found in the bone marrow, liver, kidney, testes, and blood vessels. Based on CD3-positive immunocytochemical and immunohistochemical immunophenotyping, the chronic lymphocytic leukemia was determined to be of T-cell origin.

  9. Transduction of Recombinant M3-p53-R12 Protein Enhances Human Leukemia Cell Apoptosis

    PubMed Central

    Lu, Tsung Chi; Zhao, Guan- Hao; Chen, Yao Yun; Chien, Chia-Ying; Huang, Chi-Hung; Lin, Kwang Hui; Chen, Shen Liang

    2016-01-01

    Tumor suppressor protein p53 plays important roles in initiating cell cycle arrest and promoting tumor cell apoptosis. Previous studies have shown that p53 is either mutated or defective in approximately 50% of human cancers; therefore restoring normal p53 activity in cancer cells might be an effective anticancer therapeutic approach. Herein, we designed a chimeric p53 protein flanked with the MyoD N-terminal transcriptional activation domain (amino acids 1-62, called M3) and a poly-arginine (R12) cell penetrating signal in its N-and C-termini respectively. This chimeric protein, M3-p53-R12, can be expressed in E. coli and purified using immobilized metal ion chromatography followed by serial refolding dialysis. The purified M3-p53-R12 protein retains DNA-binding activity and gains of cell penetrating ability. Using MTT assay, we demonstrated that M3-p53-R12 inhibited the growth of K562, Jurkat as well as HL-60 leukemia cells carrying mutant p53 genes. Results from FACS analysis also demonstrated that transduction of M3-p53-R12 protein induced cell cycle arrest of these leukemia cells. Of special note, M3-p53-R12 has no apoptotic effect on normal mesenchymal stem cells (MSC) and leukocytes, highlighting its differential effects on normal and tumor cells. To sum up, our results reveal that purified recombinant M3-p53-R12 protein has functions of suppressing the leukemia cell lines' proliferation and launching cell apoptosis, suggesting the feasibility of using M3-p53-R12 protein as an anticancer drug. In the future we will test whether this chimeric protein can preferentially trigger the death of malignant cancer cells without affecting normal cells in animals carrying endogenous or xenographic tumors. PMID:27390612

  10. Attenuated A20 expression of acute myeloid leukemia-derived dendritic cells increased the anti-leukemia immune response of autologous cytolytic T cells.

    PubMed

    Zhang, Xiaoying; Su, Yongfeng; Song, Haifeng; Yu, Zhiyong; Zhang, Bin; Chen, Hu

    2014-06-01

    Previous studies reported leukemic cells from acute myeloid leukemia (AML) patients can differentiate into dendritic cells (DCs), which had some immunoregulatory dysfunctions to effectively stimulate autologous CTLs' anti-leukemia immune response. The zinc-finger protein A20, a negative regulator of the nuclear factor (NF)-κB pathway, was found to play a crucial role in controlling the maturation and function of human monocyte-derived DCs. However, the effects of A20 in AML derived DCs (AML-DCs) have not yet been evaluated. In this study, A20 expression was up-regulated in AML-DCs activated with tumor necrosis factor (TNF)-α. Then, A20 attenuation with siRNA in AML-DC enhanced the expression of several co-stimulatory molecules and proinflammatory cytokines. Furthermore, after A20 attenuation in AML-DCs, the autologous cytolytic T cells (CTLs) induced by AML-DCs had higher killing capability and specificity for primary AML cells. Additionally, receptor-interacting protein (RIP) and the NF-κBp65 pathway were elevated in AML-DCs when A20 was reduced. Hence, this study identified A20 as a negative regulator for controlling AML-DC maturation and immunostimulatory potency, as A20 down-regulation resulted in AML-DCs with enhanced autologous CTLs immune capacity through the NF-κB pathway.

  11. Critical molecular pathways in cancer stem cells of chronic myeloid leukemia

    PubMed Central

    Chen, Yaoyu; Peng, Cong; Sullivan, Con; Li, Dongguang; Li, Shaoguang

    2011-01-01

    Inhibition of BCR-ABL with kinase inhibitors in the treatment of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) is highly effective in controlling but not curing the disease. This is largely due to the inability of these kinase inhibitors to kill leukemia stem cells (LSCs) responsible for disease relapse. This stem cell resistance is not associated with the BCR-ABL kinase domain mutations resistant to kinase inhibitors. Development of curative therapies for CML requires the identification of critical molecular pathways responsible for the survival and self-renewal of LSCs. In this review, we will discuss our current understanding of these critical molecular pathways in LSCs and the available therapeutic strategies for targeting these stem cells in CML. PMID:20574455

  12. Gene Signature of High White Blood Cell Count in B-Precursor Acute Lymphoblastic Leukemia.

    PubMed

    Edwards, Holly; Rubenstein, Mara; Dombkowski, Alan A; Caldwell, J Timothy; Chu, Roland; Xavier, Ana C; Thummel, Ryan; Neely, Melody; Matherly, Larry H; Ge, Yubin; Taub, Jeffrey W

    2016-01-01

    In this study we sought to identify genetic factors associated with the presenting white blood cell (WBC) count in B-precursor acute lymphoblastic leukemia (BP-ALL). Using ETV6-RUNX1-positive BP-ALL patient samples, a homogeneous subtype, we identified 16 differentially expressed genes based on the presenting WBC count (< 50,000/cumm vs > 50,000). We further confirmed that IL1R1, BCAR3, KCNH2, PIR, and ZDHHC23 were differentially expressed in a larger cohort of ETV6-RUNX1-negative BP-ALL patient samples. Statistical analysis demonstrated that expression levels of these genes could accurately categorize high and low WBC count subjects using two independent patient sets, representing positive and negative ETV6-RUNX1 cases. Further studies in leukemia cell line models will better delineate the role of these genes in regulating the white blood cell count and potentially identify new therapeutic targets.

  13. Hsp90 N- and C-terminal double inhibition synergistically suppresses Bcr-Abl-positive human leukemia cells.

    PubMed

    Chen, Chun; Zhuang, Yingting; Chen, Xianling; Chen, Xiaole; Li, Ding; Fan, Yingjuan; Xu, Jianhua; Chen, Yuanzhong; Wu, Lixian

    2017-02-07

    Heat shock protein 90 (Hsp90) contains amino (N)-terminal domain, carboxyl(C)-terminal domain, and middle domains, which activate Hsp90 chaperone function cooperatively in tumor cells. One terminal occupancy might influence another terminal binding with inhibitor. The Bcr-Abl kinase is one of the Hsp90 clients implicated in the pathogenesis of chronic myeloid leukemia (CML). Present studies demonstrate that double inhibition of the N- and C-terminal termini can disrupt Hsp90 chaperone function synergistically, but not antagonistically, in Bcr-Abl-positive human leukemia cells. Furthermore, both the N-terminal inhibitor 17-AAG and the C-terminal inhibitor cisplatin (CP) have the capacity to suppress progenitor cells; however, only CP is able to inhibit leukemia stem cells (LSCs) significantly, which implies that the combinational treatment is able to suppress human leukemia in different mature states.

  14. Telomere attrition and chromosome instability via downregulation of TRF2 contributes to arsenic trioxide-induced apoptosis of human T-Cell leukemia cell line molt-4 cells.

    PubMed

    Jiao, Yangwen; Zhang, Weifang; Liu, Junqing; Ni, Wanmao; Xu, Weilai; Jin, Jie; Qian, Wenbin

    2007-08-01

    Overexpression of human telomere repeat binding factor 2 (TRF2), which may play an important role in the fate of cancer cells, has been observed in adult T-cell leukemia. Previous reports have shown that the inhibition of TRF2 results in the apoptosis of cancer cells. In this study, we demonstrated that arsenic trioxide (As2O3) induced in vitro growth inhibition and/or apoptosis of human T-cell leukemia cell line Molt-4 in a caspase-independent manner. Telomerase activity was not inhibited, although the level of the reverse transcriptase subunit of the human telomerase gene (hTERT) mRNA expression was down regulated during the early times and then recovered to the level found in untreated controls about 48 hours after treatment with As2O3. Furthermore, a remarkable telomere shortening related to exposure of As2O3 was observed in 50 population doubling. Inc ontrast, the alteration of telomere length did not occur after exposure to higher concentration of As2O3 (10 microM) for 24 hours and 48 hours, respectively, suggesting that the shortening of telomeres induced by As2O3 is dependent of a series of cell division cycles. Chromosomal analysis showed that As2O3 exposure caused chromosomal end-to-end fusion in human T-cell leukemia cells while downregulation of TRF2 was observed. Finally, the inhibition of TRF2 protein expression and the sensitivity to As2O3 in a panel of leukemia cell lines were checked. The data revealed that inhibition of TRF2 rendered leukemia cells more susceptible to As2O3. In conclusion, the downregulation of TRF2 by As2O3 contribute to chromosomal end-to-end fusion, and apoptosis in leukemia cells, suggesting that TRF2 could be an attractive target for new therapies of leukemia.

  15. Leukemia-related chromosomal loss detected in hematopoietic progenitor cells of benzene-exposed workers

    PubMed Central

    Zhang, Luoping; Lan, Qing; Ji, Zhiying; Li, Guilan; Shen, Min; Vermeulen, Roel; Guo, Weihong; Hubbard, Alan E.; McHale, Cliona M.; Rappaport, Stephen M.; Hayes, Richard B.; Linet, Martha S.; Yin, Songnian; Smith, Martyn T.; Rothman, Nathaniel

    2012-01-01

    Benzene exposure causes acute myeloid leukemia, and hematotoxicity, shown as suppression of mature blood and myeloid progenitor cell numbers. As the leukemia-related aneuploidies monosomy 7 and trisomy 8 previously had been detected in the mature peripheral blood cells of exposed workers, we hypothesized that benzene could cause leukemia through the induction of these aneuploidies in hematopoietic stem and progenitor cells. We measured loss and gain of chromosomes 7 and 8 by fluorescence in situ hybridization in interphase colony-forming unit-granulocyte-macrophage (CFU-GM) cells cultured from otherwise healthy benzene-exposed (n=28) and unexposed (n=14) workers. CFU-GM monosomy 7 and 8 levels (but not trisomy) were significantly increased in subjects exposed to benzene overall, compared to levels in the control subjects (p=0.0055 and p=0.0034, respectively). Levels of monosomy 7 and 8 were significantly increased in subjects exposed to <10 ppm (20%, p=0.0419 and 28%, p=0.0056, respectively) and ≥10 ppm (48%, p=0.0045 and 32%, p=0.0354) benzene, compared with controls, and significant exposure-response trends were detected (ptrend=0.0033 and 0.0057). These data show that monosomies 7 and 8 are produced in a dose-dependent fashion in the blood progenitor cells of workers exposed to benzene and may be mechanistically relevant biomarkers of early effect for benzene and other leukemogens. PMID:22643707

  16. Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency.

    PubMed

    Muñoz-López, Alvaro; Romero-Moya, Damià; Prieto, Cristina; Ramos-Mejía, Verónica; Agraz-Doblas, Antonio; Varela, Ignacio; Buschbeck, Marcus; Palau, Anna; Carvajal-Vergara, Xonia; Giorgetti, Alessandra; Ford, Anthony; Lako, Majlinda; Granada, Isabel; Ruiz-Xivillé, Neus; Rodríguez-Perales, Sandra; Torres-Ruíz, Raul; Stam, Ronald W; Fuster, Jose Luis; Fraga, Mario F; Nakanishi, Mahito; Cazzaniga, Gianni; Bardini, Michela; Cobo, Isabel; Bayon, Gustavo F; Fernandez, Agustin F; Bueno, Clara; Menendez, Pablo

    2016-10-11

    Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming "boosters" also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency.

  17. Polyphenols are responsible for the proapoptotic properties of pomegranate juice on leukemia cell lines

    PubMed Central

    Dahlawi, Haytham; Jordan-Mahy, Nicola; Clench, Malcolm; McDougall, Gordon J; Maitre, Christine Lyn

    2013-01-01

    Pomegranates have shown great promise as anti-cancer agents in a number of cancers including clinical trials in prostate cancer. We have previously shown pomegranate juice (PGJ) induced apoptosis and preferentially alters the cell cycle in leukemia cell lines compared with nontumor control cells. However, the agents responsible have not yet been fully elucidated. Treatment of four leukemia cell lines with five fractions obtained from PGJ by solid phase extraction demonstrated that only the acetonitrile fractions decreased adenosine triphosphate (ATP) levels in all leukemia cell lines. Acetonitrile fractions also significantly activated caspase-3 and induced nuclear morphology characteristic of apoptosis. S phase arrest was induced by acetonitrile fractions which matched S phase arrest seen previously following whole PGJ treatments. The acetonitrile fractions contained higher phenol content than whole PGJ whereas only low levels of phenols were seen in any other fraction. Liquid chromatography mass spectrometry (LC–MS) analysis demonstrated that acetonitrile fractions were enriched in ellagitannins, ellagic acid, and hydroxycinnamic acid derivatives but depleted in anthocyanins. Individual treatments with identified compounds demonstrated that the ellagitannin: punicalagin was the most active and mimicked the responses seen following acetonitrile fraction treatment. Bioactive components within pomegranate were confined to the acetonitrile fraction of PGJ. The enrichment in ellagitannins and hydroxycinnamic acids suggest these may provide the majority of the bioactivities of PGJ. Individual treatments with compounds identified demonstrated that the ellagitannin: punicalagin was the most active agent, highlighting this compound as a key bioactive agent in PGJ. PMID:24804028

  18. Niche-based screening identifies small-molecule inhibitors of leukemia stem cells

    PubMed Central

    Mukherjee, Siddhartha; Kahn, Alissa R; Stewart, Alison L; Logan, David J; Negri, Joseph M; Duvet, Mildred; Järås, Marcus; Puram, Rishi; Dancik, Vlado; Al-Shahrour, Fatima; Kindler, Thomas; Tothova, Zuzana; Chattopadhyay, Shrikanta; Hasaka, Thomas; Narayan, Rajiv; Dai, Mingji; Huang, Christina; Shterental, Sebastian; Chu, Lisa P; Haydu, J Erika; Shieh, Jae Hung; Steensma, David P; Munoz, Benito; Bittker, Joshua A; Shamji, Alykhan F; Clemons, Paul A; Tolliday, Nicola J; Carpenter, Anne E; Gilliland, D Gary; Stern, Andrew M; Moore, Malcolm A S; Scadden, David T; Schreiber, Stuart L; Ebert, Benjamin L; Golub, Todd R

    2014-01-01

    Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone-marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on-target, via inhibition of HMGCoA reductase. These results illustrate the power of merging physiologically-relevant models with high-throughput screening. PMID:24161946

  19. Transcription factor AP-2α regulates acute myeloid leukemia cell proliferation by influencing Hoxa gene expression.

    PubMed

    Ding, Xiaofeng; Yang, Zijian; Zhou, Fangliang; Wang, Fangmei; Li, Xinxin; Chen, Cheng; Li, Xiaofeng; Hu, Xiang; Xiang, Shuanglin; Zhang, Jian

    2013-08-01

    Transcription factor AP-2α mediates transcription of a number of genes implicated in mammalian development, cell proliferation and carcinogenesis. In the current study, we identified Hoxa7, Hoxa9 and Hox cofactor Meis1 as AP-2α target genes, which are involved in myeloid leukemogenesis. Luciferase reporter assays revealed that overexpression of AP-2α activated transcription activities of Hoxa7, Hoxa9 and Meis1, whereas siRNA of AP-2α inhibited their transcription activities. We found that AP-2 binding sites in regulatory regions of three genes activated their transcription by mutant analysis and AP-2α could interact with AP-2 binding sites in vivo by chromatin immunoprecipitation (ChIP). Further results showed that the AP-2α shRNA efficiently inhibited mRNA and protein levels of Hoxa7, Hoxa9 and Meis1 in AML cell lines U937 and HL60. Moreover, decreased expression of AP-2α resulted in a significant reduction in the growth and proliferation of AML cells in vitro. Remarkably, AP-2α knockdown leukemia cells exhibit decreased tumorigenicity in vivo compared with controls. Finally, AP-2α and target genes in clinical acute myeloid leukemia samples of M5b subtype revealed variable expression levels and broadly paralleled expression. These data support a role of AP-2α in mediating the expression of Hoxa genes in acute myeloid leukemia to influence the proliferation and cell survival.

  20. Establishment of a cell line from leucocytes of a cow with chronic lymphocytic leukemia.

    PubMed

    Adomaitiene, D; Tamosiunas, V; Mauricas, M; Surovas, V; Markevicius, A

    1983-07-01

    A cell line was established from blood leucocytes of a cow with chronic lymphocytic leukemia. The leucocytes were cultured with conditioned medium (culture fluid of mouse cell line L). In vitro cell transformation was demonstrated by adaptation to permanent growth, modification of cell morphology, the alteration of cell surface phenotype, kinetic behaviour and the loss of the euploid stability of the cell karyotype. Ultrastructural studies showed rather a uniform cell pattern in a culture population heterogeneous for degree of cell vacuolization. A wide variation in the expression of surface markers in cells was demonstrated by E-, EA- and EAC-rosetting. In suspension culture the cell population was found to be sIg negative. Expression of leukemia-associated antigens by a fraction of the cultured cells was evidenced by a cytotoxic technique using complement and heterologous antisera against bovine leukemic lymphocytes, absorbed with normal lymphoid cells. Virus-like particles and BLV antigens were not identified. Culture cells failed to show spontaneous or antibody-dependent killer cytotoxicity. Comparison with blood lymphocytes of healthy and leukemic cattle was done. The established culture should be useful as a model for experimental immunology and oncology.

  1. Transferrin as a drug carrier: Cytotoxicity, cellular uptake and transport kinetics of doxorubicin transferrin conjugate in the human leukemia cells.

    PubMed

    Szwed, Marzena; Matusiak, Agnieszka; Laroche-Clary, Audrey; Robert, Jacques; Marszalek, Ilona; Jozwiak, Zofia

    2014-03-01

    Leukemias are one of most common malignancies worldwide. There is a substantial need for new chemotherapeutic drugs effective against this cancer. Doxorubicin (DOX), used for treatment of leukemias and solid tumors, is poorly efficacious when it is administered systemically at conventional doses. Therefore, several strategies have been developed to reduce the side effects of this anthracycline treatment. In this study we compared the effect of DOX and doxorubicin-transferrin conjugate (DOX-TRF) on human leukemia cell lines: chronic erythromyeloblastoid leukemia (K562), sensitive and resistant (K562/DOX) to doxorubicin, and acute lymphoblastic leukemia (CCRF-CEM). Experiments were also carried out on normal cells, peripheral blood mononuclear cells (PBMC). We analyzed the chemical structure of DOX-TRF conjugate by using mass spectroscopy. The in vitro growth-inhibition assay XTT, indicated that DOX-TRF is more cytotoxic for leukemia cells sensitive and resistant to doxorubicin and significantly less sensitive to normal cells compared to DOX alone. During the assessment of intracellular DOX-TRF accumulation it was confirmed that the tested malignant cells were able to retain the examined conjugate for longer periods of time than normal lymphocytes. Comparison of kinetic parameters showed that the rate of DOX-TRF efflux was also slower in the tested cells than free DOX. The results presented here should contribute to the understanding of the differences in antitumor activities of the DOX-TRF conjugate and free drug.

  2. Underground Adaptation to a Hostile Environment: Acute Myeloid Leukemia vs. Natural Killer Cells

    PubMed Central

    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

  3. Curcumin enhances the cytogenotoxic effect of etoposide in leukemia cells through induction of reactive oxygen species

    PubMed Central

    Papież, Monika A; Krzyściak, Wirginia; Szade, Krzysztof; Bukowska-Straková, Karolina; Kozakowska, Magdalena; Hajduk, Karolina; Bystrowska, Beata; Dulak, Jozef; Jozkowicz, Alicja

    2016-01-01

    Curcumin may exert a more selective cytotoxic effect in tumor cells with elevated levels of free radicals. Here, we investigated whether curcumin can modulate etoposide action in myeloid leukemia cells and in normal cells of hematopoietic origin. HL-60 cell line, normal myeloid progenitor cluster of differentiation (CD)-34+ cells, and granulocytes were incubated for 4 or 24 hours at different concentrations of curcumin and/or etoposide. Brown Norway rats with acute myeloid leukemia (BNML) were used to prove the influence of curcumin on etoposide action in vivo. Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment. Curcumin synergistically potentiated the cytotoxic effect of etoposide, and it intensified apoptosis and phosphorylation of the histone H2AX induced by this cytostatic drug in leukemic HL-60 cells. In contrast, curcumin did not significantly modify etoposide-induced cytotoxicity and H2AX phosphorylation in normal CD34+ cells and granulocytes. Curcumin modified the cytotoxic action of etoposide in HL-60 cells through intensification of free radical production because preincubation with N-acetyl-l-cysteine (NAC) significantly reduced the cytotoxic effect of curcumin itself and a combination of two compounds. In contrast, NAC did not decrease the cytotoxic effect of etoposide. Thus, oxidative stress plays a greater role in the cytotoxic effect of curcumin than that of etoposide in HL-60 cells. In vitro results were confirmed in a BNML model. Pretreatment with curcumin enhanced the antileukemic activity of etoposide in BNML rats (1.57-fold tumor reduction versus etoposide alone; P<0.05) and induced apoptosis of BNML cells more efficiently than etoposide alone (1.54-fold change versus etoposide alone; P<0.05), but this treatment protected nonleukemic B-cells from apoptosis. Thus, curcumin can increase the antileukemic effect of etoposide through reactive oxygen species in sensitive myeloid leukemia

  4. Fucoidan Suppresses the Growth of Human Acute Promyelocytic Leukemia Cells In Vitro and In Vivo.

    PubMed

    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.

  5. Investigation of deregulated genes of Notch signaling pathway in human T cell acute lymphoblastic leukemia cell lines and clinical samples.

    PubMed

    Paryan, Mahdi; Mohammadi-Yeganeh, Samira; Samiee, Siamak Mirab; Soleimani, Masoud; Arefian, Ehsan; Azadmanesh, Keyhan; Poopak, Behzad; Mostafavi, Ehsan; Karimipoor, Morteza; Mahdian, Reza

    2013-10-01

    In diagnostic research challenges, quantitative real-time PCR (QPCR) has been widely utilized in gene expression analysis because of its sensitivity, accuracy, reproducibility, and most importantly, quantitativeness. Real-time PCR base kits are wildly applicable in cancer signaling pathways, especially in cancer investigations. T-cell acute lymphoblastic leukemia (T-ALL) is a type of leukemia that is more common in older children and teenagers. Deregulation of the Notch signaling pathway promotes proliferation and inhibits apoptosis of the lymphoblastic T cells. The aim of this study was to investigate the effect of Notch signaling activation on the expression of target genes using real-time QPCR and further use this method in clinical examination after validation. Two T-ALL cell lines, Jurkat and Molt-4, were used as models for activation of the Notch signaling via over-expression of the Notch1 intracellular domain. Expression analysis was performed for six downstream target genes (NCSTN, APH1, PSEN1, ADAM17, NOTCH1 and C-MYC) which play critical roles in the Notch signaling pathway. The results showed significant difference in the expression of target genes in the deregulated Notch signaling pathway. These results were also verified in 12 clinical samples bearing over-expression of the Notch signaling pathway. Identification of such downstream Notch target genes, which have not been studied inclusively, provides insights into the mechanisms of the Notch function in T cell leukemia, and may help identify novel diagnoses and therapeutic targets in acute lymphoblastic leukemia.

  6. Nilotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-10-29

    B-cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

  7. Alemtuzumab and Combination Chemotherapy in Treating Patients With Untreated Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2014-03-20

    Acute Undifferentiated Leukemia; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; L1 Adult Acute Lymphoblastic Leukemia; L1 Childhood Acute Lymphoblastic Leukemia; L2 Adult Acute Lymphoblastic Leukemia; L2 Childhood Acute Lymphoblastic Leukemia; Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  8. MicroRNA-128-3p is a novel oncomiR targeting PHF6 in T-cell acute lymphoblastic leukemia.

    PubMed

    Mets, Evelien; Van Peer, Gert; Van der Meulen, Joni; Boice, Michael; Taghon, Tom; Goossens, Steven; Mestdagh, Pieter; Benoit, Yves; De Moerloose, Barbara; Van Roy, Nadine; Poppe, Bruce; Vandesompele, Jo; Wendel, Hans-Guido; Van Vlierberghe, Pieter; Speleman, Frank; Rondou, Pieter

    2014-08-01

    T-cell acute lymphoblastic leukemia arises from the leukemic transformation of developing thymocytes and results from cooperative genetic lesions. Inactivation of the PHF6 gene is frequently observed in T-cell acute lymphoblastic leukemia, suggesting an important tumor suppressive role for PHF6 in the pathobiology of this leukemia. Although the precise function of PHF6 is still unknown, this gene is most likely involved in chromatin regulation, a strongly emerging theme in T-cell acute lymphoblastic leukemia. In this context, our previous description of a cooperative microRNA regulatory network controlling several well-known T-cell acute lymphoblastic leukemia tumor suppressor genes, including PHF6, is of great importance. Given the high frequency of PHF6 lesions in T-cell acute lymphoblastic leukemia and the integration of PHF6 in this microRNA regulatory network, we aimed to identify novel oncogenic microRNAs in T-cell acute lymphoblastic leukemia which suppress PHF6. To this end, we performed an unbiased PHF6 3'UTR-microRNA library screen and combined the results with microRNA profiling data of samples from patients with T-cell acute lymphoblastic leukemia and normal thymocyte subsets. We selected miR-128-3p as a candidate PHF6-targeting, oncogenic microRNA and demonstrated regulation of PHF6 expression upon modulation of this microRNA in T-cell acute lymphoblastic leukemia cell lines. In vivo evidence of an oncogenic role of this microRNA in T-cell acute lymphoblastic leukemia was obtained through accelerated leukemia onset in a NOTCH1-induced T-cell acute lymphoblastic leukemia mouse model upon miR-128-3p over-expression. We conclude that miR-128-3p is a strong novel candidate oncogenic microRNA in T-cell acute lymphoblastic leukemia which targets the PHF6 tumor suppressor gene.

  9. Rituximab, Rasburicase, and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Advanced B-Cell Leukemia or Lymphoma

    ClinicalTrials.gov

    2014-09-10

    Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Untreated Childhood Acute Lymphoblastic Leukemia

  10. A proteomic chronology of gene expression through the cell cycle in human myeloid leukemia cells.

    PubMed

    Ly, Tony; Ahmad, Yasmeen; Shlien, Adam; Soroka, Dominique; Mills, Allie; Emanuele, Michael J; Stratton, Michael R; Lamond, Angus I

    2014-01-01

    Technological advances have enabled the analysis of cellular protein and RNA levels with unprecedented depth and sensitivity, allowing for an unbiased re-evaluation of gene regulation during fundamental biological processes. Here, we have chronicled the dynamics of protein and mRNA expression levels across a minimally perturbed cell cycle in human myeloid leukemia cells using centrifugal elutriation combined with mass spectrometry-based proteomics and RNA-Seq, avoiding artificial synchronization procedures. We identify myeloid-specific gene expression and variations in protein abundance, isoform expression and phosphorylation at different cell cycle stages. We dissect the relationship between protein and mRNA levels for both bulk gene expression and for over ∼6000 genes individually across the cell cycle, revealing complex, gene-specific patterns. This data set, one of the deepest surveys to date of gene expression in human cells, is presented in an online, searchable database, the Encyclopedia of Proteome Dynamics (http://www.peptracker.com/epd/). DOI: http://dx.doi.org/10.7554/eLife.01630.001.

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

    PubMed

    Bae, Kyoung Jun; Lee, Yura; Kim, Soon Ae; Kim, Jiyeon

    2016-04-22

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

  12. Diversity and Complexity of Ceramide Generation After Exposure of Jurkat Leukemia Cells to Irradiation

    SciTech Connect

    Ardail, Dominique Maalouf, Mira; Boivin, Anthony; Chapet, Olivier; Bodennec, Jacques; Rousson, Robert; Rodriguez-Lafrasse, Claire

    2009-03-15

    Purpose: To define which intracellular pools of sphingomyelin and ceramide are involved in the triggering of apoptosis of Jurkat leukemia cells in response to {gamma}-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 [{sup 3}H]-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 {gamma}-rays.

  13. Identifying arsenic trioxide (ATO) functions in leukemia cells by using time series gene expression profiles.

    PubMed

    Yang, Hong; Lin, Shan; Cui, Jingru

    2014-02-10

    Arsenic trioxide (ATO) is presently the most active single agent in the treatment of acute promyelocytic leukemia (APL). In order to explore the molecular mechanism of ATO in leukemia cells with time series, we adopted bioinformatics strategy to analyze expression changing patterns and changes in transcription regulation modules of time series genes filtered from Gene Expression Omnibus database (GSE24946). We totally screened out 1847 time series genes for subsequent analysis. The KEGG (Kyoto encyclopedia of genes and genomes) pathways enrichment analysis of these genes showed that oxidative phosphorylation and ribosome were the top 2 significantly enriched pathways. STEM software was employed to compare changing patterns of gene expression with assigned 50 expression patterns. We screened out 7 significantly enriched patterns and 4 tendency charts of time series genes. The result of Gene Ontology showed that functions of times series genes mainly distributed in profiles 41, 40, 39 and 38. Seven genes with positive regulation of cell adhesion function were enriched in profile 40, and presented the same first increased model then decreased model as profile 40. The transcription module analysis showed that they mainly involved in oxidative phosphorylation pathway and ribosome pathway. Overall, our data summarized the gene expression changes in ATO treated K562-r cell lines with time and suggested that time series genes mainly regulated cell adhesive. Furthermore, our result may provide theoretical basis of molecular biology in treating acute promyelocytic leukemia.

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

    PubMed

    Liu, Yuan-Fang; Wang, Bai-Yan; Zhang, Wei-Na; Huang, Jin-Yan; Li, Ben-Shang; Zhang, Ming; Jiang, Lu; Li, Jian-Feng; Wang, Ming-Jie; Dai, Yu-Jun; Zhang, Zi-Guan; Wang, Qiang; Kong, Jie; Chen, Bing; Zhu, Yong-Mei; Weng, Xiang-Qin; Shen, Zhi-Xiang; Li, Jun-Min; Wang, Jin; Yan, Xiao-Jing; Li, Yan; Liang, Ying-Min; Liu, Li; Chen, Xie-Qun; Zhang, Wang-Gang; Yan, Jin-Song; Hu, Jian-Da; Shen, Shu-Hong; Chen, Jing; Gu, Long-Jun; Pei, Deqing; Li, Yongjin; Wu, Gang; Zhou, Xin; Ren, Rui-Bao; Cheng, Cheng; Yang, Jun J; Wang, Kan-Kan; Wang, Sheng-Yue; Zhang, Jinghui; Mi, Jian-Qing; Pui, Ching-Hon; Tang, Jing-Yan; Chen, Zhu; Chen, Sai-Juan

    2016-06-01

    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.

  15. Improved FRET Biosensor for the Measurement of BCR-ABL Activity in Chronic Myeloid Leukemia Cells.

    PubMed

    Horiguchi, Mika; Fujioka, Mari; Kondo, Takeshi; Fujioka, Yoichiro; Li, Xinxin; Horiuchi, Kosui; O Satoh, Aya; Nepal, Prabha; Nishide, Shinya; Nanbo, Asuka; Teshima, Takanori; Ohba, Yusuke

    2017-02-02

    Although the co-development of companion diagnostics with molecular targeted drugs is desirable, truly efficient diagnostics are limited to diseases in which chromosomal translocations or overt mutations are clearly correlated with drug efficacy. Moreover, even for such diseases, few methods are available to predict whether drug administration is effective for each individual patient whose disease is expected to respond to the drug(s). We have previously developed a biosensor based on the principle of Förster resonance energy transfer to measure the activity of the tyrosine kinase BCR-ABL and its response to drug treatment in patient-derived chronic myeloid leukemia cells. The biosensor harbors CrkL, one of the major substrates of BCR-ABL, and is therefore named Pickles after phosphorylation indicator of CrkL en substrate. The efficacy of this technique as a clinical test has been demonstrated, but the number of cells available for analysis is limited in a case-dependent manner, owing to the cleavage of the biosensor in patient-derived leukemia cells. Here, we describe an improved biosensor with an amino acid substitution and a nuclear export signal being introduced. Of the two predicted cleavage positions in CrkL, the mutations inhibited one cleavage completely and the other cleavage partially, thus collectively increasing the number of cells available for drug evaluation. This improved version of the biosensor holds promise in the future development of companion diagnostics to predict responses to tyrosine kinase inhibitors in patients with chronic myeloid leukemia.

  16. RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML.

    PubMed

    Crews, Leslie A; Balaian, Larisa; Delos Santos, Nathaniel P; Leu, Heather S; Court, Angela C; Lazzari, Elisa; Sadarangani, Anil; Zipeto, Maria A; La Clair, James J; Villa, Reymundo; Kulidjian, Anna; Storb, Rainer; Morris, Sheldon R; Ball, Edward D; Burkart, Michael D; Jamieson, Catriona H M

    2016-11-03

    Age-related human hematopoietic stem cell (HSC) exhaustion and myeloid-lineage skewing promote oncogenic transformation of hematopoietic progenitor cells into therapy-resistant leukemia stem cells (LSCs) in secondary acute myeloid leukemia (AML). While acquisition of clonal DNA mutations has been linked to increased rates of secondary AML for individuals older than 60 years, the contribution of RNA processing alterations to human hematopoietic stem and progenitor aging and LSC generation remains unclear. Comprehensive RNA sequencing and splice-isoform-specific PCR uncovered characteristic RNA splice isoform expression patterns that distinguished normal young and aged human stem and progenitor cells (HSPCs) from malignant myelodysplastic syndrome (MDS) and AML progenitors. In splicing reporter assays and pre-clinical patient-derived AML models, treatment with a pharmacologic splicing modulator, 17S-FD-895, reversed pro-survival splice isoform switching and significantly impaired LSC maintenance. Therapeutic splicing modulation, together with monitoring splice isoform biomarkers of healthy HSPC aging versus LSC generation, may be employed safely and effectively to prevent relapse, the leading cause of leukemia-related mortality.

  17. Effect of adenosine on the growth of human T-lymphocyte leukemia cell line MOLT-4.

    PubMed

    Streitová, Denisa; Weiterová, Lenka; Hofer, Michal; Holá, Jirina; Horváth, Viktor; Kozubík, Alois; Znojil, Vladimír

    2007-09-01

    Adenosine has been observed to suppress the growth of MOLT-4 human leukemia cells in vitro. Changes in the cell cycle, especially increased percentage of cells in S phase, prolonged generation time, and induction of apoptosis at higher adenosine concentrations have been found to be responsible for the growth suppression. Dipyridamole, a drug inhibiting the cellular uptake of adenosine, reversed partially but significantly the adenosine-induced growth suppression. It follows from these results that the action of adenosine on the MOLT-4 cells comprises its cellular uptake and intracellular operation. These findings present new data on anticancer efficacy of adenosine.

  18. Management of mantle cell leukemia with cardiac involvement leading to cardiogenic shock.

    PubMed

    Furqan, Muhammad; Chen, Yamei; Akinleye, Akintunde; Sarungbam, Judy; Gass, Alan; Seiter, Karen; Liu, Delong

    2014-06-01

    Mantle cell lymphoma is an aggressive subtype of B cell non-Hodgkin lymphoma. It can progress to leukemic phase but frank leukemic picture at initial presentation is not common. Leukemic phase indicates advance stage of the disease and generally associated with extensive extra-nodal involvement. Pericardial invasion has been reported, however we could not find a report of myocardial infiltration by this disease since the appraisal of the term "mantle cell lymphoma" in 1992. Here we report a case of cardiac involvement by mantle cell leukemia leading to cardiogenic shock which complicates the treatment decisions.

  19. False and mycoplasma-contaminated leukemia-lymphoma cell lines: time for a reappraisal.

    PubMed

    Drexler, Hans G; Dirks, Wilhelm G; MacLeod, Roderick A F; Uphoff, Cord C

    2017-03-01

    Leukemia-lymphoma cell lines are important research tools in a variety of fields. To represent adequate model systems it is of utmost importance that cell lines faithfully model the primary tumor material and are not cross-contaminated with unrelated cell material (or contaminated with mycoplasma). As it has been previously reported that cross-contaminated cell lines represent a significant problem, it is of interest to know whether any improvement in the prevalence of such "false cell lines" had occurred since we called the alert in 1999. A retrospective review of our data archives covered 848 cell lines received from 1990 to 2014 from 290 laboratories in 23 countries spanning the spectrum of leukemia-lymphoma entities. Two variables were considered: authenticity and freedom from mycoplasma infection. Regarding provenance, we separately considered primary sources (original investigators having established the cell lines or reference repositories) and secondary sources. The percentages of mycoplasma-contaminated cell lines decreased significantly over the 25-year timespan. Among primary sourced material: mycoplasma-contamination fell from 23% to 0%; among secondary sourced: from 48% to 21%. The corresponding figures for cross-contamination declined from 15% to 6%, while among material obtained from secondary sources prevalence remained remarkably high, throughout the time periods at 14-18%. Taken together, our data indicate that using non-authenticated cell lines from secondary sources carries a risk of about 1:6 for obtaining a false cell line. The use of authentic leukemia-lymphoma cell lines holds important translational value for their model character and the reproducibility of the laboratory data in the clinical arena.

  20. Gene expression profiles in a panel of childhood leukemia cell lines mirror critical features of the disease.

    PubMed

    Kees, Ursula R; Ford, Jette; Watson, Marcia; Murch, Ashleigh; Ringńer, Markus; Walker, Robert L; Meltzer, Paul

    2003-07-01

    The development of new drugs against cancer requires established cell lines. They are needed for in vitro studies to identify candidate drugs and in xenograft models to measure drug efficacy in vivo. Specific criteria need to be fulfilled by cell lines used in the evaluation of potential novel therapeutic agents. It is imperative that they display the features of the particular cancer under investigation. Given the documented heterogeneity of cancers, relevant subtypes need to be represented. In this study, we have examined these aspects for pediatric acute lymphoblastic leukemia. A panel of 13 leukemia cell lines recently established in our laboratory was analyzed. We used cDNA microarrays to define the gene expression profiles and compared the data with immunophenotyping and cytogenetic analyses. The expression profiles obtained showed excellent concordance with corresponding protein levels. Importantly, the panel of lines displayed the critical genetic features identified in clinically important acute lymphoblastic leukemia subtypes in childhood leukemia patients.

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

    PubMed

    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; Sasanuma, Hiroyuki; Takeda, Shunichi; Takaori-Kondo, Akifumi

    2015-04-01

    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 chromosomal DNA of ATL cells. DSBs persisted over time in ATL cells but not in other cell lines, suggesting impaired DNA repair. We found that the reduced expression of tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme, is attributable to the cytotoxic effect of abacavir on ATL cells. We also showed that TDP1 removes abacavir from DNA ends in vitro. These results suggest a model in which ATL cells with reduced TDP1 expression are unable to excise abacavir incorporated into genomic DNA, leading to irreparable DSBs. On the basis of the above mechanism, we propose abacavir as a promising chemotherapeutic agent for ATL.

  2. Evaluation of Manisa propolis effect on leukemia cell line by telomerase activity.

    PubMed

    Gunduz, Cumhur; Biray, Cigir; Kosova, Buket; Yilmaz, Berna; Eroglu, Zuhal; Sahin, Fahri; Omay, Serdar Bedii; Cogulu, Ozgur

    2005-11-01

    Propolis is a resinous substance which is used by bees to repair and maintain their hives. It has more than 180 compounds including flavonoids, phenolic acids and its esters which have anti-inflammatory, antibacterial, antiviral, immunomodulatory, antioxidant and antiproliferative effects. Propolis is shown to inhibit cell division and protein synthesis. However the exact mechanism underlying antitumor effect is not clearly described. On the other hand progressive telomere shortening to a critical level results with senescence of normal cells by inducing apoptosis and telomerase prevents erosion of telomeres. In this study we aimed to evaluate hTERT ratios in propolis-treated T-cell acute lymphoblastic leukemia (CCFR-CEM) cell line. Cell counts and cell viability of propolis-treated and propolis-free T-cell acute lymphoblastic leukemia (CCFR-CEM) cell line were assessed by trypan blue dye exclusion test and MTT assay. The LightCycler instrument was used (online real-time PCR) for the quantification of hTERT in CCFR-CEM cell line. The hTERT ratio significantly decreased 60 and 93% after 24 and 72 h respectively compared to the initial value of the cells incubated with propolis. It had almost no cytotoxic effect and caused 30, 30, 22 and 12% decrease in cell counts after 24, 48, 72 and 96 h respectively which is statistically significant. In conclusion propolis may show antitumor and apoptotic effect via inhibiting telomerase expression besides the mechanisms which have been described previously.

  3. Elicitation Approaches for Withanolide Production in Hairy Root Culture of Withania somnifera (L.) Dunal.

    PubMed

    Sivanandhan, Ganeshan; Selvaraj, Natesan; Ganapathi, Andy; Manickavasagam, Markandan

    2016-01-01

    Withania somnifera (L.) Dunal is a versatile medicinal plant extensively utilized for production of phytochemical drug preparations. The roots and whole plants are traditionally used in Ayurveda, Unani, and Siddha medicines, as well as in homeopathy. Several studies provide evidence for an array of pharmaceutical properties due to the presence of steroidal lactones named "withanolides." A number of research groups have focused their attention on the effects of biotic and abiotic elicitors on withanolide production using cultures of adventitious roots, cell suspensions, shoot suspensions, and hairy roots in large-scale bioreactor for producing withanolides. This chapter explains the detailed procedures for induction and establishment of hairy roots from leaf explants of W. somnifera, proliferation and multiplication of hairy root cultures, estimation of withanolide productivity upon elicitation with salicylic acid and methyl jasmonate, and quantification of major withanolides by HPLC. The protocol herein described could be implemented for large-scale cultivation of hairy root biomass to improve withanolide production.

  4. Inhibiting autophagy potentiates the anticancer activity of IFN1@/IFNα in chronic myeloid leukemia cells.

    PubMed

    Zhu, Shan; Cao, Lizhi; Yu, Yan; Yang, Liangchun; Yang, Minghua; Liu, Ke; Huang, Jun; Kang, Rui; Livesey, Kristen M; Tang, Daolin

    2013-03-01

    IFN1@ (interferon, type 1, cluster, also called IFNα) has been extensively studied as a treatment for patients with chronic myeloid leukemia (CML). The mechanism of anticancer activity of IFN1@ is complex and not well understood. Here, we demonstrate that autophagy, a mechanism of cellular homeostasis for the removal of dysfunctional organelles and proteins, regulates IFN1@-mediated cell death. IFN1@ activated the cellular autophagic machinery in immortalized or primary CML cells. Activation of JAK1-STAT1 and RELA signaling were required for IFN1@-induced expression of BECN1, a key regulator of autophagy. Moreover, pharmacological and genetic inhibition of autophagy enhanced IFN1@-induced apoptosis by activation of the CASP8-BID pathway. Taken together, these findings provide evidence for an important mechanism that links autophagy to immunotherapy in leukemia.

  5. Bcl2 is not required for the development and maintenance of leukemia stem cells in mice

    PubMed Central

    González-Herrero, Inés; Vicente-Dueñas, Carolina; Orfao, Alberto; Flores, Teresa; Jiménez, Rafael; Cobaleda, César; Sánchez-García, Isidro

    2010-01-01

    The existence of leukemia stem cells (LSCs) responsible for tumor maintenance has been firmly established. Therefore, therapeutic targeting of these LSCs may have a profound impact on cancer eradication. The anti-apoptotic protein Bcl2 has been proposed as a therapeutic target, but its role in LSC biology has not been investigated. In order to understand the role of Bcl2 in LSC generation and maintenance, we have taken advantage of our Sca1-BCRABLp210 mouse model of human chronic myeloid leukemia and bcl2 gene-targeted mice. This study provides genetic evidence that the inhibition of Bcl2 is not critical for the generation, selection or maintenance of the tumor initiating and maintaining cells in mice. PMID:20299524

  6. Crystal structures of inhibitor complexes of human T-cell leukemia virus (HTLV-1) protease

    SciTech Connect

    Satoh, Tadashi; Li, Mi; Nguyen, Jeffrey-Tri; Kiso, Yoshiaki; Gustchina, Alla; Wlodawer, Alexander

    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.

  7. Crystal Structures of Inhibitir Complexes of Human T-Cell Leukemia Virus (HTLV-1) Protease

    SciTech Connect

    Satoh, Tadashi; Li, Mi; Nguyen, Jeffrey-Tri; Kiso, Yoshiaki; Gustchina, Alla; Wlodawer, Alexander

    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.

  8. Few-Layer Graphene Kills Selectively Tumor Cells from Myelomonocytic Leukemia Patients.

    PubMed

    Russier, Julie; León, Verónica; Orecchioni, Marco; Hirata, Eri; Virdis, Patrizia; Fozza, Claudio; Sgarrella, Francesco; Cuniberti, Gianaurelio; Prato, Maurizio; Vázquez, Ester; Bianco, Alberto; Delogu, Lucia G

    2017-03-06

    In the cure of cancer, a major cause of today's mortality, chemotherapy is the most common treatment, though serious frequent challenges are encountered by current anticancer drugs. We discovered that few-layer graphene (FLG) dispersions have a specific killer action on monocytes, showing neither toxic nor activation effects on other immune cells. We confirmed the therapeutic application of graphene on an aggressive type of cancer that is myelomonocytic leukemia, where the monocytes are in their malignant form. We demonstrated that graphene has the unique ability to target and boost specifically the necrosis of monocytic cancer cells. Moreover, the comparison between FLG and a common chemotherapeutic drug, etoposide, confirmed the higher specificity and toxicity of FLG. Since current chemotherapy treatments of leukemia still cause serious problems, these findings open the way to new and safer therapeutic approaches.

  9. Cytotoxic Indole Alkaloids against Human Leukemia Cell Lines from the Toxic Plant Peganum harmala

    PubMed Central

    Wang, Chunhua; Zhang, Zhenxue; Wang, Yihai; He, Xiangjiu

    2015-01-01

    Bioactivity-guided fractionation was used to determine the cytotoxic alkaloids from the toxic plant Peganum harmala. Two novel indole alkaloids, together with ten known ones, were isolated and identified. The novel alkaloids were elucidated to be 2-(indol-3-yl)ethyl-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside (2) and 3-hydroxy-3-(N-acetyl-2-aminoethyl)-6-methoxyindol-2-one (3). The cytotoxicity against human leukemia cells was assayed for the alkaloids and some of them showed potent activity. Harmalacidine (compound 8, HMC) exhibited the highest cytotoxicity against U-937 cells with IC50 value of 3.1 ± 0.2 μmol/L. The cytotoxic mechanism of HMC was targeting the mitochondrial and protein tyrosine kinase signaling pathways (PTKs-Ras/Raf/ERK). The results strongly demonstrated that the alkaloids from Peganum harmala could be a promising candidate for the therapy of leukemia. PMID:26540074

  10. Cytotoxic indole alkaloids against human leukemia cell lines from the toxic plant Peganum harmala.

    PubMed

    Wang, Chunhua; Zhang, Zhenxue; Wang, Yihai; He, Xiangjiu

    2015-11-03

    Bioactivity-guided fractionation was used to determine the cytotoxic alkaloids from the toxic plant Peganum harmala. Two novel indole alkaloids, together with ten known ones, were isolated and identified. The novel alkaloids were elucidated to be 2-(indol-3-yl)ethyl-α-L-rhamnopyranosyl-(1 → 6)-β-D-glucopyranoside (2) and 3-hydroxy-3-(N-acetyl-2-aminoethyl)-6-methoxyindol-2-one (3). The cytotoxicity against human leukemia cells was assayed for the alkaloids and some of them showed potent activity. Harmalacidine (compound 8, HMC) exhibited the highest cytotoxicity against U-937 cells with IC50 value of 3.1 ± 0.2 μmol/L. The cytotoxic mechanism of HMC was targeting the mitochondrial and protein tyrosine kinase signaling pathways (PTKs-Ras/Raf/ERK). The results strongly demonstrated that the alkaloids from Peganum harmala could be a promising candidate for the therapy of leukemia.

  11. CopA3 peptide from Copris tripartitus induces apoptosis in human leukemia cells via a caspase-independent pathway.

    PubMed

    Kang, Bo Ram; Kim, Ho; Nam, Sung-Hee; Yun, Eun-Young; Kim, Seong-Ryul; Ahn, Mi-Young; Chang, Jong Soo; Hwang, Jae Sam

    2012-02-01

    Our previous study demonstrated that CopA3, a disulfide dimer of the coprisin peptide analogue (LLCIALRKK), has antibacterial activity. In this study, we assessed whether CopA3 caused cellular toxicity in various mammalian cell lines. CopA3 selectively caused a marked decrease in cell viability in Jurkat T, U937, and AML-2 cells (human leukemia cells), but was not cytotoxic to Caki or Hela cells. Fragmentation of DNA, a marker of apoptosis, was also confirmed in the leukemia cell lines, but not in the other cells. CopA3-induced apoptosis in leukemia cells was mediated by apoptosis inducing factor (AIF), indicating induction of a caspase-independent signaling pathway.

  12. Establishment of mouse leukemia cell lines expressing human CD4/CCR5 using lentiviral vectors.

    PubMed

    Li, Ya-Jing; ZhuGe, Fu-Yan; Zeng, Chang-Chun; He, Jin-Yang; Tan, Ning; Liang, Juan

    2017-04-01

    A low-cost rodent model of HIV infection and which presents high application value is an effective tool to investigate HIV infection and pathogenesis. However, development of such a small animal model has been hampered by the unsuitability of rodent cells for HIV-1 replication given that the retrovirus HIV-1 has high selectivity to its host cell. Our study used the mouse leukemia cell lines L615 and L1210 that were induced by murine leukemia virus and transfected with hCD4/CCR5 loaded-lentiviral vector. Lentiviral vectors containing the genes hCD4/CCR5 under the transcriptional control of cytomegalovirus promoter were designed. Transfection efficiencies of human CD4 and CCR5 in L615 and L1210 cells were analyzed by quantitative real-time polymerase chain reaction (RT-PCR) and Western blot assay. Results showed that hCD4 and CCR5 proteins were expressed on the cell surface, demonstrating that the L615 and L1210 cells were humanized and that they possess the characteristics necessary for HIV infection of human host cells. Moreover, the sensitivity of human CD4/CCR5 transgenic mouse cells to HIV infection was confirmed by RT-PCR and ELISA. Mouse leukemia cell lines that could express hCD4 and CCR5 were thus established to facilitate normal entry of HIV-1 so that a human CD4/CCR5 transgenic mice cell model can be used to investigate the transmission and pathogenesis of HIV/AIDS and potential antiviral drugs against this disease.

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

    PubMed

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

    2013-11-05

    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 < 0.001) in an oxidative stress-dependent fashion via mitochondrial membrane depolarization (52-87%), activation of transcription factor p53 (6.3-25.4%), protease caspase-3 (8.3-20%) and predominance of AIF reactivity (20.6-36%) in all extracts. Similar results were obtained with 0.5 mg/mL extracts. However, extract ≥1 mg/mL concentration induced necrosis (100%). Conclusions: 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.

  14. An animal model of adult T-cell leukemia: humanized mice with HTLV-1-specific immunity.

    PubMed

    Tezuka, Kenta; Xun, Runze; Tei, Mami; Ueno, Takaharu; Tanaka, Masakazu; Takenouchi, Norihiro; Fujisawa, Jun-ichi

    2014-01-16

    Human T-cell leukemia virus type 1 (HTLV-1) is causally associated with adult T-cell leukemia (ATL), an aggressive T-cell malignancy with a poor prognosis. To elucidate ATL pathogenesis in vivo, a variety of animal models have been established; however, the mechanisms driving this disorder remain poorly understood due to deficiencies in each of these animal models. Here, we report a novel HTLV-1-infected humanized mouse model generated by intra-bone marrow injection of human CD133(+) stem cells into NOD/Shi-scid/IL-2Rγc null (NOG) mice (IBMI-huNOG mice). Upon infection, the number of CD4(+) human T cells in the periphery increased rapidly, and atypical lymphocytes with lobulated nuclei resembling ATL-specific flower cells were observed 4 to 5 months after infection. Proliferation was seen in both CD25(-) and CD25(+) CD4 T cells with identical proviral integration sites; however, a limited number of CD25(+)-infected T-cell clones eventually dominated, indicating an association between clonal selection of infected T cells and expression of CD25. Additionally, HTLV-1-specific adaptive immune responses were induced in infected mice and might be involved in the control of HTLV-1-infected cells. Thus, the HTLV-1-infected IBMI-huNOG mouse model successfully recapitulated the development of ATL and may serve as an important tool for investigating in vivo mechanisms of ATL leukemogenesis and evaluating anti-ATL drug and vaccine candidates.

  15. Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis

    PubMed Central

    Contri, Antonella; Brunati, Anna Maria; Trentin, Livio; Cabrelle, Anna; Miorin, Marta; Cesaro, Luca; Pinna, Lorenzo A.; Zambello, Renato; Semenzato, Gianpietro; Donella-Deana, Arianna

    2005-01-01

    B cell chronic lymphocytic leukemia (B-CLL) is a neoplastic disorder characterized by accumulation of B lymphocytes due to uncontrolled growth and resistance to apoptosis. Analysis of B cells freshly isolated from 40 patients with chronic lymphocytic leukemia demonstrated that the Src kinase Lyn, the switch molecule that couples the B cell receptor to downstream signaling, displays anomalous properties. Lyn is remarkably overexpressed at the protein level in leukemic cells as compared with normal B lymphocytes, with a substantial aliquot of the kinase anomalously present in the cytosol. Whereas in normal B lymphocytes Lyn activation is dependent on B cell–receptor stimulation, in resting malignant cells, the constitutive activity of the kinase accounts for high basal protein tyrosine phosphorylation and low responsiveness to IgM ligation. Addition of the Lyn inhibitors PP2 and SU6656 to leukemic cell cultures restores cell apoptosis, and treatment of malignant cells with drugs that induce cell apoptosis decreases both activity and amount of the tyrosine kinase. These findings suggest a direct correlation between high basal Lyn activity and defects in the induction of apoptosis in leukemic cells. They also support a critical role for Lyn in B-CLL pathogenesis and identify this tyrosine kinase as a potential therapeutic target. PMID:15650771

  16. Cytotoxic activity of novel palladium-based compounds on leukemia cell lines.

    PubMed

    Antunovic, Maja; Kriznik, Bojana; Ulukaya, Engin; Yilmaz, Veysel T; Mihalic, Katarina C; Madunic, Josip; Marijanovic, Inga

    2015-02-01

    Effective treatment methods for human leukemia are under development, but so far none of them have been found to be completely satisfactory. It was recently reported that palladium complexes have significant anticancer activity as well as lower toxicity compared with some clinically used chemotherapeutics. The anticancer activities of two novel palladium(II) complexes, [Pd(sac)(terpy)](sac)·4H2O and [PdCl(terpy)](sac)·2H2O, were tested against three human leukemia cell lines, Jurkat, MOLT-4, and THP-1, in comparison with cisplatin and adriamycin. The cytotoxic effect of the drugs was determined using the MTT assay. Cell death was assessed using fluorescein isothiocyanate-annexin/propidium iodide staining for flow cytometry. Furthermore, p53 phosphorylation, poly(ADP-ribose) polymerase cleavage, and Bax and Bcl-2 mRNA levels were examined to elucidate the mechanism of cell death induction. Both complexes exhibited a significant dose-dependent antigrowth effect in vitro. The complexes predominately induced apoptosis, but necrosis was also observed. In-vitro results have shown that palladium(II) complexes may be regarded as potential anticancer agents for treating human leukemia. Therefore, further analysis to determine the putative mechanism of action and in-vivo studies on animal models are warranted.

  17. Adult T-Cell Leukemia/Lymphoma (HTLV-1)

    MedlinePlus

    ... gentic material made of DNA, but instead carry RNA. These viruses selectively infect only T-cells. Only ... potential to inject its genetic material (DNA or RNA) into normal cells. Once inside the normal cells, ...

  18. The FOXM1 transcriptional factor promotes the proliferation of leukemia cells through modulation of cell cycle progression in acute myeloid leukemia.

    PubMed

    Nakamura, Satoki; Hirano, Isao; Okinaka, Keiji; Takemura, Tomonari; Yokota, Daisuke; Ono, Takaaki; Shigeno, Kazuyuki; Shibata, Kiyoshi; Fujisawa, Shinya; Ohnishi, Kazunori

    2010-11-01

    FOXM1 is an important cell cycle regulator and regulates cell proliferation. In addition, FOXM1 has been reported to contribute to oncogenesis in various cancers. However, it is not clearly understood how FOXM1 contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of FOXM1 in AML cells. The FOXM1 messenger RNA (mRNA) expressed in AML cell lines was predominantly the FOXM1B isoform, and its levels were significantly higher than in normal high aldehyde dehydrogenase activity (ALDH(hi)) cells. Reduction of FOXM1 expression in AML cells inhibited cell proliferation compared with control cells, through induction of G(2)/M cell cycle arrest, a decrease in the protein expression of Aurora kinase B, Survivin, Cyclin B1, S-phase kinase-associated protein 2 and Cdc25B and an increase in the protein expression of p21(Cip1) and p27(Kip1). FOXM1 messenger RNA (mRNA) was overexpressed in all 127 AML clinical specimens tested (n = 21, 56, 32 and 18 for M1, M2, M4 and M5 subtypes, respectively). Compared with normal ALDH(hi) cells, FOXM1 gene expression was 1.65- to 2.26-fold higher in AML cells. Moreover, the FOXM1 protein was more strongly expressed in AML-derived ALDH(hi) cells compared with normal ALDH(hi) cells. In addition, depletion of FOXM1 reduced colony formation of AML-derived ALDH(hi) cells due to inhibition of Cdc25B and Cyclin B1 expression. In summary, we found that FOXM1B mRNA is predominantly expressed in AML cells and that aberrant expression of FOXM1 induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of FOXM1 expression represents an attractive target for AML therapy.

  19. [Induction of polyploid hairy roots and its plant regeneration in Pogostemon cablin].

    PubMed

    Shi, Heping; Yu, Wu; Zhang, Guopeng; Tsang, Pokeung Eric; Chow, Cheuk Fai Stephen

    2014-08-01

    Abstract: In order to enhance the content of secondary metabolites patchouli alcohol in Pogostemon cablin, we induced polyploid hairy roots and their plant regeneration, and determined the content of patchouli alcohol through artificial chromosome doubling with colchicine. The highest rate of polyploidy induction was more than 40% when hairy roots were treated with 0.05% colchicine for 36 h. The obtained polyploid hairy roots formed adventitious shoots when cultured in an MS medium with 6-BA 0.2 mg/L and NAA 0.1 mg/L for 60 d. Compared with the control diploid plants, the polyploid hairy root-regenerated plants of P. cablin had more developed root systems, thicker stems, shorter internodes and longer, wider and thicker leaves. Observation of the chromosome number in their root tip cells reveals that the obtained polyploid regenerated plants were tetraploidy, with 128 (4n = 128) chromosomes. The leaves contained around twice as many stomatal guard cells and chloroplasts as the controls, but the stomatal density declined with increasing ploidy. The stomatal density in diploid plants was around 1.67 times of that in polyploid plants. GC-MS analysis shows that the content of patchouli alcholol in the hairy root-derived polyploid plants was about 4.25 mg/g dry weight, which was 2.3 times of that in diploid plants. The present study demonstrates that polyploidization of hairy roots can stimulate the content of patchouli alcholol in medicinal plant of P. cablin.

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

    PubMed Central

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

    2010-01-01

    Two main NF-κB signaling pathways, canonical and noncanonical, performing distinct functions in organisms have been characterized. Identification of mutations in genes encoding components of these NF-κB signaling pathways in lymphoid malignancies confirmed their key role in leukemogenesis. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes that despite significant therapeutic advances can still be fatal. Although mutations in NF-κB genes have not been reported in T-ALL, NF-κB constitutive activation in human T-ALL and in acute T-cell leukemia mouse models has been observed. Although these studies revealed activation of members of both canonical and noncanonical NF-κB pathways in acute T-cell leukemia, only inhibition of canonical NF-κB signaling was shown to impair leukemic T cell growth. Besides playing an important pro-oncogenic role in leukemic T cells, NF-κB signaling also appears to modulate T-cell leukemogenesis through its action in microenvironmental stromal cells. This article reviews recent data on the role of these transcription factors in T-ALL and pinpoints further research crucial to determine the value of NF-κB inhibition as a means to treat T-ALL. PMID:24281204

  1. Pycnogenol induces differentiation and apoptosis in human promyeloid leukemia HL-60 cells.

    PubMed

    Huang, W W; Yang, J S; Lin, C F; Ho, W J; Lee, M R

    2005-06-01

    Pycnogenol, rich of many phytochemicals of medical value, is a commercialized nutrient supplement extracted from the bark of European coastal pine. In this study, we investigated the anti-tumor effects of Pycnogenol on HL-60, U937 and K562 human leukemia cell lines. We found that Pycnogenol inhibited cell proliferation dose- and time-dependently, and the IC(50)s of Pycnogenol on HL-60, U937 and K562 cells were 150, 40 and 100 microg/ml, respectively. When HL-60 cells were incubated with low concentrations of Pycnogenol (50, 100 and 125 microg/ml) for 24 h, a prominent G0/G1 arrest was observed, followed by gradual accumulation of sub-G0/G1 nuclei. At 48 h of treatment, 50-70% of HL-60 cells differentiated, as evidenced by morphological changes, NBT reduction, induction of NSE activity, and increases of cell surface expression of CD11b. However, results from Annexin V/PI staining, DAPI staining and DNA fragmentation assay indicated that Pycnogenol induced HL-60, U937 and K562 cell apoptosis at their respective IC(50)s after 24 h of treatments. Pretreatment of z-DEVD-fmk, a caspase-3 specific inhibitor, not only decreased caspase-3 activity but also reduced the percentage of apoptotic cells induced by Pycnogenol. This indicated that caspase-3 activation was involved in Pycnogenol induced-apoptosis. In conclusion, Pycnogenol induced differentiation and apoptosis in leukemia cells. Our data suggest that Pycnogenol could serve as a potent cancer chemopreventive or chemotherapeutic agent for human leukemia.

  2. Interleukin-34 induces monocytic-like differentiation in leukemia cell lines.

    PubMed

    Booker, Burthia E; Clark, Ryan S; Pellom, Samuel T; Adunyah, Samuel E

    2015-01-01

    Interleukin-34 (IL-34) is a cytokine consisting of a 39kD homodimer, shown to be a ligand for both the Macrophage Colony Stimulating Factor (M-CSF/CSF-1) receptor and the Receptor-like protein tyrosine phosphatase-zeta (RPTP-ƺ). IL-34 has been shown to promote monocyte viability and proliferation as well as the differentiation of bone marrow cells into macrophage progenitors. Published work on IL-34 involves its effects on normal hematopoietic and osteoclast progenitors. However, it is not known whether IL-34 has biologic effects in cancer, including leukemia. Here we report that the biological effects of IL-34 include induction of differential expression of Interleukins-1α and -1β as well as induction of differentiation of U937, HL-60 and THP-1 leukemia cell lines demonstrating monocyte-like characteristics. The ability of IL-34 to induce monocytic-like differentiation is supported by strong morphological and functional evidence. Cell surface markers of myeloid lineage, CD64 and CD86, remain constant while the levels of CD11b and CD71 decline with IL-34 treatment. IL-34 also induced increases in CD14 and CD68 expression, further supporting maturation toward monocytic character. IL-34-induced differentiated U937 and THP-1 cell lines exhibited biological functions such as endocytosis and respiratory burst activities. Collectively, we conclude that while IL-34 does not induce cell growth or proliferation, it is able to induce differentiation of leukemia cell lines from monoblastic precursor cells towards monocyte- and macrophage-like cells, mediated through the JAK/STAT and PI3K/Akt pathways. To our knowledge, this is the first report that IL-34 induces differentiation in human leukemic cells, let alone any cancer model.

  3. Improving Therapy of Chronic Lymphocytic Leukemia (CLL) with Chimeric Antigen Receptor (CAR) T Cells

    PubMed Central

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

    2016-01-01

    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 re-directing 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

  4. PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL)

    PubMed Central

    Okkenhaug, Klaus; Burger, Jan A.

    2016-01-01

    B cells provide immunity to extracellular pathogens by secreting a diverse repertoire of antibodies with high affinity and specificity for exposed antigens. The B cell receptor (BCR) is a transmembrane antibody, which facilitates the clonal selection of B cells producing secreted antibodies of the same specificity. The diverse antibody repertoire is generated by V(D)J recombination of heavy and light chain genes, whereas affinity maturation is mediated by activation-induced cytidine deaminase (AID)-mediated mutagenesis. These processes, which are essential for the generation of adaptive humoral immunity, also render B cells susceptible to chromosomal rearrangements and point mutations that in some cases lead to cancer. In this chapter, we will review the central role of PI3Ks in mediating signals from the B cell receptor that not only facilitate the development of functional B cell repertoire, but also support the growth and survival of neoplastic B cells, focusing on chronic lymphocytic leukemia (CLL) B cells. Perhaps because of the central role played by PI3K in BCR signaling, B cell leukemia and lymphomas are the first diseases for which a PI3K inhibitor has been approved for clinical use. PMID:26350103

  5. Ibrutinib Therapy Increases T Cell Repertoire Diversity in Patients with Chronic Lymphocytic Leukemia.

    PubMed

    Yin, Qingsong; Sivina, Mariela; Robins, Harlan; Yusko, Erik; Vignali, Marissa; O'Brien, Susan; Keating, Michael J; Ferrajoli, Alessandra; Estrov, Zeev; Jain, Nitin; Wierda, William G; Burger, Jan A

    2017-02-15

    The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy. We noted elevated CD4(+) and CD8(+) T cell numbers and a restricted TCRβ repertoire in all pretreatment samples. After 1 y of ibrutinib therapy, elevated peripheral blood T cell numbers and T cell-related cytokine levels had normalized, and T cell repertoire diversity increased significantly. Dominant TCRβ clones in pretreatment samples declined or became undetectable, and the number of productive unique clones increased significantly during ibrutinib therapy, with the emergence of large numbers of low-frequency TCRβ clones. Importantly, broader TCR repertoire diversity was associated with clinical efficacy and lower rates of infections during ibrutinib therapy. These data demonstrate that ibrutinib therapy increases diversification of the T cell compartment in CLL patients, which contributes to cellular immune reconstitution.

  6. Monoclonal antibody therapy directed against human acute myeloid leukemia stem cells.

    PubMed

    Majeti, R

    2011-03-03

    Accumulating evidence indicates that many human cancers are organized as a cellular hierarchy initiated and maintained by self-renewing cancer stem cells. This cancer stem cell model has been most conclusively established for human acute myeloid leukemia (AML), although controversies still exist regarding the identity of human AML stem cells (leukemia stem cell (LSC)). A major implication of this model is that, in order to eradicate the cancer and cure the patient, the cancer stem cells must be eliminated. Monoclonal antibodies have emerged as effective targeted therapies for the treatment of a number of human malignancies and, given their target antigen specificity and generally minimal toxicity, are well positioned as cancer stem cell-targeting therapies. One strategy for the development of monoclonal antibodies targeting human AML stem cells involves first identifying cell surface antigens preferentially expressed on AML LSC compared with normal hematopoietic stem cells. In recent years, a number of such antigens have been identified, including CD123, CD44, CLL-1, CD96, CD47, CD32, and CD25. Moreover, monoclonal antibodies targeting CD44, CD123, and CD47 have demonstrated efficacy against AML LSC in xenotransplantation models. Hopefully, these antibodies will ultimately prove to be effective in the treatment of human AML.

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

    PubMed

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

    2015-12-22

    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 < 0.05) increase of necrotic cell death in Pb(NO₃)₂-treated cells, indicative of membrane 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

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

    PubMed Central

    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 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(NO3)2-treated cells, indicative of membrane 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

  9. Flow cytometric analysis of hemetopoietic progenitor cells in peripheral blood stem cell harvest from patients with CD34 positive acute leukemia.

    PubMed

    Miyazaki, T; Matsuda, I; Oguri, M; Amaya, H; Kiyosaki, M; Hamada, A; Tamaki, S; Tashiro, E; Kudo, Y; Taniguchi, O; Nakamura, T; Tomoyasu, S

    2001-01-01

    We analyzed CD34 positive cells in peripheral blood stem cell harvest (PBSCH) using flow cytometry. PBSCH from CD34 positive acute myelogeous leukemia (AML-M2) patient contained 1.87% CD34 positive cells, of which 1.21% was represented by MRD.PBSCH from CD34 positive acute lymphoblast leukemia (ALL) patient contained 3.14% CD34 positive cells, of which 0.11% was accounted for by minimal residual disease (MRD). If PBSCH from CD34 positive acute leukemia patient is analyzed for CD34 monoclonal antibody alone, the presence of CD34 positive MRD may escape attention so that CD34 positive hematopoietic progenitor cells may be overestimated. To avoid this risk, it is necessary to analyze PBSCH using both CD34 monoclonal antibody and characteristic markers of leukemia cells that were found pre-treatment.

  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

    ClinicalTrials.gov

    2017-01-06

    B-Cell Prolymphocytic Leukemia; Hypodiploidy; Loss of Chromosome 17p; 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(14;16); t(4;14); T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia

  11. Small Cell Variant of T-Cell Prolymphocytic Leukemia with Acquired Palmoplantar Keratoderma and Cutaneous Infiltration.

    PubMed

    Al-Musalhi, Buthaina; Shehata, Nancy; Billick, Robin

    2016-01-01

    T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive post-thymic malignancy that is characterized by the proliferation of small- to medium- sized prolymphocytes. The classic clinical features of T-PLL are lymphocytosis, lymphadenopathy, hepatosplenomegaly, and skin lesions. Skin involvement varies clinically from diffuse infiltrated erythema. Infiltration is localized to the face and ears, nodules, and erythroderma. We present a case of small cell variant of T-PLL in a patient who presented with unusual cutaneous manifestations of acquired palmoplantar keratoderma (PPK) followed by diffuse erythematous infiltrated papules and plaques involving the trunk. When the etiology of acquired PPK is not clear, the physician should consider the possibility of an underlying malignant disease. In this case, the diagnosis of T-PLL was subsequently confirmed by laboratory and cytological findings, as well as by the immunophenotyping of leukemic cells in skin biopsy. Since paraneoplastic acquired PPK may be the initial evident sign of malignancy, the physician's awareness of this manifestation may be crucial for early diagnosis and treatment. Our case emphasizes the importance of accurate evaluation of skin lesions and early skin biopsy in the diagnosis of some hematological malignancies.

  12. Cutaneous manifestations of human T cell leukemia virus type I infection in an experimental model.

    PubMed

    Simpson, R M; Leno, M; Hubbard, B S; Kindt, T J

    1996-03-01

    Skin diseases ranging from infective dermatitis to cutaneous lymphoma have been associated with human T cell leukemia virus (HTLV) type I. A generalized exfoliative papillated dermatopathy occurred in a rabbit 20 months into a course of chronic HTLV-I infection. Biopsies revealed epidermotropic T cell infiltrates, including Sezary-like cells, that resulted in a pattern mimicking cutaneous T cell lymphoma. HTLV-I was isolated from affected skin, and virus expression was detected in cutaneous cultures. Sezary-like cells also occurred in circulation. Interleukin-2-independent lymphocyte cultures, established from blood exhibiting elevated CD8 T cell levels and CD25 expression, had polyclonal integration of provirus. The findings are similar to those in evolving adult T cell leukemia lymphoma and may represent a prelymphomatous change. The cutaneous lymphoproliferative lesion resulted from HTLV-I infection and further establishes the New Zealand White rabbit inoculated with the RH/K34 cell line as a suitable model for investigation of HTLV-I pathogenesis.

  13. Induction of Apoptosis in Human Leukemia Cells by Grape Seed Extract Occurs via Activation of JNK

    PubMed Central

    Gao, Ning; Budhraja, Amit; Cheng, Senping; Yao, Hua; Zhang, Zhuo; Shi, Xianglin

    2009-01-01

    Purpose To characterize the functional role of JNK and other apoptotic pathways in grape seed extract (GSE)-induced apoptosis in human leukemia cells by using pharmacologic and genetic approaches. Experimental Design Jurkat cells were treated with various concentrations of GSE for 12 h and 24 h, or with 50 μg/ml of GSE for various time intervals, after which apoptosis, caspase activation, and cell signaling pathways were evaluated. Parallel studies were performed in U937 and HL-60 human leukemia cells. Results Exposure of Jurkat cells to GSE resulted in dose- and time-dependent increase in apoptosis and caspase activation, events associated with the pronounced increase in Cip1/p21 protein level. Furthermore, treatment of Jurkat cells with GSE resulted in marked increase in levels of phospho-JNK. Conversely, interruption of the JNK pathway by pharmacological inhibitor (e.g. SP600125) or genetic (e.g. siRNA) approaches displayed significant protection against GSE mediated lethality in Jurkat cells. Conclusions The result of the present study showed that GSE induces apoptosis in Jurkat cells through a process that involves sustained JNK activation and Cip1/p21 up-regulation, culminating in caspase activation. PMID:19118041

  14. Tonsillar mapping of determinants found on normal lymphoreticular (T,B,K, immature and macrophage) and myeloblastic leukemia cells.

    PubMed Central

    McMillan, E. M.; Stoneking, L.; Humphrey, G. B.; Rapacz, J.

    1987-01-01

    A monoclonal immunocytochemical method with 25 monoclonal antibodies was used to study the distribution in human tonsil of determinants expressed on T cells (mature and immature), Langerhans cells, B cells, killer/natural killer cells, macrophages, immature myeloid and lymphoblastic leukemia cells. Many of the respective determinants were found to have a discrete topographic distribution in normal reactive tonsil. The common acute lymphoblastic leukemia antigen and a determinant found on myeloblastic leukemia cells (My10) were not found in the specimens of the tonsil examined. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 PMID:2435159

  15. Chronic T-cell Lymphocytic Leukemia in a Black Swan ( Cygnus atratus ): Diagnosis, Treatment, and Pathology.

    PubMed

    Sinclair, Kristin M; Hawkins, Michelle G; Wright, Lewis; Chin, Richard P; Owens, Sean D; Guzman, David Sanchez-Migallon; Kent, Michael S; BVSc, H L Shivaprasad

    2015-12-01

    An asymptomatic 14-year old, male black swan ( Cygnus atratus ) housed at a zoological institution was presented for routine preshipment examination. Hematologic findings indicated that the bird had a severe lymphocytic leukocytosis, consistent with chronic lymphocytic leukemia. Radiographs showed the presence of multiple soft tissue masses within the caudal coelomic cavity; ultrasound showed one mass to be an enlarged spleen, a cystic mass near the gonads, and a mass suspected to be associated with the ventriculus. Results of further antemortem diagnostics, including bone marrow aspiration, fine-needle aspirate cytology of the coelomic masses, and immunohistochemical staining confirmed T-cell leukemia with infiltration of the bone marrow and the spleen. The bird showed partial response to treatment with chlorambucil, lomustine, prednisone, l-asparaginase, and whole-body radiation, with neither evidence of adverse effects nor clinical signs of disease. Although the leukemia showed response, there was no evidence of remission at any point. The swan died 433 days after initial evaluation and initiation of therapy. Necropsy, histopathologic findings, and immunohistochemistry results confirmed extensive infiltration of multiple organs, including the liver, spleen, heart, lungs, and kidneys with neoplastic T-cell lymphocytes.

  16. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia.

    PubMed

    Thompson, Benjamin J; Buonamici, Silvia; Sulis, Maria Luisa; Palomero, Teresa; Vilimas, Tomas; Basso, Giuseppe; Ferrando, Adolfo; Aifantis, Iannis

    2007-08-06

    Recent studies have shown that activating mutations of NOTCH1 are responsible for the majority of T cell acute lymphoblastic leukemia (T-ALL) cases. Most of these mutations truncate its C-terminal domain, a region that is important for the NOTCH1 proteasome-mediated degradation. We report that the E3 ligase FBW7 targets NOTCH1 for ubiquitination and degradation. Our studies map in detail the amino acid degron sequence required for NOTCH1-FBW7 interaction. Furthermore, we identify inactivating FBW7 mutations in a large fraction of human T-ALL lines and primary leukemias. These mutations abrogate the binding of FBW7 not only to NOTCH1 but also to the two other characterized targets, c-Myc and cyclin E. The majority of the FBW7 mutations were present during relapse, and they were associated with NOTCH1 HD mutations. Interestingly, most of the T-ALL lines harboring FBW7 mutations were resistant to gamma-secretase inhibitor treatment and this resistance appeared to be related to the stabilization of the c-Myc protein. Our data suggest that FBW7 is a novel tumor suppressor in T cell leukemia, and implicate the loss of FBW7 function as a potential mechanism of drug resistance in T-ALL.

  17. Kinetics of indium-111-labeled leukemic cells in patients with acute non-lymphocytic leukemia

    SciTech Connect

    Suzuki, Y.; Yamauchi, K.

    1984-01-01

    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.

  18. Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis

    PubMed Central

    Gausdal, G; Wergeland, A; Skavland, J; Nguyen, E; Pendino, F; Rouhee, N; McCormack, E; Herfindal, L; Kleppe, R; Havemann, U; Schwede, F; Bruserud, Ø; Gjertsen, B T; Lanotte, M; Ségal-Bendirdjian, E; Døskeland, S O

    2013-01-01

    We show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti-leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB. Either event would be expected to protect broadly against cell death, and we found cAMP elevation to protect also against 2-deoxyglucose, rotenone, proteasome inhibitor and a BH3-only mimetic. The in vitro findings were mirrored by the findings in NSG mice with orthotopic NB4 cell leukemia. The mice showed more rapid disease progression when given cAMP-increasing agents (prostaglandin E2 analog and theophylline), both with and without DNR chemotherapy. The all-trans retinoic acid (ATRA)-induced terminal APL cell differentiation is a cornerstone in current APL treatment and is enhanced by cAMP. We show also that ATRA-resistant APL cells, believed to be responsible for treatment failure with current ATRA-based treatment protocols, were protected by cAMP against death. This suggests that the beneficial pro-differentiating and non-beneficial pro-survival APL cell effects of cAMP should be weighed against each other. The results suggest also general awareness toward drugs that can affect bone marrow cAMP levels in leukemia patients. PMID:23449452

  19. Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis.

    PubMed

    Gausdal, G; Wergeland, A; Skavland, J; Nguyen, E; Pendino, F; Rouhee, N; McCormack, E; Herfindal, L; Kleppe, R; Havemann, U; Schwede, F; Bruserud, O; Gjertsen, B T; Lanotte, M; Ségal-Bendirdjian, E; Døskeland, S O

    2013-02-28

    We show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti-leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB. Either event would be expected to protect broadly against cell death, and we found cAMP elevation to protect also against 2-deoxyglucose, rotenone, proteasome inhibitor and a BH3-only mimetic. The in vitro findings were mirrored by the findings in NSG mice with orthotopic NB4 cell leukemia. The mice showed more rapid disease progression when given cAMP-increasing agents (prostaglandin E2 analog and theophylline), both with and without DNR chemotherapy. The all-trans retinoic acid (ATRA)-induced terminal APL cell differentiation is a cornerstone in current APL treatment and is enhanced by cAMP. We show also that ATRA-resistant APL cells, believed to be responsible for treatment failure with current ATRA-based treatment protocols, were protected by cAMP against death. This suggests that the beneficial pro-differentiating and non-beneficial pro-survival APL cell effects of cAMP should be weighed against each other. The results suggest also general awareness toward drugs that can affect bone marrow cAMP levels in leukemia patients.

  20. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia

    PubMed Central

    Fraietta, Joseph A.; Beckwith, Kyle A.; Patel, Prachi R.; Ruella, Marco; Zheng, Zhaohui; Barrett, David M.; Lacey, Simon F.; Melenhorst, Jan Joseph; McGettigan, Shannon E.; Cook, Danielle R.; Zhang, Changfeng; Xu, Jun; Do, Priscilla; Hulitt, Jessica; Kudchodkar, Sagar B.; Cogdill, Alexandria P.; Gill, Saar; Porter, David L.; Woyach, Jennifer A.; Long, Meixiao; Johnson, Amy J.; Maddocks, Kami; Muthusamy, Natarajan; Levine, Bruce L.; June, Carl H.; Byrd, John C.

    2016-01-01

    Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is highly promising but requires robust T-cell expansion and engraftment. A T-cell defect in chronic lymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivo expansion and response to CAR T cells. To evaluate the effect of ibrutinib treatment on the T-cell compartment in CLL as it relates to CAR T-cell generation, we examined the phenotype and function of T cells in a cohort of CLL patients during their course of treatment with ibrutinib. We found that ≥5 cycles of ibrutinib therapy improved the expansion of CD19-directed CAR T cells (CTL019), in association with decreased expression of the immunosuppressive molecule programmed cell death 1 on T cells and of CD200 on B-CLL cells. In support of these findings, we observed that 3 CLL patients who had been treated with ibrutinib for ≥1 year at the time of T-cell collection had improved ex vivo and in vivo CTL019 expansion, which correlated positively together and with clinical response. Lastly, we show that ibrutinib exposure does not impair CAR T-cell function in vitro but does improve CAR T-cell engraftment, tumor clearance, and survival in human xenograft models of resistant acute lymphocytic leukemia and CLL when administered concurrently. Our collective findings indicate that ibrutinib enhances CAR T-cell function and suggest that clinical trials with combination therapy are warranted. Our studies demonstrate that improved T-cell function may also contribute to the efficacy of ibrutinib in CLL. These trials were registered at www.clinicaltrials.gov as #NCT01747486, #NCT01105247, and #NCT01217749. PMID:26813675

  1. Antibody-directed double suicide gene therapy targeting of MUC1- positive leukemia cells in vitro and in vivo.

    PubMed

    Dong, Xiao-Ya; Wang, Wen-Qian; Zhao, Yu; Li, Xu-Dong; Fang, Zhi-Gang; Lin, Dong-Jun; Xiao, Ruo-Zhi; Huang, Ren-Wei; Pan, Guang-Jin; Liu, Jia-Jun

    2013-10-01

    Our aim was to specifically transfer the cytosine deaminase (CD) and thymidine kinase (TK) genes into mucin 1 (MUC1)-positive leukemia cells by anti-MUC1 antibody directed infection of replication-defective lentivirus and to evaluate the targeted cytotoxicity of double suicide genes to leukemia. The target gene vector (containing CD and TK) and envelope (containing GFP and anti-MUC1) and packaging plasmids were cotransfected into 293T cells to produce the recombinant lentivirus. Suicide genes in virus-infected leukemia cells (U937, Jurkat, and K562) were detected by western blot. The cytotoxicity and bystander effect in vitro and the therapeutic effect in vivo were detected after treatment with the prodrugs. The results revealed that combined treatment with prodrug 5-fluorocytosine (5-FC) and ganciclovir (GCV) inhibited leukemia cell growth and caused significant bystander effect than treatment with either prodrug alone. TK/GCV treatment alone induced degeneration and cell death while the effect of CD/5-FC alone mainly caused vacuolar degeneration and necrosis. The addictive effects of combinatorial use of GCV and 5-FC mainly induced swelling of the mitochondria followed by necrosis of the leukemia cells. In vivo experiments revealed that both single and combinatorial prodrug treatments could prolong the survival time of leukemic mice. In summary, anti-MUC1 antibody directed lentiviral vector successfully transduced dual suicide genes and exerted targeted cytotoxicity against MUC1 positive leukemia cells. This targeted lentiviral dual suicide gene delivering system provides a promising approach for clinical treatment of leukemia in future.

  2. PEITC in End-Stage B-Cell Prolymphocytic Leukemia: Case Report of Possible Sensitization to Salvage R-CHOP

    PubMed Central

    Nachat, Arian; Turoff-Ortmeyer, Sam; Liu, Chunnan; McCulloch, Michael

    2016-01-01

    Introduction: B-cell prolymphocytic leukemia (B-PLL) is a rare, aggressive leukemia distinct from chronic lymphocytic leukemia, with median survival of only 3 years. B-PLL is resistant to most chemotherapy and newer targeted therapies such as alemtuzumab and thalidomide. Phenylethyl isothiocyanate (PEITC) is a natural compound from horseradish with evidence for therapeutic potential in multiple leukemia types. Case Presentation: Here we present a case report of a 53-year-old man whose chronic lymphocytic leukemia transformed to end-stage B-PLL, disqualifying him for allogenic stem cell transplantation. He was treated with PEITC followed by salvage R-CHOP (Rituximab, Cyclophosphamide, Hydroxydaunorubicin [doxorubicin hydrochloride], Oncovin [vincristine sulfate], Prednisone or Prednisolone) chemotherapy, which led to normalized white blood cell count and disease stabilization that requalified him for allogenic peripheral stem-cell transplant therapy. We conducted a systematic review to analyze and interpret the potential contribution of PEITC to his unexpectedly favorable R-CHOP response. Following sequential 8 weeks of PEITC/pentostatin and 6 cycles of R-CHOP, the patient received allogenic peripheral blood stem cell transplant on an outpatient basis and remains well at the time of this publication, with no evidence of CD20+ small B-cells. Discussion: Given the limited data for R-CHOP in B-PLL, this patient’s recovery suggests presensitization of B-PLL cells toward R-CHOP, potentially justifying further investigation. PMID:27168399

  3. Hyoscyamine biosynthesis in Datura stramonium hairy root in vitro systems with different ploidy levels.

    PubMed

    Pavlov, A; Berkov, S; Weber, J; Bley, Th

    2009-05-01

    Hyoscyamine biosynthesis in Datura stramonium hairy roots with different ploidy levels was investigated. For the first time, we report that hairy roots undergo endoreduplication and therefore consist mainly of cells with doupled sets of chromosomes of primary plant tissues, used for Agrobacterium transformation. The alkaloid profiles of hairy roots obtained from diploid and tetraploid plants were similar in terms of the major compounds, but they differed significantly with respect to the minor compounds (here defined as those that accounted for <1% of the total ion current of the alkaloid mixture in gas chromatography-mass spectrometric analyses). Significant differences in the effects of the main nutrients on the growth of the hairy roots obtained from diploid and tetraploid plants and their hyoscyamine contents were observed. The maximal yield of hyoscyamine (177 mg/L) was obtained when hairy roots from tetraploid plants were cultivated in Murashige-Skoog nutrient medium supplemented with 6% sucrose. Time courses of utilization of the main nutrients in the medium during cultivation of D. stramonium hairy root cultures are also presented.

  4. Deregulated Levels of the NF-κB1, NF-κB2, and Rel Genes in Ukrainian Patients with Leukemia and Lymphoma in the Post-Chernobyl Period

    PubMed Central

    Savlı, Hakan; Akkoyunlu, Ramis Ufuk; Çine, Naci; Gluzman, Daniil F.; Zavelevich, Michael P.; Sklyarenko, Lilia M.; Koval, Stella V.; Sünnetçi, Deniz

    2016-01-01

    Objective: Nuclear factor kappa B (NF-κB) is an important transcription factor in cancer and NF-κB activation has been seen in angiogenesis, tumor progression, and metastasis. Relationships between specific NF-κB gene networks, leukemogenesis, and radiation exposure are still unknown. Our aim was to study the expression levels of the NF-κB1, NF-κB2, and Rel genes in hematological malignancies in the post-Chernobyl period. Materials and Methods: We analyzed gene expression levels of NF-κB1, NF-κB2, and Rel in 49 B-cell chronic lymphocytic leukemia, 8 B-cell non-Hodgkin’s lymphoma, 3 acute myeloid leukemia, 3 chronic myeloid leukemia, 2 hairy cell leukemia, 2 myelodysplastic syndrome, and 2 T-cell large granular lymphocytic leukemia patients using real-time polymerase chain reaction. Results: Expression levels of NF-κB1, NF-κB2, and Rel genes were found to be deregulated. Conclusion: These results could be accepted as specific gene traces to radiation-induced leukemia or as potential candidates for new diagnostic biomarker studies. Larger experiments and non-exposed control malignant cell populations are needed to clarify these suggestions. PMID:25912249

  5. G2/M Cell Cycle Arrest and Tumor Selective Apoptosis of Acute Leukemia Cells by a Promising Benzophenone Thiosemicarbazone Compound

    PubMed Central

    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

  6. Kv3.4 potassium channel-mediated electrosignaling controls cell cycle and survival of irradiated leukemia cells.

    PubMed

    Palme, Daniela; Misovic, Milan; Schmid, Evi; Klumpp, Dominik; Salih, Helmut R; Rudner, Justine; Huber, Stephan M

    2013-08-01

    Aberrant ion channel expression in the plasma membrane is characteristic for many tumor entities and has been attributed to neoplastic transformation, tumor progression, metastasis, and therapy resistance. The present study aimed to define the function of these "oncogenic" channels for radioresistance of leukemia cells. Chronic myeloid leukemia cells were irradiated (0-6 Gy X ray), ion channel expression and activity, Ca(2+)- and protein signaling, cell cycle progression, and cell survival were assessed by quantitative reverse transcriptase-polymerase chain reaction, patch-clamp recording, fura-2 Ca(2+)-imaging, immunoblotting, flow cytometry, and clonogenic survival assays, respectively. Ionizing radiation-induced G2/M arrest was preceded by activation of Kv3.4-like voltage-gated potassium channels. Channel activation in turn resulted in enhanced Ca(2+) entry and subsequent activation of Ca(2+)/calmodulin-dependent kinase-II, and inactivation of the phosphatase cdc25B and the cyclin-dependent kinase cdc2. Accordingly, channel inhibition by tetraethylammonium and blood-depressing substance-1 and substance-2 or downregulation by RNA interference led to release from radiation-induced G2/M arrest, increased apoptosis, and decreased clonogenic survival. Together, these findings indicate the functional significance of voltage-gated K(+) channels for the radioresistance of myeloid leukemia cells.

  7. Xenotransplantation elicits salient tumorigenicity of adult T-cell leukemia-derived cells via aberrant AKT activation.

    PubMed

    Yamaguchi, Kazunori; Takanashi, Tomoka; Nasu, Kentaro; Tamai, Keiichi; Mochizuki, Mai; Satoh, Ikuro; Ine, Shoji; Sasaki, Osamu; Satoh, Kennichi; Tanaka, Nobuyuki; Harigae, Hideo; Sugamura, Kazuo

    2016-05-01

    The transplantation of human cancer cells into immunodeficient NOD/SCID/IL-2Rγc(null) (NOG) mice often causes highly malignant cell populations like cancer stem cells to emerge. Here, by serial transplantation in NOG mice, we established two highly tumorigenic adult T-cell leukemia-derived cell lines, ST1-N6 and TL-Om1-N8. When transplanted s.c., these cells formed tumors significantly earlier and from fewer initial cells than their parental lines ST1 and TL-Om1. We found that protein kinase B (AKT) signaling was upregulated in ST1-N6 and TL-Om1-N8 cells, and that this upregulation was due to the decreased expression of a negative regulator, INPP5D. Furthermore, the introduction of a constitutively active AKT mutant expression vector into ST1 cells augmented the tumorigenicity of the cells, whereas treatment with the AKT inhibitor MK-2206 attenuated the progression of tumors induced by ST1-N6 cells. Collectively, our results reveal that the AKT signaling pathway plays a critical role in the malignancy of adult T-cell leukemia-derived cells.

  8. The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro.

    PubMed

    Steele, A J; Jones, D T; Ganeshaguru, K; Duke, V M; Yogashangary, B C; North, J M; Lowdell, M W; Kottaridis, P D; Mehta, A B; Prentice, A G; Hoffbrand, A V; Wickremasinghe, R G

    2006-06-01

    We have studied the in vitro actions of the sesquiterpene lactone parthenolide (PTL) on cells isolated from patients with chronic lymphocytic leukemia (CLL). Dye reduction viability assays showed that the median LD(50) for PTL was 6.2 muM (n=78). Fifteen of these isolates were relatively resistant to the conventional agent chlorambucil but retained sensitivity to PTL. Brief exposures to PTL (1-3 h) were sufficient to induce caspase activation and commitment to cell death. Chronic lymphocytic leukemia cells were more sensitive towards PTL than were normal T lymphocytes or CD34(+) haematopoietic progenitor cells. The mechanism of cell killing was via PTL-induced generation of reactive oxygen species, resulting in turn in a proapoptotic Bax conformational change, release of mitochondrial cytochrome c and caspase activation. Parthenolide also decreased nuclear levels of the antiapoptotic transcription factor nuclear factor-kappa B and diminished phosphorylation of its negative regulator IkappaB. Killing of CLL cells by PTL was apparently independent of p53 induction. This is the first report showing the relative selectivity of PTL towards CLL cells. The data here warrant further investigation of this class of natural product as potential therapeutic agents for CLL.

  9. Soluble mediators released by acute myeloid leukemia cells increase capillary-like networks.

    PubMed

    Hatfield, Kimberley J; Evensen, Lasse; Reikvam, Håkon; Lorens, James B; Bruserud, Øystein

    2012-12-01

    Increased bone marrow angiogenesis is seen in several hematological malignancies, including acute myeloid leukemia (AML). We used a co-culture assay of endothelial and vascular smooth muscle cells (vSMC) to investigate the effects of AML-conditioned medium on capillary networks. We investigated primary AML cells derived from 44 unselected patients and observed that for a large subset of patients, the constitutive cytokine release by the leukemic cells stimulated endothelial cell organization into capillary-like networks, while there were only minor or no effects for other patients. We analyzed the constitutive AML cell release of 31 cytokines for all the patients and performed a hierarchical cluster analysis of the cytokine profile which identified two major patient subsets that differed in their ability to enhance capillary-like networks; increased capillary-like networks was then associated with high constitutive release of several cytokines and especially high levels of several pro-angiogenic chemokines. Significantly increased network formation was not seen for any of the 11 acute lymphoblastic leukemia patients investigated. The cytokine response by activated normal T cells inhibited endothelial network formation in our in vitro model of angiogenesis and activated normal monocytes had only a minor influence on tube formation. Our study shows that AML-derived cytokines can induce the organization of endothelial cells into vessel-like structures.

  10. Reduced-Intensity Conditioning Before Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

    ClinicalTrials.gov

    2016-10-19

    -Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Cytopenia With Multilineage Dysplasia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

  11. [A TIM-3/galectin-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemia progression].

    PubMed

    Kikushige, Yoshikane

    2016-04-01

    Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. We previously reported that the T-cell immunoglobulin mucin-3 (TIM-3) is expressed on the LCS surface in most types of AML. Since only the TIM-3(+), i.e. not the TIM-3(-), fraction of human AML cells can reconstitute human AML in immunodeficient mice, we hypothesized that the TIM-3 has an essential function in maintaining AML LSCs. Herein, we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for human AML LSC development. Serum Gal-9 was significantly elevated in primary AML patients and in mice xenografted with human AML. Neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML, as well as Gal-9 ligation of TIM-3 co-activated NF-κB and β-catenin signaling, suggesting that TIM-3 signaling is necessary for LSC self-renewal. Interestingly, identical changes were found to be involved in the progressive transformation of a variety of pre-leukemic disorders into myeloid leukemia. Thus, molecules constituting the TIM-3/Gal-9 autocrine loop are potential therapeutic targets applicable to most types of myeloid leukemia.

  12. Barriers to Infection of Human Cells by Feline Leukemia Virus: Insights into Resistance to Zoonosis.

    PubMed

    Terry, Anne; Kilbey, Anna; Naseer, Asif; Levy, Laura S; Ahmad, Shamim; Watts, Ciorsdaidh; Mackay, Nancy; Cameron, Ewan; Wilson, Sam; Neil, James C

    2017-03-01

    The human genome displays a rich fossil record of past gammaretrovirus infections, yet no current epidemic is evident, despite environmental exposure to viruses that infect human cells in vitro Feline leukemia viruses (FeLVs) rank high on this list, but neither domestic nor workplace exposure has been associated with detectable serological responses. Nonspecific inactivation of gammaretroviruses by serum factors appears insufficient to explain these observations. To investigate further, we explored the susceptibilities of primary and established human cell lines to FeLV-B, the most likely zoonotic variant. Fully permissive infection was common in cancer-derived cell lines but was also a feature of nontransformed keratinocytes and lung fibroblasts. Cells of hematopoietic origin were generally less permissive and formed discrete groups on the basis of high or low intracellular protein expression and virion release. Potent repression was observed in primary human blood mononuclear cells and a subset of leukemia cell lines. However, the early steps of reverse transcription and integration appear to be unimpaired in nonpermissive cells. FeLV-B was subject to G→A hypermutation with a predominant APOBEC3G signature in partially permissive cells but was not mutated in permissive cells or in nonpermissive cells that block secondary viral spread. Distinct cellular barriers that protect primary human blood cells are likely to be important in protection against zoonotic infection with FeLV.IMPORTANCE Domestic exposure to gammaretroviruses such as feline leukemia viruses (FeLVs) occurs worldwide, but the basis of human resistance to infection remains incompletely understood. The potential threat is evident from the human genome sequence, which reveals many past epidemics of gammaretrovirus infection, and from recent cross-species jumps of gammaretroviruses from rodents to primates and marsupials. This study examined resistance to infection at the cellular level with the most

  13. Barriers to Infection of Human Cells by Feline Leukemia Virus: Insights into Resistance to Zoonosis

    PubMed Central

    Terry, Anne; Kilbey, Anna; Naseer, Asif; Levy, Laura S.; Ahmad, Shamim; Watts, Ciorsdaidh; Mackay, Nancy; Cameron, Ewan; Wilson, Sam

    2016-01-01

    ABSTRACT The human genome displays a rich fossil record of past gammaretrovirus infections, yet no current epidemic is evident, despite environmental exposure to viruses that infect human cells in vitro. Feline leukemia viruses (FeLVs) rank high on this list, but neither domestic nor workplace exposure has been associated with detectable serological responses. Nonspecific inactivation of gammaretroviruses by serum factors appears insufficient to explain these observations. To investigate further, we explored the susceptibilities of primary and established human cell lines to FeLV-B, the most likely zoonotic variant. Fully permissive infection was common in cancer-derived cell lines but was also a feature of nontransformed keratinocytes and lung fibroblasts. Cells of hematopoietic origin were generally less permissive and formed discrete groups on the basis of high or low intracellular protein expression and virion release. Potent repression was observed in primary human blood mononuclear cells and a subset of leukemia cell lines. However, the early steps of reverse transcription and integration appear to be unimpaired in nonpermissive cells. FeLV-B was subject to G→A hypermutation with a predominant APOBEC3G signature in partially permissive cells but was not mutated in permissive cells or in nonpermissive cells that block secondary viral spread. Distinct cellular barriers that protect primary human blood cells are likely to be important in protection against zoonotic infection with FeLV. IMPORTANCE Domestic exposure to gammaretroviruses such as feline leukemia viruses (FeLVs) occurs worldwide, but the basis of human resistance to infection remains incompletely understood. The potential threat is evident from the human genome sequence, which reveals many past epidemics of gammaretrovirus infection, and from recent cross-species jumps of gammaretroviruses from rodents to primates and marsupials. This study examined resistance to infection at the cellular level

  14. The novel compound OSI-461 induces apoptosis and growth arrest in human acute myeloid leukemia cells.

    PubMed

    Singh, Raminder; Fröbel, Julia; Cadeddu, Ron-Patrick; Bruns, Ingmar; Schroeder, Thomas; Brünnert, Daniela; Wilk, Christian Matthias; Zerbini, Luiz Fernando; Haas, Rainer; Czibere, Akos

    2012-02-01

    Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy. Treatment of patients suffering from high-risk AML as defined by clinical parameters, cytogenetics, and/or molecular analyses is often unsuccessful. OSI-461 is a pro-apoptotic compound that has been proposed as a novel therapeutic option for patients suffering from solid tumors like prostate or colorectal carcinoma. But little is known about its anti-proliferative potential in AML. Hence, we treated bone marrow derived CD34(+) selected blast cells from 20 AML patients and the five AML cell lines KG-1a, THP-1, HL-60, U-937, and MV4-11 with the physiologically achievable concentration of 1 μM OSI-461 or equal amounts of DMSO as a control. Following incubation with OSI-461, we found a consistent induction of apoptosis and an accumulation of cells in the G2/M phase of the cell cycle. In addition, we demonstrate that the OSI-461 mediated anti-proliferative effects observed in AML are associated with the induction of the pro-apoptotic cytokine mda-7/IL-24 and activation of the growth arrest and DNA-damage inducible genes (GADD) 45α and 45γ. Furthermore, OSI-461 treated leukemia cells did not regain their proliferative potential for up to 8 days after cessation of treatment following the initial 48 h treatment period with 1 μM OSI-461. This indicates sufficient targeting of the leukemia-initiating cells in our in vitro experiments through OSI-461. The AML samples tested in this study included samples from patients who were resistant to conventional chemotherapy and/or had FLT3-ITD mutations demonstrating the high potential of OSI-461 in human AML.

  15. Generation and preclinical characterization of an NKp80-Fc fusion protein for redirected cytolysis of natural killer (NK) cells against leukemia.

    PubMed

    Deng, Gang; Zheng, Xiaodong; Zhou, Jing; Wei, Haiming; Tian, Zhigang; Sun, Rui

    2015-09-11

    The capacity of natural killer (NK) cells to mediate Fc receptor-dependent effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), largely contributes to their clinical application. Given that activation-induced C-type lectin (AICL), an identified ligand for the NK-activating receptor NKp80, is frequently highly expressed on leukemia cells, the lack of therapeutic AICL-specific antibodies limits clinical application. Here we explore a strategy to reinforce NK anti-leukemia reactivity by combining targeting AICL-expressing leukemia cells with the induction of NK cell ADCC using NKp80-Fc fusion proteins. The NKp80-Fc fusion protein we generated bound specifically to leukemia cells in an AICL-specific manner. Cell binding assays between NK and leukemia cells showed that NKp80-Fc significantly increased NK target cell conjugation. In functional analyses, treatment with NKp80-Fc clearly induced the ADCC effect of NK cells. NKp80-Fc not only promoted NK-mediated leukemia cell apoptosis in the early stage of cell conjugation but also enhanced NK cell degranulation and cytotoxicity activity in the late stage. The bifunctional NKp80-Fc could redirect NK cells toward leukemia cells and triggered NK cell killing in vitro. Moreover, NKp80-Fc enhanced the lysis of NK cells against tumors in leukemia xenograft non-obese diabetic/severe combined immunodeficiency mice. Taken together, our results demonstrate that NKp80-Fc potently amplifies NK cell anti-leukemia effects in vitro and in vivo through induction of the NK cell ADCC effect. This method could potentially be useful for molecular targeted therapy, and the fusion proteins may be a promising drug for immunotherapy of leukemia.

  16. Aloe-emodin induced in vitro G2/M arrest of cell cycle in human promyelocytic leukemia HL-60 cells.

    PubMed

    Chen, H C; Hsieh, W T; Chang, W C; Chung, J G

    2004-08-01

    In this study, we have evaluated the chemopreventive role of aloe-emodin in human promyelocytic leukemia HL-60 cells in vitro by studying the regulation of proliferation, cell cycle and apoptosis. Aloe-emodin inhibited cell proliferation and induced G2/M arrest and apoptosis in HL-60 cells. Investigation of the levels of cyclins B1, E and A by immunoblot analysis showed that cyclin E level was unaffected, whereas cyclin B1 and A levels increased with aloe-emodin in HL-60 cells. Investigation of the levels of cyclin-dependent kinases, Cdk1 and 2, showed increased levels of Cdk1 but the levels of Cdk2 were not effected with aloe-emodin in HL-60 cells. The levels of p27 were increased after HL-60 cells were cotreated with various concentrations of aloe-emodin. The increase of the levels of p27 may be the major factor for aloe-emodin to cause G2/M arrest in these examined cells. Flow cytometric assays and DNA fragmentation gel electrophoresis also confirmed aloe-emodin induced apoptosis in HL-60 cells. The levels of caspase-3 were increased after HL-60 cells were cotreated with 10 microM aloe-emodin for 12, 24, 48, and 72 hours. Taken together, aloe-emodin therefore appears to exert its anticarcinogenesis properties by inhibiting proliferation and inducing cell cycle arrest and apoptosis underwent activation of caspase-3 in human leukemia HL-60 cells.

  17. Hematopoietic stem cell transplantation from alternative sources in adults with high-risk acute leukemia.

    PubMed

    Aversa, Franco; Reisner, Yair; Martelli, Massimo F

    2004-01-01

    Since 75% of patients with high-risk acute leukemia do not have a human leukocyte antigen (HLA)-identical sibling, alternative sources for hematopoietic stem cell transplantation (HSCT) are matched unrelated donors (MUD), unrelated umbilical cord blood (UD-UCB) and one HLA haplotype mismatched family members (haploidentical). The chance of finding a suitable donor in the international voluntary donor registries is limited by frequency of the HLA phenotype and the time required to identify the right donor from a potential panel, to establish eligibility and to harvest the cells. In adult MUD recipients, event-free survival ranges up to 50% and refers only to patients who undergo transplant, without taking into account those who do not find a donor. Umbilical cord blood offers the advantages of easy procurement, the absence of risks to donors, the reduced risk of transmitting infections, immediate availability of cryopreserved samples and acceptance of mismatches at two of the six antigens. Although UD-UCB transplantation is a viable option for children, it is seldom considered for adults. The great divergency between body weight and the number of hematopoietic cells in a standard cord blood unit, particularly if associated with a two-antigen mismatch, increases the risk of graft failure and delays hematopoietic reconstitution. Work on full-haplotype mismatched transplants has been proceeding for over 20 years. Originally, outcome in leukemia patients was disappointing because of high incidence of severe graft-vs.-host disease in T-replete transplants and high rejection rates in T-cell-depleted transplants. The breakthrough came with the use of a megadose of T-cell-depleted progenitor cells after a high-intensity conditioning regimen. Treating end-stage patients inevitably confounded clinical outcome in the early pilot studies. Today, high-risk acute leukemia patients are treated at less advanced stages of disease, receive a reasonably well tolerated conditioning

  18. Platelets promote mitochondrial uncoupling and resistance to apoptosis in leukemia cells: a novel paradigm for the bone marrow microenvironment.

    PubMed

    Velez, Juliana; Enciso, Leonardo José; Suarez, Marta; Fiegl, Michael; Grismaldo, Adriana; López, Catalina; Barreto, Alfonso; Cardozo, Claudia; Palacios, Pilar; Morales, Ludis; Duque, Jorge Eduardo; Carmona, Jorge Uriel; Konopleva, Marina; Andreeff, Michael; Samudio, Ismael

    2014-08-01

    Here we report that leukemia cell lines and primary CD34+ leukemic blasts exposed to platelet rich plasma (PRP) or platelet lysates (PL) display increased resistance to apoptosis induced by mitochondria-targeted agents ABT-737 and CDDO-Me. Intriguingly, leukemia cells exposed to platelet components demonstrate a reduction in mitochondrial membrane potential (ΔΨM) and a transient increase in oxygen consumption, suggestive of mitochondrial uncoupling. Accompanying the ranolazine-sensitive increase in oxygen consumption, a reduction in triglyceride content was also observed in leukemia cells cultured with platelet components indicating that lipolysis and fatty acid oxidation may support the molecular reduction of oxygen in these cells. Mechanistically, platelet components antagonized Bax oligomerization in accordance with previous observations supporting an antiapoptotic role for fatty acid oxidation in leukemia cells. Lastly, substantiating the notion that mitochondrial uncoupling reduces oxidative stress, platelet components induced a marked decrease in basal and rotenone-induced superoxide levels in leukemia cells. Taken together, the decrease in ΔΨM, the transient increase in ranolazine-sensitive oxygen consumption, the reduction in triglyceride levels, and the reduced generation of superoxide, all accompanying the increased resistance to mitochondrial apoptosis, substantiate the hypothesis that platelets may contribute to the chemoprotective sanctuary of the bone marrow microenvironment via promotion of mitochondrial uncoupling.

  19. Potential of autologous NK cell therapy to eradicate leukemia: "Education is [not] the best provision for old age" -Aristotle.

    PubMed

    Abdel-Azim, Hisham; Heisterkamp, Nora

    2015-02-01

    B-precursor acute lymphoblastic leukemia (BP-ALL) patients are immunocompromised. We recently reported that functional natural killer (NK) cells can be grown from patient bone marrow and blood samples at diagnosis. Surprisingly, such NK cells exhibit cytotoxicity against autologous BP-ALL cells. Here, we outline unanswered questions, challenges and possible applications associated with these findings.

  20. Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia.

    PubMed

    Takam Kamga, Paul; Bassi, Giulio; Cassaro, Adriana; Midolo, Martina; Di Trapani, Mariano; Gatti, Alessandro; Carusone, Roberta; Resci, Federica; Perbellini, Omar; Gottardi, Michele; Bonifacio, Massimiliano; Nwabo Kamdje, Armel Hervé; Ambrosetti, Achille; Krampera, Mauro

    2016-04-19

    Both preclinical and clinical investigations suggest that Notch signalling is critical for the development of many cancers and for their response to chemotherapy. We previously showed that Notch inhibition abrogates stromal-induced chemoresistance in lymphoid neoplasms. However, the role of Notch in acute myeloid leukemia (AML) and its contribution to the crosstalk between leukemia cells and bone marrow stromal cells remain controversial. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML cells in co-culture with bone marrow mesenchymal stromal cells expanded from both healthy donors (hBM-MSCs) and AML patients (hBM-MSCs*). As compared to hBM-MSCs, hBM-MSCs* showed higher level of Notch1, Jagged1 as well as the main Notch target gene HES1. Notably, hBM-MSCs* induced expression and activation of Notch signalling in AML cells, supporting AML proliferation and being more efficientin inducing AML chemoresistance than hBM-MSCs*. Pharmacological inhibition of Notch using combinations of Notch receptor-blocking antibodies or gamma-secretase inhibitors (GSIs), in presence of chemotherapeutic agents, significant lowered the supportive effect of hBM-MSCs and hBM-MSCs* towards AML cells, by activating apoptotic cascade and reducing protein level of STAT3, AKT and NF-κB.These results suggest that Notch signalling inhibition, by overcoming the stromal-mediated promotion of chemoresistance,may represent a potential therapeutic targetnot only for lymphoid neoplasms, but also for AML.

  1. α-Tomatine inhibits growth and induces apoptosis in HL-60 human myeloid leukemia cells.

    PubMed

    Huang, Huarong; Chen, Shaohua; Van Doren, Jeremiah; Li, Dongli; Farichon, Chelsea; He, Yan; Zhang, Qiuyan; Zhang, Kun; Conney, Allan H; Goodin, Susan; Du, Zhiyun; Zheng, Xi

    2015-06-01

    α‑Tomatine is a glycoalkaloid that occurs naturally in tomatoes (Lycopersicon esculentum). In the present study, the effects of α‑tomatine on human myeloid leukemia HL‑60 cells were investigated. Treatment of HL‑60 cells with α‑tomatine resulted in growth inhibition and apoptosis in a concentration‑dependent manner. Tomatidine, the aglycone of tomatine had little effect on the growth and apoptosis of HL‑60 cells. Growth inhibition and apoptosis induced by α‑tomatine in HL‑60 cells was partially abrogated by addition of cholesterol indicating that interactions between α‑tomatine and cell membrane‑associated cholesterol may be important in mediating the effect of α‑tomatine. Activation of nuclear factor‑κB by the phorbol ester, 12‑O‑tetradecanoylphorbol‑13‑acetate failed to prevent apoptosis in HL‑60 cells treated with α‑tomatine. In animal experiments, it was found that treatment of mice with α‑tomatine inhibited the growth of HL‑60 xenografts in vivo. Results from the present study indicated that α‑tomatine may have useful anti‑leukemia activities.

  2. Hispidulin induces mitochondrial apoptosis in acute myeloid leukemia cells by targeting extracellular matrix metalloproteinase inducer

    PubMed Central

    Gao, Hui; Liu, Yongji; Li, Kan; Wu, Tianhui; Peng, Jianjun; Jing, Fanbo

    2016-01-01

    Acute myeloid leukemia (AML) represents a heterogeneous group of hematological neoplasms with marked heterogeneity in response to both standard therapy and survival. Hispidulin, a flavonoid compound that is anactive ingredient in the traditional Chinese medicinal herb Salvia plebeia R. Br, has recently been reported to have anantitumor effect against solid tumors in vitro and in vivo. The aim of the present study was to investigate the effects of hispidulin on the human leukemia cell line in vitro and the underlying mechanisms of its actions on these cells. Our results showed that hispidulin inhibits AML cell proliferation in a dose- and time-dependent manner, and induces cell apoptosis throughan intrinsic mitochondrial pathway. Our results also revealed that hispidulin treatment significantly inhibits extracellular matrix metalloproteinase inducer (EMMPRIN) expression in both tested AML cell lines in a dose-dependent manner, and that the overexpression of EMMPRIN protein markedly attenuates hispidulin-induced cell apoptosis. Furthermore, our results strongly indicated that the modulating effect of hispidulin on EMMPRIN is correlated with its inhibitory effect on both the Akt and STAT3 signaling pathways. PMID:27158398

  3. α-tomatine inhibits growth and induces apoptosis in HL-60 human myeloid leukemia cells

    PubMed Central

    HUANG, HUARONG; CHEN, SHAOHUA; VAN DOREN, JEREMIAH; LI, DONGLI; FARICHON, CHELSEA; HE, YAN; ZHANG, QIUYAN; ZHANG, KUN; CONNEY, ALLAN H; GOODIN, SUSAN; DU, ZHIYUN; ZHENG, XI

    2015-01-01

    α-tomatine is a glycoalkaloid that occurs naturally in tomatoes (Lycopersicon esculentum). In the present study, the effects of α-tomatine on human myeloid leukemia HL-60 cells were investigated. Treatment of HL-60 cells with α-tomatine resulted in growth inhibition and apoptosis in a concentration-dependent manner. Tomatidine, the aglycone of tomatine had little effect on the growth and apoptosis of HL-60 cells. Growth inhibition and apoptosis induced by α-tomatine in HL-60 cells was partially abrogated by addition of cholesterol indicating that interactions between α-tomatine and cell membrane-associated cholesterol may be important in mediating the effect of α-tomatine. Activation of nuclear factor-κB by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate failed to prevent apoptosis in HL-60 cells treated with α-tomatine. In animal experiments, it was found that treatment of mice with α-tomatine inhibited the growth of HL-60 xenografts in vivo. Results from the present study indicated that α-tomatine may have useful anti-leukemia activities. PMID:25625536

  4. Molecular analysis of the apoptotic effects of BPA in acute myeloid leukemia cells

    PubMed Central

    Bontempo, Paola; Mita, Luigi; Doto, Antonella; Miceli, Marco; Nebbioso, Angela; Lepore, Ilaria; Franci, GianLuigi; Menafra, Roberta; Carafa, Vincenzo; Conte, Mariarosaria; De Bellis, Floriana; Manzo, Fabio; Di Cerbo, Vincenzo; Benedetti, Rosaria; D'Amato, Loredana; Marino, Maria; Bolli, Alessandro; Del Pozzo, Giovanna; Diano, Nadia; Portaccio, Marianna; Mita, Gustavo D; Vietri, Maria Teresa; Cioffi, Michele; Nola, Ernesto; Dell'Aversana, Carmela; Sica, Vincenzo; Molinari, Anna Maria; Altucci, Lucia

    2009-01-01

    Background: BPA (bisphenol A or 2,2-bis(4-hydroxy-phenol)propane) 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. PMID:19538739

  5. Interphase cytogenetics of B-cell chronic lymphocytic leukemia by FISH-technique

    SciTech Connect

    Peddanna, N.; Gogineni, S.K.; Rosenthal, C.J.

    1994-09-01

    Chronic lymphocytic leukemia [CLL] accounts for about 30% of all lymphoproliferative disorders. In over 95% of these cases, the leukemia is caused by B-cells, rarely T-cells. Fifty percent of B-CLL have chromosomal aberrations and of such cases, one-third have trisomy 12. Malignant B-cells have a very low mitotic index and those metaphases that can be analyzed usually represent the normal T-cell population. Retrospectively, we decided to identify the additional chromosome 12 (trisomy 12) directly at interphase by the FISH-technique using centrometric 12 specific alphoid probe (Oncor, Gaithersburg, MD). Preparations were made from 9 patients with B-CLL. All cultures except one failed to produce metaphases for conventional karyotyping. Eighty percent of the cells have two dots (normal cells) over the interphase nuclei while the remaining 20% have three dots (trisomy 12). The clinical implication of trisomy 12 in the pathogenesis of CLL including age, staging and duration of disease, differentials and immunological markers are correlated with interphase cytogenetic data. The loss and/or gain of specific chromosomes in human neoplasia is common and rapid evaluation of such cases should be considered as a routine approach.

  6. Inhibiting B-cell receptor signaling pathways in chronic lymphocytic leukemia.

    PubMed

    Burger, Jan A

    2012-03-01

    B-cell receptor (BCR) signaling is a central pathologic mechanism in B-cell malignancies, including chronic lymphocytic leukemia (CLL), in which it promotes leukemia cell survival and proliferation, and modulates CLL cell migration and tissue homing. BCR signaling now can be targeted with new, small molecule inhibitors of the spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk), or phosphoinositide 3'-kinase (PI3K) isoform p110δ (PI3Kδ), which have recently entered the clinical stage and show promising results in patients with CLL. During the first weeks of therapy, these agents characteristically induce rapid resolution of lymphadenopathy and organomegaly, accompanied by a transient surge in lymphocyte counts due to "mobilization" of tissue-resident CLL cells into the blood. Then, often after months of continuous therapy, a major proportion of patients achieve remissions. This article reviews key biologic aspects of BCR-associated kinases in CLL and other B cell neoplasias, and develops perspectives for future development of this exciting new class of kinase inhibitors.

  7. 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

    ClinicalTrials.gov

    2016-07-18

    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

  8. Levofloxacin in Preventing Infection in Young Patients With Acute Leukemia Receiving Chemotherapy or Undergoing Stem Cell Transplantation

    ClinicalTrials.gov

    2017-02-13

    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

  9. Rituximab, Romidepsin, and Lenalidomide in Treating Patients With Recurrent or Refractory B-cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-08-09

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

  10. Vaccine Therapy in Preventing Cytomegalovirus Infection in Patients With Hematological Malignancies Undergoing Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-11-23

    Treated Myelodysplastic Syndromes; Primary Central Nervous System Hodgkin Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Primary Myelofibrosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Multiple Myeloma; Stage I Small Lymphocytic Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Adult Hodgkin Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Lymphoblastic Lymphoma

  11. Secondary Philadelphia chromosome and erythrophagocytosis in a relapsed acute myeloid leukemia after hematopoietic cell transplantation

    PubMed Central

    Kelemen, Katalin; Galani, Komal; Conley, Christopher R.; Greipp, Patricia T.

    2015-01-01

    The acquisition of Philadelphia chromosome (Ph) as a secondary change during the course of hematopoietic malignancies is rare and is associated with poor prognosis. Few cases of secondary Ph have been reported after hematopoietic cell transplantation (HCT). A secondary Ph at relapse is of clinical importance because it provides a therapeutic target for tyrosine kinase inhibitors along with or in replacement of chemotherapy. We describe a case of relapsed acute myeloid leukemia after HCT that developed a BCR/ABL-1 translocation along with erythrophagocytosis by blasts as a secondary change at the time of relapse. The progression of this patient's myeloid neoplasm from myelodysplastic syndrome to acute myeloid leukemia and relapsed AML after HCT was accompanied by a stepwise cytogenetic evolution: a deletion 20q abnormality subsequently acquired deletion 7q and, finally, at relapse after HCT, a secondary Ph was gained. The relationship between the secondary Ph and the erythrophagocytosis by blasts is not clear. We review the possible pathogenesis and cytogenetic associations of erythrophagocytosis by blasts, a rare feature in acute leukemias. PMID:25074248

  12. Next-Generation Sequencing in Adult B Cell Acute Lymphoblastic Leukemia Patients.

    PubMed

    Sala Torra, Olga; Othus, Megan; Williamson, David W; Wood, Brent; Kirsch, Ilan; Robins, Harlan; Beppu, Lan; O'Donnell, Margaret R; Forman, Stephen J; Appelbaum, Frederick R; Radich, Jerald P

    2017-04-01

    We used next-generation sequencing (NGS) of the immunoglobulin genes to evaluate residual disease in 153 specimens from 32 patients with adult B cell acute lymphoblastic leukemia enrolled in a single multicenter study. The sequencing results were compared with multiparameter flow cytometry (MFC) data in 66 specimens (25 patients) analyzed by both methods. There was a strong concordance (82%) between the methods in the qualitative determination of the presence of disease. However, in 17% of cases, leukemia was detected by sequencing but not by MFC. In 54 bone marrow (BM) and peripheral blood (PB) paired specimens, the burden of leukemia detected by NGS was lower in PB than in BM, although it was still detectable in 68% of the 28 paired specimens with positive BM. Lastly, patients without disease detected by NGS or MFC had a 5-year relapse free survival of > 80%. The results suggest that residual disease detection by immunoglobulin gene sequencing is an extremely sensitive technique and may identify patients that might benefit from transplantation. Moreover, the increased sensitivity of the method may allow frequent peripheral blood testing to supplement marrow sampling to measure disease response.

  13. [(Sp)-8-chloroadenosine 3',5'-cyclophosphate induced differentiation on human leukemia HL-60 cells].

    PubMed

    Su, J; Yang, X B; Wang, L X; Xu, B; Zhang, L H

    1996-01-01

    (Sp)-octyl 8-chloroadenosine 3',5'-cyclophosphate(OCC), a newly synthesized cAMP analog, strongly induced growth inhibition and differentiation in human leukemia HL-60 cells. The effects were dose- and time-dependent and irreversible. In flow cytometry, OCC brought about a block at the G1 phase of HL-60 cell cycle. Determined by incorporation assay, OCC was shown to strongly inhibit DNA synthesis without affecting the synthesis of RNA and protein in HL-60 cells. OCC activated the protein kinase A(PKA) in the cytosol of HL-60 cells and inhibited its binding to cAMP. The activities of PKA in the cytosol of HL-60 cells treated with OCC were more significantly increased than those in control cells. It can be concluded that OCC binds itself to PKA in competition with cAMP and, as a result, activates PKA.

  14. Genistein decreases cellular redox potential, partially suppresses cell growth in HL‑60 leukemia cells and sensitizes cells to γ‑radiation‑induced cell death.

    PubMed

    Kim, In Gyu; Kim, Jin Sik; Lee, Jae Ha; Cho, Eun Wie

    2014-12-01

    Various mechanisms have been proposed to underlie the cellular activity of genistein, based on biological experiments and epidemiological studies. The present study demonstrated that genistein inhibited the expression of cytoplasmic nicotinamide adenine dinucleotide phosphate (NADP)‑dependent isocitrate dehydrogenase (cICDH), thus increasing levels of intracellular reactive oxygen species (ROS) in human promyeloid leukemia HL‑60 cells. In genistein‑treated cells, the cellular redox potential (GSH/GSSG) was significantly decreased. This decrease in redox potential was caused by significant downregulation of the cICDH gene, generating the reducing equivalents (NADPH) for maintenance of cellular redox potential and cellular ROS level, which may regulate cell growth and cell death. Genistein‑induced ROS partially induced rapid transition into the G2/M phase by upregulation of p21wap1/cip1 and apoptotic cell death. Treatment of cells with N‑acetylcysteine, a well‑known antioxidant (ROS scavenger), not only partially restored cell growth and inhibited cell cycle arrest in G2/M, but also prevented apoptotic cell death. By contrast, normal lymphocytes did not significantly progress into the G2/M phase and radiation‑induced cell death was inhibited by genistein treatment. Therefore, genistein and γ‑irradiation together synergistically cause cell death in leukemia cells, however, genistein has a radioprotective effect in normal human lymphocytes. In conclusion, it was suggested that genistein selectively functions, not as an antioxidant, but as a pro‑oxidant in HL‑60 cells. This property can increase ionizing radiation‑induced cell cycle arrest and sensitivity to apoptotic cell death in human promyeloid leukemia HL‑60 cells, but does not cause significant damage to normal cells.

  15. Functional invariant natural killer T-cell and CD1d axis in chronic lymphocytic leukemia: implications for immunotherapy.

    PubMed

    Weinkove, Robert; Brooks, Collin R; Carter, John M; Hermans, Ian F; Ronchese, Franca

    2013-03-01

    Invariant natural killer T cells recognize glycolipid antigens such as α-galactosylceramide presented by CD1d. In preclinical models of B-cell malignancies, α-galactosylceramide is an adjuvant to tumor vaccination, enhancing tumor-specific T-cell responses and prolonging survival. However, numerical and functional invariant natural killer T-cell defects exist in patients with some cancers. Our aim was to assess this axis in patients with chronic lymphocytic leukemia. The numbers of circulating invariant natural killer T cells and the expression of CD1d on antigen-presenting cells were evaluated in patients with chronic lymphocytic leukemia and age-matched controls. Cytokine profile and in vitro proliferative capacity were determined. Patient- and control-derived invariant natural killer T-cell lines were generated and characterized, and allogeneic and autologous responses to α-galactosylce-ramide-treated leukemia cells were assessed. Absolute numbers and phenotype of invariant natural killer T cells were normal in patients with untreated chronic lymphocytic leukemia, and cytokine profile and proliferative capacity were intact. Chemotherapy-treated patients had reduced numbers of invariant natural killer T cells and myeloid dendritic cells, but α-galactosylceramide-induced proliferation was preserved. Invariant natural killer T-cell lines from patients lysed CD1d-expressing targets. Irradiated α-galactosylceramide-treated leukemic cells elicited allogeneic and autologous invariant natural killer T-cell proliferation, and α-galactosylceramide treatment led to increased proliferation of conventional T cells in response to tumor. In conclusion, the invariant natural killer T-cell and CD1d axis is fundamentally intact in patients with early-stage chronic lymphocytic leukemia and, despite reduced circulating numbers, function is retained in fludarabine-treated patients. Immunotherapies exploiting the adjuvant effect of α-galactosylceramide may be feasible.

  16. B-cell chronic lymphocytic leukemia: recent progress in biology, diagnosis, and therapy.

    PubMed

    Montserrat, E; Bosch, F; Rozman, C

    1997-01-01

    B-cell chronic lymphocytic leukemia (CLL) is a highly common form of leukemia characterized by the accumulation of long-lived, functionally inactive, mature appearing neoplastic B lymphocytes. In addition, immune disturbances such as hypogammaglobulinemia and autoimmune phenomena (particularly, autoimmune hemolytic anemia) are frequently found in CLL patients [1-2]. The etiology of CLL is unknown. In contrast with other leukemias, there is no relationship between CLL and exposure to radiation or other cytotoxic agents. A genetic basis is highly likely since there are differences in the incidence of CLL in different countries (e.g., CLL accounts for 30%-40% of all the leukemias in Western countries as compared to 5%-10% in Asian countries) and the risk of contracting CLL is higher among persons with first-degree relatives with the disease [3]. Because the incidence of CLL increases with age and the longer life expectancy of the general population, the age of patients at diagnosis is increasing. The median age at diagnosis is now about 70 years, with only one-third of the patients being less than 60 years of age. In the majority of the series, males predominate over females in a proportion of 1.5/1. The prognosis of patients with CLL is variable. However, clinical stages and other prognostic factors allow the individual risk of each patient to be assessed very accurately, which is useful for making treatment decisions. In the past two decades, significant progress has been made in CLL [4-10]. This review summarizes recent advances in the biology, diagnosis, and therapy of CLL.

  17. Transcriptomic analysis reveals that reactive oxygen species and genes encoding lipid transfer protein are associated with tobacco hairy root growth and branch development.

    PubMed

    Wang, Jung-Hao; Lin, Hsiao-Han; Liu, Chi-Te; Lin, Ta-Chung; Liu, Li-yu Daisy; Lee, Kung-Ta

    2014-07-01

    The hairy root, a specialized plant tissue that emerges from a cell transformed with transfer DNA (T-DNA) from Agrobacterium rhizogenes, can be used to study root biology and utilized in biotechnological applications. The rol genes are known to participate in the generation of hairy roots; however, the means by which the rol genes contribute to the initiation and the maintenance of hairy roots remains largely unknown. We demonstrated that tobacco hairy roots lacking either rolB or rolC exhibited fewer branch roots and lost their growth ability in long-term subculture. Additionally, a microarray analysis revealed that the expression of several genes encoding lipid transfer proteins (LTP) and reactive oxygen species (ROS)-related genes was significantly suppressed in rolB- or rolC-deficient hairy roots. We found that hairy root clones that exhibited greater branching expressed higher levels of RolB or RolC and the genes encoding LTP identified from the microarray. When hairy roots were compared with intact roots, the expression levels of LTP-encoding genes were dramatically different. In addition, ROS were present at lower levels in rolB- and rolC-deficient hairy roots. We therefore suggest that upregulating LTP and increasing the level of ROS is important for hairy root growth.

  18. Lithium Carbonate in Treating Patients With Acute Intestinal Graft-Versus-Host-Disease (GVHD) After Donor Stem Cell Transplant

    ClinicalTrials.gov

    2017-01-24

    ; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Small Lymphocytic Lymphoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage II Ovarian Epithelial Cancer; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Malignant Testicular Germ Cell Tumor; Stage III Mantle

  19. Discovery of siRNA lipid nanoparticles to transfect suspension leukemia cells and provide in vivo delivery capability.

    PubMed

    He, Wei; Bennett, Michael J; Luistro, Leopoldo; Carvajal, Daisy; Nevins, Thomas; Smith, Melissa; Tyagi, Gaurav; Cai, James; Wei, Xin; Lin, Tai-An; Heimbrook, David C; Packman, Kathryn; Boylan, John F

    2014-02-01

    As a powerful research tool, siRNA's therapeutic and target validation utility with leukemia cells and long-term gene knockdown is severely restricted by the lack of omnipotent, safe, stable, and convenient delivery. Here, we detail our discovery of siRNA-containing lipid nanoparticles (LNPs) able to effectively transfect several leukemia and difficult-to-transfect adherent cell lines also providing in vivo delivery to mouse spleen and bone marrow tissues through tail-vein administration. We disclose a series of novel structurally related lipids accounting for the superior transfection ability, and reveal a correlation between expression of Caveolins and successful transfection. These LNPs, bearing low toxicity and long stability of >6 months, are ideal for continuous long-term dosing. Our discovery represents the first effective siRNA-containing LNPs for leukemia cells, which not only enables high-throughput siRNA screening with leukemia cells and difficult-to-transfect adherent cells but also paves the way for the development of therapeutic siRNA for leukemia treatment.

  20. Activation of MYC in a masked t(8;17) translocation results in an aggressive B-cell leukemia.

    PubMed Central

    Gauwerky, C E; Huebner, K; Isobe, M; Nowell, P C; Croce, C M

    1989-01-01

    We have analyzed the oncogene rearrangements involving BCL2 and MYC in the leukemia cells of a patient with an aggressive prolymphocytic leukemia that had an abnormal karyotype including a t(14;18) translocation and a chromosome 17q+. Molecular analysis showed that BCL2 was rearranged in the major breakpoint cluster region and had joined into the immunoglobulin heavy chain gene as in follicular lymphoma. Cloning and sequence analysis of the rearranged MYC gene revealed that MYC was truncated at the Pvu II site at the end of the first exon of MYC and had joined into the regulatory elements of a gene that we called BCL3 (B-cell leukemia/lymphoma 3). The BCL3 locus was mapped to chromosome 17 band q22. We found BCL3 transcribed as a message of 1.7 kilobases in many hematopoietic cell lines representing all hematopoietic lineages. In the patient's leukemia cells, the truncated MYC gene was highly expressed under the influence of BCL3 regulatory elements, leading to an aggressive B-cell leukemia that presumably had been derived from an indolent lymphoma carrying a rearranged BCL2 gene. Images PMID:2682663

  1. HTLV-1 and associated adult T-cell leukemia/lymphoma.

    PubMed

    Mahieux, Renaud; Gessain, Antoine

    2003-12-01

    Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) infects 15-20 millions individuals worldwide. This oncoretrovirus can be transmitted through 3 ways: horizontally, vertically (mother to child) and via blood transfusion. HTLV-1 causes 2 major diseases: adult T-cell leukemia/lymphoma (ATLL) and tropical spastic paraparesis/HTLV-1-associated myelopathy. Tax is a 40-kDa phosphoprotein that is encoded by the pX region of the virus. Several lines of evidence have demonstrated a central role for this protein in the immortalization or transformation of the HTLV-1 infected cells. Apart from its ability to drive transcription from the viral promoter, it also deregulates the cell cycle, inhibits apoptosis, has an effect on the maintenance of the genomic stability and induces the production of several cytokines. In addition, several arguments strongly suggest the existence of host genetic factors, that could be involved in the HTLV-1 infection as well as in the development of ATLL among HTLV-1 infected individuals. ATLL can be classified into 4 major subtypes: a smoldering type, a chronic type, a lymphoma type and a leukemic type. The demonstration by Southern blot analysis of the clonal integration of an HTLV-1 provirus in the tumoral cells represents the gold-standard to define biologically ATLL. The survival rate of ATLL patients, especially those who develop the acute leukemic or lymphomas forms, is very poor, and such clonal malignant CD4 expansion remains one of the most severe lymphoproliferations.

  2. [T-cell lymphoma-leukemia caused by HTLV-1 in adults: two lymphomatous forms].

    PubMed

    Gning, S B; Fall, F; Ba-Fall, K; Thiam, M; Ndoye, B; Gueye, P M; Mbaye, P S

    2003-01-01

    The adult T-cells lymphoma-leukemia is a serious complication by the HTLV-1 infection. It is a rarely described diseases in Africa, in spite of the frequency of the infection by this virus. We report two clinical observations of lymphomatous forms. The first observation concerned a 43 year old Senegalese woman, admitted for a deep alteration of her general status and peripheral polyadenopathies. The adenopathy biopsy set up the diagnosis of pleiomorph T lymphoma with great and medium cells. The HTLV-1 serology was positive. She had benefited of six polychemotherapy cures (cyclophosphamide, farmarubicine, oncovin, prednisone) within which she died in a cachectic presentation. The second observation concerned a 44 year old Senegalese man, admitted for peripheral polyadenopathies, ulcerated lesions of sole of the foot, and deep alteration of the general status. He presented a moderate hypercalcemia by 117 mg/l. The histological examination of a ganglionar biopsy concluded to a diffuse T lymphoma with great cells. The HTLV-1 serology was positive. The cutaneous lesions were due to a phaeohyphomycosis of Exophiala jeanselmei. The symptomatic therapeutic measures had been applied and he died within four weeks in a septicemic clinical manifestation. The adult T-cells lymphoma leukemia due to the HTLV-1 ought to be researched before any lymphomatous and leucemic manifestation by T-cells through a serological research. The prognostic stays very bad.

  3. Computer aided detection and classification of acute lymphoblastic leukemia cell subtypes based on microscopic image analysis.

    PubMed

    MoradiAmin, Morteza; Memari, Ahmad; Samadzadehaghdam, Nasser; Kermani, Saeed; Talebi, Ardeshir

    2016-10-01

    Acute lymphoblastic leukemia (ALL) is a cancer that starts from the early version of white blood cells called lymphocytes in the bone marrow. It can spread to different parts of the body rapidly and if not treated, would probably be deadly within a couple of months. Leukemia cells are categorized into three types of L1, L2, and L3. The cancer is detected through screening of blood and bone marrow smears by pathologists. But manual examination of blood samples is a time-consuming and boring procedure as well as limited by human error risks. So to overcome these limitations a computer-aided detection system, capable of discriminating cancer from noncancer cases and identifying the cancerous cell subtypes, seems to be necessary. In this article an automatic detection method is proposed; first cell nucleus is segmented by fuzzy c-means clustering algorithm. Then a rich set of features including geometric, first- and second-order statistical features are obtained from the nucleus. A principal component analysis is used to reduce feature matrix dimensionality. Finally, an ensemble of SVM classifiers with different kernels and parameters is applied to classify cells into four groups, that is noncancerous, L1, L2, and L3. Results show that the proposed method can be used as an assistive diagnostic tool in laboratories.

  4. Cyclo-oxygenase 2 inhibitor, nabumetone, inhibits proliferation in chronic myeloid leukemia cell lines.

    PubMed

    Vural, Filiz; Ozcan, Mehmet Ali; Ozsan, Güner Hayri; Ateş, Halil; Demirkan, Fatih; Pişkin, Ozden; Undar, Bülent

    2005-05-01

    The anti-tumor effect of cyclo-oxygenase (COX) inhibitors has been documented in several studies. COX2 inhibitors have attracted more attention because of the fewer side-effects and the more prominent anti-tumor effects. However, experience with these drugs in hematological malignancies is limited. In our study, a potent COX2 inhibitor, nabumetone (NBT), was investigated for its anti-proliferative and apoptotic effects in K-562 and Meg-01 chronic myeloid leukemia blastic cell lines as a single agent or in combination with adriamycin (ADR) and interferon alpha (IFN-a). In these cell lines, a dose-dependent inhibition of proliferation was observed with NBT. We observed no significant apoptotic effect of NBT. However, NBT potentiated the apoptotic effect of ADR in the K-562 cell line. Bcl-2 expression was reduced by NBT (11% vs. 2%). The combination of NBT with IFN did not have any significant effect on the K-562 cell line. We suggest that NBT inhibits proliferation and potentiates the apoptotic effect of ADR in chronic myeloid leukemia cell lines.

  5. Progression of cutaneous plasmacytoma to plasma cell leukemia in a dog.

    PubMed

    Rout, Emily D; Shank, Alba Maria M; Waite, Angharad H K; Siegel, Andrea; Avery, Anne C; Avery, Paul R

    2017-02-10

    A 5-year-old male neutered Bernese Mountain Dog was presented for cutaneous plasmacytoma, which was treated by surgical excision. Four months later, the dog developed multiple skin masses, hyphema, pericardial and mild bicavitary effusions, myocardial masses, and marked plasmacytosis in the peripheral blood. Circulating plasma cells expressed CD34 and MHC class II by flow cytometry. Immunocytochemistry demonstrated that these cells were strongly positive for multiple myeloma oncogene 1/interferon regulatory factor 4 (MUM-1) and weakly to moderately positive for Pax5. The dog was hypoglobulinemic but had a monoclonal IgA gammopathy detected by serum immunofixation electrophoresis. The PCR analysis of antigen receptor gene rearrangements (PARR) by fragment analysis using GeneScan methodology revealed that plasmacytoid cells in the original cutaneous plasmacytoma and peripheral blood had an identical immunoglobulin heavy chain gene (IgH) rearrangement, indicating that both populations were derived from the same neoplastic clone. Canine cutaneous plasmacytoma rarely progresses to a malignant form and plasma cell leukemia is rarely diagnosed in the dog. This report describes a case of cutaneous plasmacytoma progressing to plasma cell leukemia with a rapid and aggressive clinical course. This report also highlights the utility of flow cytometry, immunocytochemistry, immunofixation electrophoresis, and PARR by fragment analysis using GeneScan methodology in the diagnosis of this hematopoietic neoplasm.

  6. Cell death induction by the acute promyelocytic leukemia-specific PML/RARα fusion protein

    PubMed Central

    Ferrucci, Pier Francesco; Grignani, Francesco; Pearson, Mark; Fagioli, Marta; Nicoletti, Ildo; Pelicci, Pier Giuseppe

    1997-01-01

    PML/RARα is the abnormal protein product generated by the acute promyelocytic leukemia-specific t(15;17). Expression of PML/RARα in hematopoietic precursor cell lines induces block of differentiation and promotes survival. We report here that PML/RARα has a potent growth inhibitory effect on all nonhematopoietic cell lines and on the majority of the hematopoietic cell lines tested. Inducible expression of PML/RARα in fibroblasts demonstrated that the basis for the growth suppression is induction of cell death. Deletion of relevant promyelocytic leukemia (PML) and retinoic acid receptor (RARα) domains within the fusion protein revealed that its growth inhibitory effect depends on the integrity of the PML aminoterminal region (RING, B1, B2, and coiled coil regions) and the RARα DNA binding region. Analysis of the nuclear localization of the same PML/RARα deletion mutants by immunofluorescence and cell fractionation revealed that the biological activity of the fusion protein correlates with its microspeckled localization and its association to the nuclear matrix. The PML aminoterminal region, but not the RARα zinc fingers, is required for the proper nuclear localization of PML/RARα. We propose that the matrix-associated microspeckles are the active sites of PML/RARα and that targeting of RARα sequences to this specific nuclear subdomain through PML sequences is crucial to the activity of the fusion protein on survival regulation. PMID:9380732

  7. Protein kinase CK2 regulates AKT, NF-κB and STAT3 activation, stem cell viability and proliferation in acute myeloid leukemia.

    PubMed

    Quotti Tubi, L; Canovas Nunes, S; Brancalion, A; Doriguzzi Breatta, E; Manni, S; Mandato, E; Zaffino, F; Macaccaro, P; Carrino, M; Gianesin, K; Trentin, L; Binotto, G; Zambello, R; Semenzato, G; Gurrieri, C; Piazza, F

    2017-02-01

    Protein kinase CK2 sustains acute myeloid leukemia cell growth, but its role in leukemia stem cells is largely unknown. Here, we discovered that the CK2 catalytic α and regulatory β subunits are consistently expressed in leukemia stem cells isolated from acute myeloid leukemia patients and cell lines. CK2 inactivation with the selective inhibitor CX-4945 or RNA interference induced an accumulation of leukemia stem cells in the late S-G2-M phases of the cell cycle and triggered late-onset apoptosis. As a result, leukemia stem cells displayed an increased sensitivity to the chemotherapeutic agent doxorubicin. From a molecular standpoint, CK2 blockade was associated with a downmodulation of the stem cell-regulating protein BMI-1 and a marked impairment of AKT, nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, whereas FOXO3a nuclear activity was induced. Notably, combined CK2 and either NF-κB or STAT3 inhibition resulted in a superior cytotoxic effect on leukemia stem cells. This study suggests that CK2 blockade could be a rational approach to minimize the persistence of residual leukemia cells.

  8. HJC, a new arylnaphthalene lignan isolated from Justicia procumbens, causes apoptosis and caspase activation in K562 leukemia cells.

    PubMed

    Luo, Jiaoyang; Kong, Weijun; Yang, Meihua

    2014-01-01

    The aim of this study is to investigate whether HJC, isolated from Justicia procumbens for the first time, can suppress the proliferation and induce apoptosis of human leukemia K562 cells and finally clarify its related mechanism. The chemical structure of HJC was validated by LC-ESI-MS/MS, cytotoxicity was assayed using MTT, and apoptosis was investigated by flow cytometry. These assays indicated that HJC remarkably inhibited the growth in K562 cells by decreasing cell proliferation, reducing the SOD activity, enhancing ROS levels and inducing apoptosis. Activation of caspase-3 indicated that HJC may be inducing intrinsic and extrinsic apoptosis pathways and that HJC-induced apoptosis was caspase-dependent. This study suggests that HJC is a high-potency anti-tumor agent, and it induces apoptosis through a caspase-dependent pathway in human leukemia K562 cells. It also presents a potential alternative to leukemia therapy.

  9. Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells

    PubMed Central

    Nonami, Atsushi; Weisberg, Ellen L.; Bonal, Dennis; Kirschmeier, Paul T.; Salgia, Sabrina; Podar, Klaus; Galinsky, Ilene; Chowdary, Tirumala K.; Neuberg, Donna; Tonon, Giovanni; Stone, Richard M.; Asara, John; Griffin, James D.; Sattler, Martin

    2015-01-01

    The rapid proliferation of myeloid leukemia cells is highly dependent on increased glucose metabolism. Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMPK (AMP kinase), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism. PMID:25703587

  10. Leukemia inhibitory factor (LIF)-dependent, pluripotent stem cells established from inner cell mass of porcine embryos.

    PubMed

    Telugu, Bhanu Prakash V L; Ezashi, Toshihiko; Sinha, Sunilima; Alexenko, Andrei P; Spate, Lee; Prather, Randall S; Roberts, R Michael

    2011-08-19

    The pig is important for agriculture and as an animal model in human and veterinary medicine, yet despite over 20 years of effort, there has been a failure to generate pluripotent stem cells analogous to those derived from mouse embryos. Here we report the production of leukemia inhibitory factor-dependent, so-called naive type, pluripotent stem cells from the inner cell mass of porcine blastocysts by up-regulating expression of KLF4 and POU5F1. The alkaline phosphatase-positive colonies resulting from reprogramming resemble mouse embryonic stem cells in colony morphology, cell cycle interval, transcriptome profile, and expression of pluripotent markers, such as POU5F1, SOX2, and surface marker SSEA1. They are dependent on leukemia inhibitory factor signaling for maintenance of pluripotency, can be cultured over extended passage, and have the ability to form teratomas. These cells derived from the inner cell mass of pig blastocysts are clearly distinct from the FGF2-dependent "primed" induced pluripotent stem cells described recently from porcine mesenchymal cells. The data are consistent with the hypothesis that the up-regulation of KLF4, as well as POU5F1, is required to create and stabilize the naive pluripotent state and may explain why the derivation of embryonic stem cells from pigs and other ungulates has proved so difficult.

  11. Hairy roots as a vaccine production and delivery system.

    PubMed

    Skarjinskaia, Marina; Ruby, Karen; Araujo, Adriana; Taylor, Karina; Gopalasamy-Raju, Vengadesan; Musiychuk, Konstantin; Chichester, Jessica A; Palmer, Gene A; de la Rosa, Patricia; Mett, Vadim; Ugulava, Natalia; Streatfield, Stephen J; Yusibov, Vidadi

    2013-01-01

    Prevention of infectious diseases by vaccination is often limited because of the lack of safe, effective, and accessible vaccines. Traditional vaccines are expensive and require special conditions for storage, distribution, and administration. Plants have potential for large-scale production of a variety of inexpensive and highly effective recombinant proteins for biomedical and pharmaceutical applications, including subunit vaccines. There are several approaches for the production of vaccine antigens in plants, including transient expression systems based on Agrobacterium delivery of binary vectors or plant viral vectors, stable transgenic plants, and plant cell or tissue cultures. Axenic plant cultures maintained under defined physical and chemical conditions appear to be an attractive production platform when target proteins need to be synthesized in a fully controlled environment. Hairy root cultures meet the criteria for such a system. Hairy root cultures, generated from edible plants and producing target antigens, provide a potential approach for the development of vaccines for oral delivery. With this approach, there are no protein extraction and purification costs and the active biomolecule is protected by the plant cell wall during passage through the upper gastrointestinal tract. This allows for gradual release of antigen at mucosal surfaces in the gut. Lyophilized hairy root cultures expressing vaccine antigens can be stored at ambient temperature for extended periods of time, which should facilitate storage and distribution, ultimately allowing for large populations to be vaccinated.

  12. [Effect of metformin on acute promyelocytic leukemia cell line NB4 and its mechanism].

    PubMed

    Huai, Lei; Wang, Cui-Cui; Zhang, Cui-Ping; Li, Qi-Hui; Chen, Yi-Rui; Jia, Yu-Jiao; Wang, Min; Wang, Jian-Xiang

    2012-12-01

    The purpose of this study was to investigate the effect and molecular mechanism of metformin (Met) on biological characteristics of acute promyelocytic leukemia (APL) cell line NB4. NB4 cells were treated with various concentrations of Met for different time, MTT method was used to detect cell proliferation, the alteration of cell apoptosis was analyzed by flow cytometry, and the change of cell adhesion ability was examined by cell adhesion assay. NB4 cells were pretreated with U0126, a specific inhibitor for extracellular signal-regulated kinase (ERK) phosphorylation, ERK phosphorylation was assessed by Western blot analysis, apoptosis and cell adhesion ability were evaluated by flow cytometry and cell adhesion test respectively. The results showed that Met could inhibit the cell proliferation, induce the cell apoptosis and increase the ability of cell adhesion. The pretreatment of NB4 cells with 5 µmol/L U0126 could effectively inhibit the phosphorylation of ERK, and reduce cell apoptosis and adhesion induced by 5 mmol/L Met. It is concluded that Met can inhibit the proliferation and promote the apoptosis and adhesion of NB4 cells. MEK/ERK signaling pathway may be one of the molecular mechanisms of metformin on NB4 cells.

  13. Hairy root culture for mass-production of high-value secondary metabolites.

    PubMed

    Srivastava, Smita; Srivastava, Ashok K

    2007-01-01

    Plant cell cultivations are being considered as an alternative to agricultural processes for producing valuable phytochemicals. Since many of these products (secondary metabolites) are obtained by direct extraction from plants grown in natural habitat, several factors can alter their yield. The use of plant cell cultures has overcome several inconveniences for the production of these secondary metabolites. Organized cultures, and especially root cultures, can make a significant contribution in the production of secondary metabolites. Most of the research efforts that use differentiated cultures instead of cell suspension cultures have focused on transformed (hairy) roots. Agrobacterium rhizogenes causes hairy root disease in plants. The neoplastic (cancerous) roots produced by A. rhizogenes infection are characterized by high growth rate, genetic stability and growth in hormone free media. These genetically transformed root cultures can produce levels of secondary metabolites comparable to that of intact plants. Hairy root cultures offer promise for high production and productivity of valuable secondary metabolites (used as pharmaceuticals, pigments and flavors) in many plants. The main constraint for commercial exploitation of hairy root cultivations is the development and scaling up of appropriate reactor vessels (bioreactors) that permit the growth of interconnected tissues normally unevenly distributed throughout the vessel. Emphasis has focused on designing appropriate bioreactors suitable to culture the delicate and sensitive plant hairy roots. Recent reactors used for mass production of hairy roots can roughly be divided as liquid-phase, gas-phase, or hybrid reactors. The present review highlights the nature, applications, perspectives and scale up of hairy root cultures for the production of valuable secondary metabolites.

  14. Effects of Novel Dinuclear Cisplatinum(II) Complexes on the Electrical Properties of Human Molt-4 Leukemia Cells.

    PubMed

    Dobrzyńska, Izabela; Skrzydlewska, Elżbieta; Figaszewski, Zbigniew A

    2015-04-01

    The aim of this study was to determine the influence of cisplatin and novel dinuclear platinum(II) complexes on the membrane electrical properties and lipid peroxidation levels of the Molt-4 human leukemia cell line. Changes in cell function may affect the basal electrical surface properties of cell membranes. These changes can be detected using electrokinetic measurements. Surface charge densities of Molt-4 cells were measured as a function of pH. A four-component equilibrium model was used to describe the interaction between the ions in solution and on cell membrane surfaces. Agreement was found between the experimental and theoretical charge variation curves of the leukemia cells at pH 2.5-9. Lipid peroxidation was estimated by measuring levels of 8-iso-prostaglandine F2α [isoprostanes]. Acid and base functional group concentrations and average association constants with hydroxyl ions were smaller in cisplatin- or dinuclear platinum(II) complex-treated leukemia cell membranes compared to those in untreated cancer cells, and the average association constants with hydrogen ions were higher. Levels of lipid peroxidation products in cisplatin- or dinuclear platinum(II) complex-treated leukemia cell were higher than those found in untreated cancer cells.

  15. Heme oxygenase-1 suppresses the apoptosis of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway.

    PubMed

    Lin, Xiaojing; Fang, Qin; Chen, Shuya; Zhe, Nana; Chai, Qixiang; Yu, Meisheng; Zhang, Yaming; Wang, Ziming; Wang, Jishi

    2015-05-01

    There are few studies on the correlation between heme oxygenase-1 (HO-1) and acute myeloid leukemia (AML). We found that HO-1 was aberrantly overexpressed in the majority of AML patients, especially in patients with acute monocytic leukemia (M5) and leukocytosis, and inhibited the apoptosis of HL-60 and U937 cells. Moreover, silencing HO-1 prolonged the survival of xenograft mouse models. Further studies demonstrated that HO-1 suppressed the apoptosis of AML cells through activating the JNK/c-JUN signaling pathway. These data indicate a molecular role of HO-1 in inhibiting cell apoptosis, allowing it to be a potential target for treating AML.

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

    PubMed

    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-