Sample records for hairy cell leukemia

  1. Stages of Hairy Cell Leukemia

    MedlinePLUS

    ... Cancers by Body Location Childhood Cancers Adolescent & Young Adult Cancers Metastatic Cancer Research NCI’s Role in Cancer ... Search Home Cancer Types Leukemia Patient Leukemia Patient Adult ALL Treatment Adult AML Treatment CLL Treatment CML ...

  2. Hairy Cell Leukemia: An Elusive but Treatable Disease

    Microsoft Academic Search

    Sam O. Wanko; Carlos de Castro

    Hairy cell leukemia (HCL) is a unique chronic lympho- proliferative disorder that can mimic or coexist with other clonal hematologic disorders and has been asso- ciated with autoimmune disorders. It should be enter- tained as an alternative diagnosis in patients with cyto- penias being assigned the diagnosis of aplastic anemia, hypoplastic myelodysplastic syndrome, atypical chronic lymphocytic leukemia, B-prolymphocytic leukemia, or

  3. Treatment Options for Hairy Cell Leukemia

    MedlinePLUS

    ... is made mostly of fat. Leukemia may affect red blood cells, white blood cells, and platelets. Normally, ... one of three types of mature blood cells: Red blood cells that carry oxygen and other substances ...

  4. Immunotoxin Therapy for Treatment-Resistant Hairy Cell Leukemia

    Cancer.gov

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

  5. General Information about Hairy Cell Leukemia

    MedlinePLUS

    ... Cancers by Body Location Childhood Cancers Adolescent & Young Adult Cancers Metastatic Cancer Research NCI’s Role in Cancer ... Search Home Cancer Types Leukemia Patient Leukemia Patient Adult ALL Treatment Adult AML Treatment CLL Treatment CML ...

  6. Two Cases of Q-Fever in Hairy Cell Leukemia

    PubMed Central

    Iannitto, Emilio; Tick, Lidwine W.; Arents, Nicolaas L. A.; Kuijper, Philip H.; Nijziel, Marten R.

    2014-01-01

    Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder accounting for about 2% of all leukemias. The clinical course is indolent, however HCL patients are particularly susceptible to infections. Here we report two cases of Q-fever as first manifestation of disease in two patients affected by HCL. Both patients described in this report showed an unusually sluggish clinical response to the antibiotic treatment with ciprofloxacin probably because of the marked immunodeficiency. However, treatment of HCL with cladribine administered soon after the resolution of QF pneumonitis was uneventful and led to a complete remission in both cases. Most probably the association of Coxiella burnetii (CB) infection and HCL that we observed in two patients is due to chance. However, a hairy cell resembling transformation of freshly isolated human peripheral blood lymphocytes upon CB has been showed. We think that the possibility of CB infection in febrile HCL patient should be always taken in mind, especially in endemic areas. In addition the potential for such infections to become chronic in HCL patients should not be overlooked and the reporting of further cases should be encouraged. PMID:25180111

  7. Variant hairy cell leukemia following papillary urothelial neoplasm of bladder.

    PubMed

    Beyan, Cengiz; Kaptan, Kürsat

    2014-03-01

    A 65 years old man was admitted with multiple lymphadenopathy, weight loss, night sweats and fatigue for 2 months. He had been treated for bladder cancer 2 years ago. Leukocyte count was 37.9 x10(9)/l. Peripheral blood smear had 91% lymphocytes. Lymphocytes had large nuclei with prominent nucleoli, heterogeneous appearance, and large cytoplasm with hairy projections. Flow cytometric immunophenotyping revealed CD20, CD22, CD24, CD45 and HLA-DR positivity. Atypical lymphocytes were stained with tartrate resistant acid phosphatase. Increased metabolic activity was detected in multiple lymph nodes, bone marrow and extremely enlarged spleen with positron emission tomography-computed tomography. Excisional biopsy of the left axillary lymph node revealed infiltration with diffuse B-cell leukemia/lymphoma. Immunohistochemistry showed CD20 positive atypical cells with weak expression of CD11c. The patient was diagnosed as a case of variant hairy cell leukemia and cladribine was administered. A probable second primary malignancy should be kept in mind in cases with a defined malignancy in the presence of unusual symptoms. PMID:24717996

  8. A Very Rare Case -? Hairy Cell Leukemia in Patient with Sarcoidosis.

    PubMed

    Karadurmus, N; Erdem, G; Basaran, Y; Naharci, I; Tasci, C; Dogan, T; Ifran, A; Kaptan, K; Saglam, K; Beyan, C

    2015-01-01

    Although the coexistence of hairy cell leukemia with sarcoidosis has been reported in a few cases in the literature, in our case the patient had been diagnosed and followed about 10 years with sarcoidosis and massive splenomegaly. It has been demonstrated that T helper 1 cells exist in organs influenced by sarcoidosis. These cells produce IL-2 and IFN-? and induce a nonspecific inflammatory response and granuloma formation. Also these cytokines may play a role in the development of hairy cell leukemia.Key words: hairy cell leukemia -? sarcoidosis - massive splenomegaly. PMID:26062623

  9. Effective Treatment of a Refractory Hairy Cell Leukemia Variant with Splenic Pre-Irradiation and Alemtuzumab

    Microsoft Academic Search

    Makoto Sasaki; Koichi Sugimoto; Takeshi Mori; Kumiko Karasawa; Kazuo Oshimi

    2008-01-01

    A 72-year-old Japanese man presented with 43.1 × 109\\/l hairy cells and apparent splenomegaly. The leukemia cells had unevenly distributed microvilli and round nuclei with dense chromatin and one or two clear nucleoli, lacked CD25 expression and were negative for tartrate-resistant acid phosphatase. The case was diagnosed as hairy cell leukemia variant (HCLv) and proved refractory to various chemotherapies, including

  10. Hairy cell leukemia in a patient with situs inversus totalis: an extremely rare combination.

    PubMed

    Pathak, Prajwol; Zilberman, Valeria; Avezbakiyev, Boris; Gotlieb, Vladimir

    2013-05-01

    Hairy cell leukemia is a rare cancer of the blood. The occurrence of hairy cell leukemia with another very rare genetic disorder makes us question whether it is just a coincidence. This article reports the first case of hairy cell leukemia in a patient with situs inversus totalis in western literature. There have been studies into the pathogenesis of situs inversus totalis that suggest it is caused by the failure of embryonic cells to properly rotate during embryogenesis. On the molecular level, the nodal cilia, which are responsible for embryonic rotation, are built by transport through the KIF3 complex - a kinesin superfamily of molecular motors. The KIF3 complex is also responsible for N-cadherin movement in cells. Furthermore, it is well known that these cell adhesion molecules play an important role in carcinogenesis and its progression. This report attempts to link the rare conditions and propose a possible genetic relationship between the two. PMID:23647303

  11. Persistent Legionnaire's disease in an adult with hairy cell leukemia successfully treated with prolonged levofloxacin therapy.

    PubMed

    Cunha, Burke A; Munoz-Gomez, Sigridh; Gran, Arthur; Raza, Muhammad; Irshad, Nadia

    2015-01-01

    Legionnaire's disease (LD) manifests most commonly as an atypical community acquired pneumonia (CAP) with systemic extrapulmonary manifestations. Disorders associated with impaired cell mediated immunity (CMI) are particularly predisposed to LD. Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative leukemia associated with decreased CMI. LD has only rarely been reported in HCL. We present a most interesting case of persistent LD in a elderly male with HCL who required prolonged antibiotic therapy. PMID:26021547

  12. Detection of BRAF mutations in patients with hairy cell leukemia and related lymphoproliferative disorders.

    PubMed

    Blombery, Piers A; Wong, Stephen Q; Hewitt, Chelsee A; Dobrovic, Alexander; Maxwell, Ellen L; Juneja, Surender; Grigoriadis, George; Westerman, David A

    2012-05-01

    Hairy cell leukemia has been shown to be strongly associated with the BRAF V600E mutation. We screened 59 unenriched archived bone marrow aspirate and peripheral blood samples from 51 patients with hairy cell leukemia using high resolution melting analysis and confirmatory Sanger sequencing. The BRAF V600E mutation was detected in 38 samples (from 36 patients). The BRAF V600E mutation was detected in all samples with disease involvement above the limit of sensitivity of the techniques used. Thirty-three of 34 samples from other hematologic malignancies were negative for BRAF mutations. A BRAF K601E mutation was detected in a patient with splenic marginal zone lymphoma. Our data support the recent finding of a disease defining point mutation in hairy cell leukemia. Furthermore, high resolution melting with confirmatory Sanger sequencing are useful methods that can be employed in routine diagnostic laboratories to detect BRAF mutations in patients with hairy cell leukemia and related lymphoproliferative disorders. PMID:22133769

  13. Detection of BRAF mutations in patients with hairy cell leukemia and related lymphoproliferative disorders

    PubMed Central

    Blombery, Piers A.; Wong, Stephen Q.; Hewitt, Chelsee A.; Dobrovic, Alexander; Maxwell, Ellen L.; Juneja, Surender; Grigoriadis, George; Westerman, David A.

    2012-01-01

    Hairy cell leukemia has been shown to be strongly associated with the BRAF V600E mutation. We screened 59 unenriched archived bone marrow aspirate and peripheral blood samples from 51 patients with hairy cell leukemia using high resolution melting analysis and confirmatory Sanger sequencing. The BRAF V600E mutation was detected in 38 samples (from 36 patients). The BRAF V600E mutation was detected in all samples with disease involvement above the limit of sensitivity of the techniques used. Thirty-three of 34 samples from other hematologic malignancies were negative for BRAF mutations. A BRAF K601E mutation was detected in a patient with splenic marginal zone lymphoma. Our data support the recent finding of a disease defining point mutation in hairy cell leukemia. Furthermore, high resolution melting with confirmatory Sanger sequencing are useful methods that can be employed in routine diagnostic laboratories to detect BRAF mutations in patients with hairy cell leukemia and related lymphoproliferative disorders. PMID:22133769

  14. Second Cancer Incidence and Cause-Specific Mortality Among 3104 Patients With Hairy Cell Leukemia: A Population-Based Study

    Microsoft Academic Search

    Michie Hisada; Bingshu E. Chen; Elaine S. Jaffe; Lois B. Travis

    2007-01-01

    Hairy cell leukemia is a malignancy of mature B lymphocytes and accounts for about 2% of all leukemias ( 1 ). The introduction of purine analogs ( 2 ) and interferon alfa ( 3 ) as therapeutics for this disease since the 1990s has resulted in substantially improved sur- vival. However, treatment with these agents has also been associ- ated

  15. Unusual soft tissue infiltrates with 18F-FDG uptake in a patient with hairy cell leukemia.

    PubMed

    Gibson, Glenna; Lai, Jerome; Thomas, Paul

    2015-05-01

    Hairy cell leukemia (HCL) is an uncommon B-cell lymphoproliferative disorder, representing approximately 2% of leukemias. Diagnostic features include pancytopenia, splenomegaly, bone marrow reticulin fibrosis, and circulating hairy cells. Less commonly, there may be involvement of the liver and lymph nodes. We present a case of a 53-year-old man with HCL who was found to have soft tissue masses within the mediastinum and neck during pretreatment workup. An F-FDG PET/CT scan was requested to assess these lesions before treatment. These extensive infiltrates were FDG avid, and core biopsy of the mediastinal tissue was undertaken. Results were consistent with HCL. PMID:25783506

  16. Cotreatment of hairy cell leukemia and melanoma with the BRAF inhibitor dabrafenib.

    PubMed

    Blachly, James S; Lozanski, Gerard; Lucas, David M; Grever, Michael R; Kendra, Kari; Andritsos, Leslie A

    2015-01-01

    The activating BRAF mutation p.V600E has been identified in many cancers, including colon and lung adenocarcinomas, papillary thyroid cancer, malignant melanoma, and hairy cell leukemia (HCL). Malignant melanoma and HCL are of particular interest because of both the high proportion of cases harboring the mutation and the dramatic responses to BRAF inhibitor therapy reported in the literature. This report presents a patient with HCL and malignant melanoma with the BRAF p.V600E mutation, and discusses the successful treatment of both cancers with the BRAF inhibitor dabrafenib. PMID:25583765

  17. NFkB is activated by multiple mechanisms in hairy cell leukemia.

    PubMed

    Nagel, Stefan; Ehrentraut, Stefan; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans G; MacLeod, Roderick A F

    2015-07-01

    Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder of unclear pathogenesis. Recent studies have identified BRAF(V600E) mutations in most HCL patients, highlighting this abnormality as a molecular hallmark for this disease. Cell lines originating from HCL patients lack BRAF mutations but retain the typical piliferous morphology and the distinctive HCL immunophenotype, thus, constituting suitable tools for identifying alternative tumor genes and leukemic mechanisms in this malignancy. To this end, we integrated genomic and transcriptional profiling of the HCL cell line MLMA. The expression levels of genomically targeted genes were compared to four HCL control cell lines, thus, identifying 91 chromosomally deregulated genes. Gene set enrichment analysis of these indicted apoptosis, proliferation, and DNA damage response as altered processes. Accordingly, prominent target genes overexpressed in this cell line include ATM, BRAF, CDK6, CUTL1/CUX1, H2AFX, and REL. Treatment of MLMA with selective pharmacological inhibitors and specific siRNA-mediated gene knockdowns highlighted a central role for NFkB in their deregulation in HCL. Moreover, relevant expression profiling data from HCL and ABC-DLBCL cell lines display elevated NFkB-pathway activity when compared to GC-DLBCL equivalents. Finally, analysis of HCL patient samples in silico collectively supported the clinical significance of NFkB activation in this disease. In conclusion, we identified deregulated genes and multiple mechanisms underlying aberrantly activated NFkB-pathway in HCL. Therefore, NFkB may represent a B-cell specific hallmark of HCL and a promising novel therapeutic target, most notably in patients lacking BRAF mutations in this entity including variant HCL. © 2015 Wiley Periodicals, Inc. PMID:25960206

  18. Hairy cell sarcoma

    PubMed Central

    Waxman, Jonathan H. Y.

    1983-01-01

    The first case of a hairy cell sarcoma is presented. Subsequent to surgical resection and post-operative radiotherapy the patient has survived two years without systemic evidence of hairy cell leukaemia. ImagesFig. 1 PMID:6866872

  19. BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity

    PubMed Central

    Pettirossi, Valentina; Santi, Alessia; Imperi, Elisa; Russo, Guido; Pucciarini, Alessandra; Bigerna, Barbara; Schiavoni, Gianluca; Fortini, Elisabetta; Spanhol-Rosseto, Ariele; Sportoletti, Paolo; Mannucci, Roberta; Martelli, Maria Paola; Klein-Hitpass, Ludger; Falini, Brunangelo

    2015-01-01

    Hairy cell leukemia (HCL) shows unique clinicopathological and biological features. HCL responds well to purine analogs but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF–mitogen-activated protein kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (vemurafenib; dabrafenib) or MEK (trametinib) inhibitors. Results were validated in vivo in samples from vemurafenib-treated HCL patients within a phase 2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, tartrate-resistant acid phosphatase, and cyclin D1, smoothening of leukemic cellshairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by coculture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL. PMID:25480661

  20. Kytococcus schroeteri Bacteremia in a Patient with Hairy Cell Leukemia: A Case Report and Review of the Literature

    PubMed Central

    Amaraneni, Akshay; Malik, Devin; Jasra, Sakshi; Chandana, Sreenivasa R.; Garg, Deepak

    2015-01-01

    The Kytococcus genus formerly belonged to Micrococcus. The first report of a Kytococcus schroeteri infection was in 2002 in a patient diagnosed with endocarditis. We report a case of central line associated Kytococcus schroeteri bacteremia in a patient with underlying Hairy Cell Leukemia. Kytococcus schroeteri is an emerging infection in the neutropenic population and in patients with implanted artificial tissue. It is thought to be a commensal bacterium of the skin; however, attempts to culture the bacteria remain unsuccessful. There have been a total of 5 cases (including ours) of K. schroeteri bacteremia in patients with hematologic malignancies and neutropenia and only 18 documented cases in any population. Four of the cases of bacteria in neutropenic patients have been fatal, but early detection and treatment could make a difference in clinical outcomes.

  1. Incidence of Response and Long-Term Follow-Up in Patients With Hairy Cell Leukemia Treated With Recombinant Interferon Alfa-2a

    Microsoft Academic Search

    Ellin Berman; Glenn Heller; Sanford Kempin; Timothy Gee; Ly-Le Tran; Bayard Clarkson

    1990-01-01

    HE EFFICACY OF partially purified alfa interferon T (IFN-a) in patients with hairy cell leukemia (HCL) was first reported in 1984 by Quesada et a1.l Shortly thereafter, two recombinant preparations, rIFN-a2a (Rof- eron-A; Hoffmann-LaRoche Inc, Nutley, NJ) and rIFN-a2b (Intron-A; Schering Corp, Kenilworth, NJ), identical in structure except at amino acid 23, entered clinical trials in the United States and

  2. Primary hairy cell leukemia/lymphoma of the breast: a case report and review of the literature.

    PubMed

    Pilichowska, Monika; Shariftabrizi, Ahmad; Mukand-Cerro, Ian; Miller, Kenneth

    2014-01-01

    Hairy cell leukemia/lymphoma (HCL) is a rare B-cell neoplasm primarily involving spleen, bone marrow, and blood. However, other sites of primary involvement do occur and can present a diagnostic and therapeutic challenge. We present an unusual case of HCL involving predominantly the breast that was diagnosed as an incidental finding during an elective reduction mammoplasty in an otherwise healthy asymptomatic woman. Bone marrow performed for staging revealed limited involvement by HCL. Notably, there was no splenomegaly and/or involvement of other extramedullary sites. The peripheral blood revealed minimal involvement detected by flow cytometry. Extensive immunohistochemical studies supported by positive BRAF V600E mutational status confirmed the diagnosis of HCL. The patient remains asymptomatic without treatment one year following the diagnosis. This is the first case of a well-documented HCL presenting primarily in the breast in an asymptomatic patient. We review the literature on extramedullary, extrasplenic involvement by HCL and discuss the diagnostic challenges as well as the utility of immunohistochemistry and molecular studies in the diagnosis of atypical presentations of HCL. PMID:25133005

  3. Immunohistochemical Detection of Cyclin D1 Using Optimized Conditions Is Highly Specific for Mantle Cell Lymphoma and Hairy Cell Leukemia

    Microsoft Academic Search

    Roberto N. Miranda; Robert C. Briggs; Marsha C. Kinney; Pat A. Veno; Richard D. Hammer; John B. Cousar

    2000-01-01

    Mantle cell lymphoma (MCL) is more aggressive when compared with other lymphomas composed of small, mature B lymphocytes. Cyclin D1 is overexpressed in MCL as a result of the translocation t(11;14)(q13;q32). Cyclin D1 immunohistochemistry in fixed, paraffin-embedded tissue contributes to the precise and reproducible diagnosis of MCL without the requirement of fresh tissue. However, its use in bone marrow biopsies

  4. Drugs Approved for Leukemia

    MedlinePLUS

    ... Questions to Ask Your Doctor about Treatment Research Drugs Approved for Leukemia This page lists cancer drugs ... Hairy Cell Leukemia Drugs Approved for Meningeal Leukemia Drugs Approved for Acute Lymphoblastic Leukemia (ALL) Abitrexate (Methotrexate) ...

  5. 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, Enik?

    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. PMID:24092261

  6. What Is Chronic Lymphocytic Leukemia?

    MedlinePLUS

    ... of this document focuses mainly on CLL in adults, with some limited information on hairy cell leukemia. For information on other types of leukemia in adults and children, please see our separate documents on ...

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

    ClinicalTrials.gov

    2015-06-29

    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; Waldenström Macroglobulinemia; 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

  8. 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…

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

    ClinicalTrials.gov

    2015-06-08

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

  10. 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

  11. Reactivity of Acute Lymphoblastic Leukemia and Normal Bone Marrow Cells with the Monoclonal Anti-B-Lymphocyte Antibody, Anti-Y 29\\/551

    Microsoft Academic Search

    Andreas Hirt; Christoph Baumgartner; Paul Imbach; Hans P. Wagner

    Malignant lymphocyte populations in peripheral blood of pa tients with B-cell chronic lymphocytic leukemia, leukemic variant of B-cell non-Hodgkin's lymphoma, and hairy cell leukemia can be characterized by the use of a monoclonal murine antibody (anti-Y 29\\/55) which is directed against a cell membrane com ponent normally confined to the sessile nonrecirculating cells of the B-lymphocyte population in lymphoid tissues.

  12. 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. ...

  13. 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/?L 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

  14. Leukemia among participants in military maneuvers at a nuclear bomb test. [Plumbbob Project

    Microsoft Academic Search

    G. G. Caldwell; D. B. Kelley; C. W. Jr. Heath

    1980-01-01

    Preliminary studies indicate that nine cases of leukemia have occurred among 3224 men who participated in military maneuvers during the 1957 nuclear test explosion Smoky. This represents a significant increase over the expected incidence of 3.5 cases. They included four cases of acute myelocytic leukemia, three of chronic myelocytic leukemia, and one each of hairy cell and acute lymphocytic leukemia.

  15. 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

  16. Adult T-cell leukemia-lymphoma.

    PubMed Central

    Neely, S M

    1989-01-01

    Adult T-cell leukemia-lymphoma, an aggressive T-cell leukemia, is characterized by the presence in the peripheral blood of malignant T cells that have highly indented or lobulated nuclei. Phenotypically the cells are usually helper T cells, but functionally they behave as suppressor cells. Patients have skin and lung involvement, hepatosplenomegaly, moderate lymphadenopathy sparing the mediastinum, and various metabolic abnormalities such as hypercalcemia. The clinical course may be chronic or acute, usually followed by a rapidly progressive terminal course. Adult T-cell leukemia-lymphoma is now known to be caused by human T-cell lymphotropic virus type I, which has been identified in the cells of patients with the disease. PMID:2662614

  17. Leukemia cells induce changes in human bone marrow stromal cells

    PubMed Central

    2013-01-01

    Background Bone marrow stromal cells (BMSCs) are multipotent cells that support angiogenesis, wound healing, and immunomodulation. In the hematopoietic niche, they nurture hematopoietic cells, leukemia, tumors and metastasis. BMSCs secrete of a wide range of cytokines, growth factors and matrix proteins which contribute to the pro-tumorigenic marrow microenvironment. The inflammatory cytokines IFN-? and TNF-? change the BMSC secretome and we hypothesized that factors produced by tumors or leukemia would also affect the BMSC secretome and investigated the interaction of leukemia cells with BMSCs. Methods BMSCs from healthy subjects were co-cultured with three myeloid leukemia cell lines (TF-1, TF-1? and K562) using a trans-well system. Following co-culture, the BMSCs and leukemia cells were analyzed by global gene expression analysis and culture supernatants were analyzed for protein expression. As a control, CD34+ cells were also cocultured with BMSCs. Results Co-culture induced leukemia cell gene expression changes in stem cell pluripotency, TGF-? signaling and carcinoma signaling pathways. BMSCs co-cultured with leukemia cells up-regulated a number of proinflammatory genes including IL-17 signaling-related genes and IL-8 and CCL2 levels were increased in co-culture supernatants. In contrast, purine metabolism, mTOR signaling and EIF2 signaling pathways genes were up-regulated in BMSCs co-cultured with CD34+ cells. Conclusions BMSCs react to the presence of leukemia cells undergoing changes in the cytokine and chemokine secretion profiles. Thus, BMSCs and leukemia cells both contribute to the creation of a competitive niche more favorable for leukemia stem cells. PMID:24304929

  18. Adult T-cell leukemia/lymphoma

    PubMed Central

    Burch, Micah; Krause, John R.

    2014-01-01

    Adult T-cell leukemia/lymphoma is a rare malignancy associated with the human retrovirus human T-cell lymphotropic virus type 1. It is characterized by the proliferation of highly pleomorphic lymphocytes. Involvement of peripheral blood, bone marrow, lymph nodes, spleen, and extranodal sites such as skin, liver, gastrointestinal tract, and central nervous system can occur. There are four distinct clinical variants, and the prognosis and clinical course range from highly aggressive to a more protracted course depending on the subtype. We describe a man with de novo adult T-cell leukemia/lymphoma and discuss the unique clinical, morphologic, immunophenotypic, and molecular features of this entity. PMID:24982574

  19. Autofluorescence characteristics of human leukemia cells and mononuclear cells

    NASA Astrophysics Data System (ADS)

    Xiao, Lifu; Liao, Xiaoying; Lin, Lisheng; Huang, Huifang; Chen, Yuanzhong; Li, Buhong

    2010-11-01

    Autofluorescence spectroscopy is a powerful method to identify the endogenous fluorophores in normal and cancerous cells. The purpose of this study is to characterize the autofluorescence spectra of human normal and leukemia cells. Autofluorescence measurements of each cell line are performed over a wide range of cell concentrations. All of the leukemia cells indicate a statistically significant increase in the tryptophan fluorescence relative to that of the normal cells, while no statistically significant differences are observed in the reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD) fluorescence between the normal and leukemia cells. The results suggest that the differences in autofluorescence spectra for leukemia cells and mononuclear cells may be attributed in part to differences in endogenous fluorophores of different cells.

  20. Effects of cycloartane saponins from hairy roots of Astragalus membranaceus Bge., on human tumor cell targets.

    PubMed

    Ionkova, I; Momekov, G; Proksch, P

    2010-07-01

    For the first time three different natural compounds, isolated from hairy roots of Astragalus membranaceus, cultivated in airlift bioreactor were tested for their cytotoxic potential and apoptosis induction in a panel of human tumor cell lines. Root cultures, cultivated in bioreactor gave 18.5 g l(-1) dry wt roots with the highest astragaloside production in vitro up to now - 1.64% (astragaloside I), 1.12% (astragaloside II) and 1.08% (astragaloside III). In this manner the production in airlift bioreactor can be used as means of reliable supply of cycloartane saponins to extend the research to human clinical studies. PMID:20060881

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

    SciTech Connect

    Wang, Jiying [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020 (China)] [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020 (China); Rao, Qing, E-mail: raoqing@gmail.com [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020 (China)] [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020 (China); Wang, Min; Wei, Hui; Xing, Haiyan; Liu, Hang; Wang, Yanzhong; Tang, Kejing; Peng, Leiwen; Tian, Zheng; Wang, Jianxiang [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020 (China)] [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020 (China)

    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.

  2. 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

  3. 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

    2013-07-03

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

  4. Mast cell leukemia: an extremely rare disease.

    PubMed

    Lu, Dai-Yin; Gau, Jyh-Pyng; Hong, Ying-Chung; Liu, Chun-Yu; Yu, Yuan-Bin; Hsiao, Liang-Tsai; Liu, Jin-Hwang; Chen, Po-Min; Chiou, Tzeon-Jye; Tzeng, Cheng-Hwai

    2014-08-01

    Systemic mastocytosis is characterized by pathologic proliferation and accumulation of mast cells in at least one extracutaneous organ such as liver, spleen, bone marrow, or lymph nodes. The clinical features are highly variable depending on impairment of the involved organ systems. It often raises diagnostic challenges. Here we report a case of a 78-year-old patient with mast cell leukemia. The literature is reviewed regarding the diagnosis and updated management of this rare disease. PMID:25028296

  5. [Expression of Smad4 in leukemia cells].

    PubMed

    Zhang, Yan; Cao, Xu; Jiang, Ming; Ha, Li-Dai; Wen, Bing-Zhao; Li, Ling; Liu, Hui; Zhong, Di; Lin, Ren-Yong; Lu, Xiao-Mei; Feng, Xiao-Hui; Wen, Hao

    2006-08-01

    Loss of transforming growth factor (TGF)-beta signaling has been implicated in malignant transformation of various tissues. Smad4 plays a central role in the signal transduction of TGF-beta. Deletion or mutation of Smad4 has been described in a number of cancers. This study was aimed to investigate a potential role of Smad4 in leukemia including its expression and location in blast cells. The mononuclear cells were separated from bone marrow of leukemia patients. The samples, blast cells of which were more than 90% in mononuclear cells, were selected. The expression and location of Smad4 protein were analyzed by immunohistochemistry methods. The results showed that the Smad4 protein located mainly in nucleus, part of this protein located in cytoplasma, the expressions of Smad4 were not detected in 6 out of 9 ALL patients, in 7 out of 24 AML patients and in 1 out of 2 CML patients; these leukemia patients, in whose cells the expression of Smad4 was not detected, included one L1 and one L3, four L2, one M0, one M1, two M2a, one M3a, one M4b, one M6 and one CML. In conclusion, the Smad4 protein was mainly in nucleus, the deletion or functional change of Smad4 may related with the pathogenesis of human AML. PMID:16928297

  6. 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

  7. Hairy-Cell Leukaemia Associated with AutoImmune Disorders in the Form of a ‘Lupus-Type’ Anticoagulant and a Positive Direct Coombs’ Test

    Microsoft Academic Search

    C. Richard; M. C. Sedano; F. Mázorra; M. Redo; M A Cuadrado; C. Bello; M. A. Gandarillas; A. Zubizarreta

    1986-01-01

    An account is given of a case of hairy-cell leukaemia associated with a ‘lupus-type’ anticoagulant and a positive direct Coombs’ test, both of which were clinically symptom free. This is yet another example of the coexistence of hairy-cell leukaemia and an auto-immune disorder, but the disorder in question has not been described previously.Copyright © 1986 S. Karger AG, Basel

  8. CXCR4 Is Required for Leukemia-Initiating Cell Activity in T Cell Acute Lymphoblastic Leukemia.

    PubMed

    Passaro, Diana; Irigoyen, Marta; Catherinet, Claire; Gachet, Stéphanie; Da Costa De Jesus, Cindy; Lasgi, Charlène; Tran Quang, Christine; Ghysdael, Jacques

    2015-06-01

    Impaired cell migration has been demonstrated in T cell acute lymphoblastic leukemia (T-ALL) cells upon calcineurin inactivation, among other phenotypic traits including increased apoptosis, inhibition of cell proliferation, and ultimately inhibition of leukemia-initiating cell (LIC) activity. Herein we demonstrate that the chemokine receptor CXCR4 is essential to the LIC activity of T-ALL leukemic cells both in NOTCH-induced mouse T-ALL and human T-ALL xenograft models. We further demonstrate that calcineurin regulates CXCR4 cell-surface expression in a cortactin-dependent manner, a mechanism essential to the migratory properties of T-ALL cells. Because 20%-25% of pediatric and over 50% of adult patients with T-ALL do not achieve complete remission and relapse, our results call for clinical trials incorporating CXCR4 antagonists in T-ALL treatment. PMID:26058076

  9. Human Adult T-Cell Leukemia Virus: Complete Nucleotide Sequence of the Provirus Genome Integrated in Leukemia Cell DNA

    Microsoft Academic Search

    Motoharu Seiki; Seisuke Hattori; Yoko Hirayama; Mitsuaki Yoshida

    1983-01-01

    Human retrovirus adult T-cell leukemia virus (ATLV) has been shown to be closely associated with human adult T-cell leukemia (ATL) [Yoshida, M., Miyoshi, I. & Hinuma, Y. (1982) Proc. Natl. Acad. Sci. USA 79, 2031-2035]. The provirus of ATLV integrated in DNA of leukemia T cells from a patient with ATL was molecularly cloned and the complete nucleotide sequence of

  10. Anti-leukemia T cells in AML

    PubMed Central

    Flörcken, Anne; van Lessen, Antje; Terwey, Theis H.; Dörken, Bernd; Arnold, Renate; Pezzutto, Antonio; Westermann, Jörg

    2013-01-01

    Leukemia-associated antigens such as proteinase-3 (PR3) and Wilms´ tumor protein-1 (WT-1) are potential targets of T-cell responses, which can be monitored by T-cell assays within vaccination trials and after allogeneic stem cell transplantation (SCT). In chronic myeloid leukemia (CML) an aberrant cytokine profile of antigen-specific T-cells with predominant TNF-a secretion has previously been described. The aim of this study was to investigate whether these TNF-?+/IFN-?- CD8+ T-cells can also be observed in AML patients after SCT. Eight HLA-A2+ AML patients at different time points after SCT were evaluated for HLA-A2-restricted CD8+ T-cell responses against PR3, WT-1 and influenza-A using pentamer staining and different cytokine-based T-cell assays. Antigen-specific T-cell immune responses against influenza-A and PR3 were observed in 4/8 patients, WT-1-specific T-cells could be detected in in 3/8 patients. Interestingly, four different cytokine secretion profiles of antigen-specific T-cells were detected:1 IFN-?+/TNF-?+,2 IFN-?+/TNF-?-,3 TNF-?+/ IFN-?- and4 IFN-?-/TNF-?-. TNF-?+/ IFN-?- CD8+ T-cells are an interesting biological phenomenon which can obviously be observed also in AML patients. This finding has important implications for both T-cell biology and monitoring within immunotherapy trials. The functional characterization of these TNF-?+/ IFN-?- CD8+ T-cells needs further investigations. PMID:23571180

  11. Leukemia

    MedlinePLUS

    ... A-Z > Leukemia: What Is Leukemia? In This Topic What Is Leukemia? Who Is at Risk? Symptoms ... for More Information National Institute on Aging Related Topics Life After Cancer Other Cancer Topics The information ...

  12. BRAF mutation detection in hairy cell leukaemia from archival haematolymphoid specimens.

    PubMed

    Thomas, Carla; Amanuel, Benhur; Finlayson, Jill; Grieu-Iacopetta, Fabienne; Spagnolo, Dominic V; Erber, Wendy N

    2015-06-01

    Hairy cell leukaemia (HCL) is a rare, indolent chronic B-cell leukaemia accounting for approximately 2% of all adult leukaemias. The recent association of the BRAF p.Val600Glu (V600E) mutation in HCL makes it a valuable molecular diagnostic marker. We compared the ability of Sanger sequencing, fluorescent single-strand conformational polymorphism (F-SSCP) and high resolution melting (HRM) analysis to detect BRAF mutations in 20 cases of HCL consisting of four archival Romanowsky stained air-dried peripheral blood and bone marrow aspirate smears, 12 mercury fixed decalcified bone marrow trephine biopsies, three formalin fixed, paraffin embedded (FFPE) splenectomy samples and one fresh peripheral blood sample. DNA was amplified and BRAF mutation status determined by the three methods above. V600E mutation was identified in 94%, 89% and 72% of HCL cases by F-SSCP, HRM and Sanger sequencing, respectively. In one case, in addition to the p.Val600Glu mutation, a p.Lys601Thr (K601T) mutation was identified. DNA from archival slide scrapings, mercury-fixed and FFPE tissue can be used to identify BRAF mutations with high sensitivity, especially using HRM/F-SSCP. The V600E mutation can be used as a supplementary molecular marker to aid in the diagnosis of HCL and the presence of the mutation may provide a target for therapy. PMID:25938346

  13. Monoclonal Integration of Human T-Cell Leukemia Provirus in All Primary Tumors of Adult T-Cell Leukemia Suggests Causative Role of Human T-Cell Leukemia Virus in the Disease

    Microsoft Academic Search

    M. Yoshida; M. Seiki; K. Yamaguchi; K. Takatsuki

    1984-01-01

    The genome of human T-cell leukemia virus (HTLV) was surveyed in fresh tumor cells of 163 patients with lymphoma and leukemia from the southwest part of Japan where adult T-cell leukemia (ATL) is endemic. Leukemic cells of all 88 cases of ATL tested so far were found to contain the provirus genome and also found to be monoclonal with respect

  14. A genomic analysis of adult T-cell leukemia

    Microsoft Academic Search

    Y L Choi; K Tsukasaki; M C O'Neill; Y Yamada; Y Onimaru; K Matsumoto; J Ohashi; Y Yamashita; S Tsutsumi; R Kaneda; S Takada; H Aburatani; S Kamihira; T Nakamura; M Tomonaga; H Mano

    2007-01-01

    Adult T-cell leukemia (ATL) is an intractable malignancy of CD4+ T cells that is etiologically associated with infection by human T-cell leukemia virus-type I. Most individuals in the chronic stage of ATL eventually undergo progression to a highly aggressive acute stage. To clarify the mechanism responsible for this stage progression, we isolated CD4+ cells from individuals in the chronic (n=19)

  15. Stem Cell Biomarkers in Chronic Myeloid Leukemia

    PubMed Central

    Jiang, Xiaoyan; Zhao, Yun; Forrest, Donna; Smith, Clayton; Eaves, Allen; Eaves, Connie

    2008-01-01

    Chronic myeloid leukemia (CML) is a clonal multi-step myeloproliferative disease that is initially produced and ultimately sustained by a rare subpopulation of BCR-ABL+ cells with multi-lineage stem cell properties. These BCR-ABL+ CML stem cells are phenotypically similar to normal hematopoietic stem cells which are also maintained throughout the course of the disease at varying levels in different patients. Defining the unique properties of the leukemic stem cells that produce the chronic phase of CML has therefore had to rely heavily on access to samples from rare patients in which the stem cell compartment is dominated by leukemic elements. Here we review past and ongoing approaches using such samples to identify biologically and clinically relevant biomarkers of BCR-ABL+ stem cells that explain their unusual biology and that may help to design, or at least predict, improved treatment responses in CML patients. These studies are of particular interest in light of recent evidence that chronic phase CML stem cells are not only innately resistant to imatinib mesylate and other drugs that target the BCR-ABL oncoprotein, but are also genetically unstable. PMID:18525114

  16. Dendritic cell leukemia in a Golden Retriever.

    PubMed

    Allison, Robin W; Brunker, Jill D; Breshears, Melanie A; Avery, Anne C; Moore, Peter F; Affolter, Verena K; Vernau, William

    2008-06-01

    An 8-year-old castrated male Golden Retriever was evaluated for decreased appetite, lethargy, and labored breathing of 1-week duration. Bilateral pulmonary infiltrates, hepatomegaly, and splenomegaly were present. Results of a CBC revealed marked leukocytosis (62,600/microL; reference interval 4000-15,500/microL) and large numbers of atypical cells (30,700/microL) with abundant cytoplasm. There was no concurrent anemia, neutropenia, or thrombocytopenia. Morphology of the atypical cells was most consistent with a histiocytic origin. Similar cells were identified in bone marrow aspirates, and were morphologically suggestive of the macrophage variant of disseminated histiocytic sarcoma. However, flow cytometry of the abnormal circulating cells revealed CD1c, CD11c, and major histocompatibility complex (MHC) Class II expression without expression of CD11d or lymphoid markers, consistent with myeloid dendritic antigen-presenting cells. At necropsy, the splenic architecture was effaced by neoplastic histiocytes that were also infiltrating lung, liver, an abdominal lymph node, myocardium, an bone marrow. Immunohistochemistry of the splenic neoplastic cells confirmed dendritic cell origin (CD1c+, CD11c+, MHC II+, no expression of CD11d and lymphoid markers). To the authors' knowledge, this is the first report of canine dendritic cell leukemia-in this instance accompanied by marked tissue infiltration. PMID:18533919

  17. 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

  18. Long-term follow-up and second malignancies in 487 patients with hairy cell leukaemia.

    PubMed

    Cornet, Edouard; Tomowiak, Cécile; Tanguy-Schmidt, Aline; Lepretre, Stéphane; Dupuis, Jehan; Feugier, Pierre; Devidas, Alain; Mariette, Clara; Leblond, Véronique; Thiéblemont, Catherine; Validire-Charpy, Patricia; Sutton, Laurent; Gyan, Emmanuel; Eisenmann, Jean-Claude; Cony-Makhoul, Pascale; Ysebaert, Loïc; Troussard, Xavier

    2014-08-01

    A large, multicentre, retrospective survey of patients with hairy cell leukaemia (HCL) was conducted in France to determine the frequency of second malignancies and to analyse the long-term effects of the established purine nucleoside analogues (PNAs), cladribine and pentostatin. The survey retrospectively reviewed the medical history of patients and their immediate family, clinical and biological presentation at the time of HCL diagnosis, treatment choice, response to treatment, time to relapse and cause of death. Data were collected for 487 patients with HCL. Of the patients included in the survey, 18% (88/487) had a familial history of cancers, 8% (41/487) presented with malignancies before HCL diagnosis and 10% (48/487) developed second malignancies after HCL was diagnosed. An excess incidence of second malignancies was observed, with a standardized incidence ratio (SIR) of 1·86 (95% confidence interval (CI): 1·34-2·51), with no significant difference between PNAs. For second haematological malignancies alone, the SIR was markedly increased at 5·32 (95% CI: 2·90-8·92). This study highlights the high frequency of cancers in HCL patients and their family members. The frequency of second malignancies is notably increased, particularly for haematological malignancies. The respective role of pentostatin and cladribine in the development of second malignancies is debatable. PMID:24749839

  19. Leukemia-associated genetic aberrations in mesenchymal stem cells of children with acute lymphoblastic leukemia

    Microsoft Academic Search

    Shabnam Shalapour; Cornelia Eckert; Karl Seeger; Madlen Pfau; Javier Prada; Günter Henze; Thomas Blankenstein; Thomas Kammertoens

    2010-01-01

    Childhood acute lymphoblastic leukemia (ALL) is caused by malignant immature lymphocytes. Even though childhood ALL can be\\u000a cured in a large number of patients, around 20% of the patients suffer a relapse after chemotherapy. The origin of the relapse\\u000a is unclear at the present time. Given the high plasticity of cells, we searched for leukemia-associated genetic aberrations\\u000a and immunoglobulin (IG)

  20. Crystal structure of human T cell leukemia virus protease, a novel target for anticancer drug design

    E-print Network

    Crystal structure of human T cell leukemia virus protease, a novel target for anticancer drug the structure of a complex of human T cell leukemia virus type 1 (HTLV-1) PR with a substrate- based inhibitor of such anticancer therapies. inhibitor leukemia retroviral protease Human T cell leukemia virus type 1 (HTLV-1

  1. Common acute lymphoblastic leukemia antigen expressed on leukemia and melanoma cell lines has neutral endopeptidase activity.

    PubMed Central

    Jongeneel, C V; Quackenbush, E J; Ronco, P; Verroust, P; Carrel, S; Letarte, M

    1989-01-01

    We have previously reported that the amino acid sequence of the common acute lymphoblastic leukemia antigen (CALLA, CD10) translated from a normal human kidney cDNA clone is identical to that of neutral endopeptidase (NEP, EC 3.4.24.11). In this study, we show that by flow cytometry, a monoclonal antibody (135A3) produced against rabbit NEP reacted selectively with leukemia and melanoma cell lines expressing CALLA on their surface. A glycoprotein of apparent Mr 100,000 was immunoprecipitated from surface labeled NALM-1 leukemia or Mel-1477 melanoma cells with monoclonal antibodies to NEP (135A3) or CALLA (44C10). mRNAs hybridizing to a NEP-specific probe were present in CALLA+ leukemia and melanoma cell lines, but absent from CALLA- lines. NEP enzymatic activity was detected on intact cells from CALLA+ lines, but not CALLA- lines. The activity was blocked by two selective inhibitors of NEP, thiorphan and phosphoramidon. CALLA antigen purified from the NALM-6 leukemic cell line by affinity to 44C10-IgG Sepharose retained a peptidase activity that was completely blocked by thiorphan and phosphoramidon. Thus the CALLA antigen present at the surface of leukemia and melanoma cell lines is an enzymatically active neutral endopeptidase. Images PMID:2521492

  2. Leukemia

    MedlinePLUS

    ... FR. The acute leukemias. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 24th ed. Philadelphia, Pa: ... Brien S. The chronic leukemias. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 24th ed. Philadelphia, Pa: ...

  3. 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

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

    ClinicalTrials.gov

    2015-05-18

    Chronic Lymphocytic Leukemia in Remission; 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

  5. Dietary bioflavonoids induce apoptosis in human leukemia cells

    Microsoft Academic Search

    Jun Matsui; Nobutaka Kiyokawa; Hisami Takenouchi; Tomoko Taguchi; Kyoko Suzuki; Yusuke Shiozawa; Masahiro Saito; Wei-ran Tang; Yohko U. Katagiri; Hajime Okita; Junichiro Fujimoto

    2005-01-01

    Dietary bioflavonoids are secondary metabolites of plants that are known to have a variety of bio-effects, including anti-cancer activity. In this study, we examined the effects of flavonoids on the growth of human leukemia cells and found that certain flavonoids induce apoptosis in a variety of human leukemia cells. The apoptosis induced by bioflavonoids was dose-dependent and was accompanied by

  6. Dietary bioflavonoids induce apoptosis in human leukemia cells

    Microsoft Academic Search

    Jun Matsui; Nobutaka Kiyokawa; Hisami Takenouchi; Tomoko Taguchi; Kyoko Suzuki; Yusuke Shiozawa; Masahiro Saito; Wei-ran Tang; Yohko U. Katagiri; Hajime Okita; Junichiro Fujimoto

    Dietary bioflavonoids are secondary metabolites of plants that are known to have a variety of bio-effects, including anti-cancer activity. In this study, we examined the effects of flavonoids on the growth of human leukemia cells and found that certain flavonoids induce apoptosis in a variety of human leukemia cells. The apoptosis induced by bioflavonoids was dose-dependent and was accompanied by

  7. Plasma cell leukemia: from biology to treatment.

    PubMed

    Jelinek, Tomas; Kryukov, Fedor; Rihova, Lucie; Hajek, Roman

    2015-07-01

    Plasma cell leukemia (PCL) is a very aggressive and rare form of malignant monoclonal gammopathy characterized by the presence of plasmocytes in peripheral blood. It is classified as primary PCL occuring 'de novo', or as secondary PCL in patients with relapsed/refractory multiple myeloma. Primary PCL is a distinct clinicopathological entity from myeloma with different cytogenetic abnormalities and molecular findings, which are usually found only in advanced multiple myeloma. The clinical course is aggressive with short remissions and reduced overall survival. The diagnostic criteria are based on the percentage (>20%) and absolute number (2 × 10(9) /L) of plasma cells in peripheral blood. After establishing diagnosis, induction therapy should begin promptly which is aimed to rapid disease control and to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens, followed by high-dose therapy with autologous stem cell transplantation, are recommended. Allogeneic transplantation can be considered in younger patients. This article reviews recent knowledge of this hematological malignancy that is associated with a very poor prognosis. PMID:25778450

  8. Neutrophil elastase and its therapeutic effect on leukemia cells.

    PubMed

    Jiang, Kai-Ling; Ma, Peng-Peng; Yang, Xiao-Qun; Zhong, Liang; Wang, Hui; Zhu, Xin-Yu; Liu, Bei-Zhong

    2015-09-01

    Neutrophil elastase (NE) is an early myeloid-specific serine protease, which is predominantly produced by promyelocytes. A previous study demonstrated that NE has an important role in the development of acute promyelocytic leukemia (APL). The process of APL was shown to be accelerated in animals that expressed abundant NE, whereas NE?deficient mice were protected from APL development; thus suggesting an important role for NE in the development of APL. The present study aimed to investigate the effects and possible mechanisms of NE. Up- and downregulation of NE in various leukemia cell lines was conducted in order to explore its significance in the occurrence and procession of leukemia, with the aim of identifying novel targeted therapeutic drugs for the treatment of leukemia. NE was overexpressed in cells following infection with an adenovirus, and Cell Counting kit?8 and flow cytometry results demonstrated that cell proliferation was promoted, and cell apoptosis was inhibited, as compared with the untreated cells. NE was downregulated in the cells by both RNA interference and treatment with GW311616A, a specific inhibitor of NE, following which cell growth was shown to be inhibited and apoptosis was induced. These results suggested that NE may promote the development of APL, therefore, NE may be a therapeutic target and its inhibitor GW311616A may be a potential therapeutic drug for leukemia. Furthermore, the apoptosis?associated protein B?cell lymphoma 2 (Bcl?2)?associated X protein was significantly increased, whereas Bcl?2 was markedly decreased in the cells with downregulated NE. Further experiments revealed that the probable apoptosis?associated signaling pathway was the phosphoinositide 3?kinase/AKT pathway. The present study is the first, to the best of our knowledge, to demonstrate that GW311616A, a specific NE inhibitor, may act as a potential targeted drug for leukemia, which may have a profound impact on the future of leukemia-targeted therapy. PMID:26081156

  9. Biclonal light chain gammopathy with aberrant CD33 expression in secondary plasma cell leukemia

    PubMed Central

    Gentry, Michael; Pettenati, Mark; Pang, Changlee S

    2013-01-01

    Plasma cell leukemia is a rare neoplastic proliferation of circulating plasma cells. Clonal proliferations of plasma cells, such as in plasma cell leukemia or plasma cell myeloma, are typically characterized by production of a monoclonal heavy and/or light chain immunoglobulin. We present a case of a secondary plasma cell leukemia arising from plasma cell myeloma with dual expression of lambda and kappa light chains along with aberrant expression of CD33, CD20, and dim CD56. This case emphasizes the importance of recognizing aberrant immunophenotypes in plasma cell leukemias and represents the first reported case of biclonal light chain expression in a secondary plasma cell leukemia. PMID:24133602

  10. Malignancy: 2'-Chlorodeoxyadenosine Effectively Induces Complete Remission in Hairy Cell Leukaemia.

    PubMed

    Jacobs, PETER; Wood, LUCILLE; Mansvelt, ERNA P. G.; Gartrell, KEVIN

    2000-01-01

    Hairy cell leukaemia, previously known as leukaemic reticuloendotheliosis, is an indolent lymphoproliferative disorder of unknown etiology. It typically affects males, causes marked splenomegaly and moderate enlargement of the liver, whilst lymphadenopathy is inconspicuous. Pancytopenia is characteristic with unusually profound monocytopenia, variable reduction in platelets, and the presence in the peripheral blood and marrow of abnormal small lymphocytes having irregular cytoplasmic margins. Ultrastructure, combined with cytochemistry and flow cytometry, have refined diagnosis. A variant exists between this classical entity and B prolymphocytic leukaemia, where blastic transformation or massive lymph node enlargement are found, and this is of ominous significance. In all these patients with this entity conventional chemotherapy is ineffective and shortens survival. Our previous experience with splenectomy results in excellent clinical control for long periods of time, but without disease eradication. There followed a vogue for the use of interferon but this is limited by high cost and dose-dependent side-effects. Contemporary management centres on the purine analogues, where durable responses are possible with fludarabine and deoxycoformycin, but best with 2'chlorodeoxyadenosine (2-CDA). To document the efficacy of the latter agent, we analysed the outcome in seventeen consecutive patients treated over the last five years. Four were ineligible for analysis, although two had 2-CDA. The other thirteen, managed on a standard seven-day course of 0.1 mg/kg 2-CDA given as a continuous intravenous infusion, all responded promptly. Apart from transient leucopenia complications have been minimal, and oral co-trimoxazole prophylaxis for pneumocystis carinii was maintained during the first one year. In all thirteen there was a rapid return to normal of peripheral blood count and marrow on aspiration and trephine biopsy. Even in the longest follow-up clinical and haematologic remission has been maintained and no patients have required retreatment. One individual has relapsed in the marrow at two years. Despite the relative expense of the agent the excellent treatment outcome and patient acceptability, coupled with its safety, leads to the recommendation that in South Africa - as elsewhere in the world - this be regarded as the first line of treatment. PMID:11399582

  11. Multiple transformation of plant cells by Agrobacterium may be responsible for the complex organization of T-DNA in crown gall and hairy root

    Microsoft Academic Search

    Annik Petit; André Berkaloff; Jacques Tempé

    1986-01-01

    Inoculation of carrot discs and Lotus corniculatus plantlets with mixtures of different Agrobacterium rhizogenes or of A. rhizogenes and A. tumefaciens or with Agrobacterium strains harboring both an Ri and a modified Ti plasmid resulted in frequent multiple (pluribacterial) transformation of cells, as revealed by the mixed opine-type of hairy roots arising from them. Multiple transformation may account for the

  12. POSTER PRESENTATION Open Access Recurrent TET2 mutations in adult T cell leukemia

    E-print Network

    Paris-Sud XI, Université de

    POSTER PRESENTATION Open Access Recurrent TET2 mutations in adult T cell leukemia Ambroise Marçais1 this article as: Marçais et al.: Recurrent TET2 mutations in adult T cell leukemia. Retrovirology 2014 11(Suppl

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

    SciTech Connect

    Eshel, Rinat [Hematology Institute, Sourasky Medical Center, Tel-Aviv (Israel); Ben-Zaken, Olga [Department of Oncology, Hadassah-Hebrew University hospital, Jerusalem (Israel); Vainas, Oded [The Hematology Institute, Sourasky Medical Center, Tel-Aviv (Israel); Nadir, Yona [Department of Hematology, Rambam Medical Center, Haifa (Israel); Minucci, Saverio [European Institute of Oncology, Milan (Italy); Polliack, Aaron [Department of Hematology, Hadassah-Hebrew University hospital, Jerusalem (Israel); Naparstek, Ella [Hematology Institute, Sourasky Medical Center, Tel-Aviv (Israel); Vlodavsky, Israel [Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa (Israel); Katz, Ben-Zion [Hematology Institute, Sourasky Medical Center, Tel-Aviv (Israel); Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); 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.

  14. A novel self-lipid antigen targets human T cells against CD1c(+) leukemias.

    PubMed

    Lepore, Marco; de Lalla, Claudia; Gundimeda, S Ramanjaneyulu; Gsellinger, Heiko; Consonni, Michela; Garavaglia, Claudio; Sansano, Sebastiano; Piccolo, Francesco; Scelfo, Andrea; Häussinger, Daniel; Montagna, Daniela; Locatelli, Franco; Bonini, Chiara; Bondanza, Attilio; Forcina, Alessandra; Li, Zhiyuan; Ni, Guanghui; Ciceri, Fabio; Jenö, Paul; Xia, Chengfeng; Mori, Lucia; Dellabona, Paolo; Casorati, Giulia; De Libero, Gennaro

    2014-06-30

    T cells that recognize self-lipids presented by CD1c are frequent in the peripheral blood of healthy individuals and kill transformed hematopoietic cells, but little is known about their antigen specificity and potential antileukemia effects. We report that CD1c self-reactive T cells recognize a novel class of self-lipids, identified as methyl-lysophosphatidic acids (mLPAs), which are accumulated in leukemia cells. Primary acute myeloid and B cell acute leukemia blasts express CD1 molecules. mLPA-specific T cells efficiently kill CD1c(+) acute leukemia cells, poorly recognize nontransformed CD1c-expressing cells, and protect immunodeficient mice against CD1c(+) human leukemia cells. The identification of immunogenic self-lipid antigens accumulated in leukemia cells and the observed leukemia control by lipid-specific T cells in vivo provide a new conceptual framework for leukemia immune surveillance and possible immunotherapy. PMID:24935257

  15. ?-Arrestin1 promotes the self-renewal of the leukemia-initiating cell-enriched subpopulation in B-lineage acute lymphoblastic leukemia related to DNMT1 activity.

    PubMed

    Shu, Yi; Zhou, Xiaoyan; Qi, Xinkun; Liu, Shan; Li, Kang; Tan, Junjie; Liu, Zhidai; Yu, Jie; Zhang, Penghui; Zou, Lin

    2015-02-01

    The self-renewal ability of the leukemia initiating cell-enriched subpopulation is critical for leukemia initiation and maintenance. However, the regulation of leukemia initiating cells for the leukemia progression is poorly understood. In this study, we observed that ?-Arrestin1, a multiple-function protein, is elevated in leukemia initiating cells-enriched fraction from B-lineage acute lymphoblastic leukemia patients. The loss of ?-Arrestin1 in leukemia initiating cells-enriched fraction attenuates its self-renewal capacity both in vitro and in vivo. Further experiments showed that the mRNA expression level of ?-Arrestin1 is negatively correlated with that of PTEN in leukemia initiating cells-enriched fraction. Moreover, DNA methylation of the PTEN promoter region, the activity and expression of DNMTs were enhanced in the leukemia initiating cells-enriched fraction. The inhibition of DNMT1 activity impaired the self-renewal and increased expression of PTEN of leukemia initiating cells-enriched fraction. In addition, depletion of ?-Arrestin1 significantly decreased DNMT1 activity and PTEN methylation, and consistently increased PTEN expression in leukemia initiating cells-enriched fraction. Our study reveals a novel function of ?-Arrestin1 in the regulation of the self-renewal of leukemia initiating cells-enriched fraction from B-lineage acute lymphoblastic leukemia patients related to DNMT1 activity, indicating that ?-Arrestin1 is a potential therapeutic target in B-lineage acute lymphoblastic leukemia. PMID:25444908

  16. Different roles of the mevalonate and methylerythritol phosphate pathways in cell growth and tanshinone production of Salvia miltiorrhiza hairy roots.

    PubMed

    Yang, Dongfeng; Du, Xuhong; Liang, Xiao; Han, Ruilian; Liang, Zongsuo; Liu, Yan; Liu, Fenghua; Zhao, Jianjun

    2012-01-01

    Salvia miltiorrhiza has been widely used in the treatment of coronary heart disease. Tanshinones, a group of diterpenoids are the main active ingredients in S. miltiorrhiza. Two biosynthetic pathways were involved in tanshinone biosynthesis in plants: the mevalonate (MVA) pathway in the cytosol and the methylerythritol phosphate (MEP) pathway in the plastids. The 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme of the MVA pathway. The 1-deoxy-D-xylulose 5-phosphate synthase (DXS) and 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) are the key enzymes of the MEP pathway. In this study, to reveal roles of the MVA and the MEP pathways in cell growth and tanshinone production of S. miltiorrhiza hairy roots, specific inhibitors of the two pathways were used to perturb metabolic flux. The results showed that the MVA pathway inhibitor (mevinolin, MEV) was more powerful to inhibit the hairy root growth than the MEP pathway inhibitor (fosmidomycin, FOS). Both MEV and FOS could significantly inhibit tanshinone production, and FOS was more powerful than MEV. An inhibitor (D, L-glyceraldehyde, DLG) of IPP translocation strengthened the inhibitory effects of MEV and FOS on cell growth and tanshinone production. Application of MEV resulted in a significant increase of expression and activity of HMGR at 6 h, and a sharp decrease at 24 h. FOS treatment resulted in a significant increase of DXR and DXS expression and DXS activity at 6 h, and a sharp decrease at 24 h. Our results suggested that the MVA pathway played a major role in cell growth, while the MEP pathway was the main source of tanshinone biosynthesis. Both cell growth and tanshinone production could partially depend on the crosstalk between the two pathways. The inhibitor-mediated changes of tanshinone production were reflected in transcript and protein levels of genes of the MVA and MEP pathways. PMID:23209548

  17. Different Roles of the Mevalonate and Methylerythritol Phosphate Pathways in Cell Growth and Tanshinone Production of Salvia miltiorrhiza Hairy Roots

    PubMed Central

    Yang, Dongfeng; Du, Xuhong; Liang, Xiao; Han, Ruilian; Liang, Zongsuo; Liu, Yan; Liu, Fenghua; Zhao, Jianjun

    2012-01-01

    Salvia miltiorrhiza has been widely used in the treatment of coronary heart disease. Tanshinones, a group of diterpenoids are the main active ingredients in S. miltiorrhiza. Two biosynthetic pathways were involved in tanshinone biosynthesis in plants: the mevalonate (MVA) pathway in the cytosol and the methylerythritol phosphate (MEP) pathway in the plastids. The 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme of the MVA pathway. The 1-deoxy-D-xylulose 5-phosphate synthase (DXS) and 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) are the key enzymes of the MEP pathway. In this study, to reveal roles of the MVA and the MEP pathways in cell growth and tanshinone production of S. miltiorrhiza hairy roots, specific inhibitors of the two pathways were used to perturb metabolic flux. The results showed that the MVA pathway inhibitor (mevinolin, MEV) was more powerful to inhibit the hairy root growth than the MEP pathway inhibitor (fosmidomycin, FOS). Both MEV and FOS could significantly inhibit tanshinone production, and FOS was more powerful than MEV. An inhibitor (D, L-glyceraldehyde, DLG) of IPP translocation strengthened the inhibitory effects of MEV and FOS on cell growth and tanshinone production. Application of MEV resulted in a significant increase of expression and activity of HMGR at 6 h, and a sharp decrease at 24 h. FOS treatment resulted in a significant increase of DXR and DXS expression and DXS activity at 6 h, and a sharp decrease at 24 h. Our results suggested that the MVA pathway played a major role in cell growth, while the MEP pathway was the main source of tanshinone biosynthesis. Both cell growth and tanshinone production could partially depend on the crosstalk between the two pathways. The inhibitor-mediated changes of tanshinone production were reflected in transcript and protein levels of genes of the MVA and MEP pathways. PMID:23209548

  18. Primary plasma cell leukemia followed by testicular plasmacytoma.

    PubMed

    Valentini, Caterina Giovanna; Bozzoli, Valentina; Fianchi, Luana; Voso, Maria Teresa; Di Paolantonio, Gianluigi; Criscuolo, Marianna; Leone, Giuseppe; Larocca, Luigi Maria; Pagano, Livio

    2011-02-01

    Plasma cell leukemia (PCL) is a highly aggressive plasma cell disease characterized by a poor prognosis and a low response rate to conventional therapy. Herein, we describe a 69-year-old patient with primary PCL, developing testicular disease while in complete hematological remission, following by muscle involvement and peritoneal dissemination. PMID:21229400

  19. Glucocorticosteroids induce DNA fragmentation in human lymphoid leukemia cells.

    PubMed

    Distelhorst, C W

    1988-10-01

    The present study was undertaken to investigate the potential role of glucocorticoid-induced DNA damage in the lysis of human lymphoid leukemia cells by glucocorticoids. Lymphoblasts were isolated from patients with acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) in blast crisis and cultured in vitro with or without dexamethasone. DNA was then purified from the cells and analyzed by agarose gel electrophoresis. Only high molecular weight (mol wt) DNA was present in cells cultured without dexamethasone, but a ladder of DNA fragments ranging in size from 180 to 200 base pairs (bp) to greater than 1,500 bp was present in cells cultured with dexamethasone. The DNA fragments were multiples of 180 to 200 bp, suggesting an internucleosomal site of DNA cleavage. The same pattern of DNA fragmentation was detected in normal thymocytes isolated from adrenalectomized rats following in vivo treatment with dexamethasone and in S49 mouse thymoma cells after in vitro incubation with dexamethasone. Dexamethasone-induced DNA fragmentation preceded overt loss of viability in glucocorticoid-sensitive cells but was not detected in two variants of the S49 cell line that are glucocorticoid resistant owing to glucocorticoid receptor defects. The results suggest that glucocorticoids kill human lymphoblastic leukemia cells and both normal and malignant murine thymocytes by a common mechanism that involves glucocorticoid induction of an endonucleolytic activity with cleavage of genomic DNA. PMID:3262387

  20. NFKB1 Is a Direct Target of the TAL1 Oncoprotein in Human T Leukemia Cells

    E-print Network

    Miyamoto, Shigeki

    NFKB1 Is a Direct Target of the TAL1 Oncoprotein in Human T Leukemia Cells Pei-Yun Chang, 1 Kyle Abstract We recently showed that a subset of human T acute lymphoblastic leukemia (T-ALL) cell lines in CEM T leukemia cells, basal NFKB1 expression is increased, and the levels of p65:cRel complex

  1. The characterization and role of leukemia cell-derived dendritic cells in immunotherapy for leukemic diseases

    PubMed Central

    Yuan, Changjin; Song, Guanhua; Jiang, Guosheng

    2012-01-01

    Summary Usually, an effective anti-leukemia immune response cannot be initiated effectively in patients with leukemia. This is probably related to immunosuppression due to chemotherapy, down-regulation of major histocompatibility complex (MHC) II molecules, and the lack of co-stimulatory molecules on dendritic cells (DC). In light of this problem, some methods had been used to induce leukemia cells to differentiate into mature DCs, causing them to present leukemia-associated antigens and activating naïve T cells. Furthermore, leukemia-derived DCs could be modified with tumor antigens or tumor-associated antigens to provide a new approach to anti-leukemia therapy. Numerous studies have indicated factors related to the induction and functioning of leukemia-derived DCs and the activation of cytotoxic T-lymphocytes (CTLs). These include the amount of purified DCs, cytokine profiles appropriate for inducing leukemia-derived DCs, effective methods of activating CTLs, reasonable approaches to DC vaccines, and the standardization of their clinical use. Determining these factors could lead to more effective leukemia treatment and benefit both mankind and scientific development. What follows in a review of advances in and practices of inducing leukemia-derived DCs and the feasibility of their clinical use. PMID:25343074

  2. Detection of mutant p53 in clam leukemia cells.

    PubMed

    Barker, C M; Calvert, R J; Walker, C W; Reinisch, C L

    1997-05-01

    Leukemia in the soft-shell clam, Mya arenaria, is characterized by tumor cells which are detected initially in the hemolymph. This disease is much more common in clams inhabiting polluted waters, suggesting an environmental component to its pathogenesis. In this study, leukemia cells were identified using a murine monoclonal antibody, 1E10, which recognizes a leukemia-specific protein expressed by tumor cells. Mutant p53 protein was detected using a murine monoclonal antibody (PAb 240) which reacts with mutant p53. Using immunofluorescence, the reactivity of clam cells to the 1E10 antibody was evaluated along with mutant p53 protein reactivity. Reverse transcriptase-polymerase chain reactions followed by sequence analyses were utilized to examine clams with hemocytes reacting with the p53 antibody for possible p53 gene mutations. Mutant p53 protein was expressed by tumor cells from five animals with advanced disease (in which greater than 90% of cells reacted with 1E10). A C-->G transversion was detected at the end of exon 6 from two of the five animals that reacted with both the mutant p53 antibody and 1E10. This substitution changes the amino acid of this codon from proline to alanine. Overall, our results suggest that environmentally induced alterations in p53 can contribute to the pathogenesis of leukemia in soft-shell clams inhabiting polluted water and/or sediment. PMID:9168798

  3. [Allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia].

    PubMed

    Shao, Qun; Wang, Zhi-Dong; Zheng, Xiao-Li; Dong, Lei; Han, Dong-Mei; Yan, Hong-Ming; Wang, Heng-Xiang; Duan, Lian-Ning

    2014-08-01

    This study was purposed to explore the therapeutic efficacy and influencing factors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with chronic myelomonocytic leukemia (CMML) and in patients with juvenile myelomonocytic leukemia (JMML). The clinical data of 3 cases of CMML and 2 cases of JMML underwent allo-HSCT were analysed in term of multiparameter. The results showed that the hematopoietic stem cells in 5 patients grafted successfully. One case of JMML died of pulmonary disease, other 4 cases survive without disease. The analysis found that the disease burden before transplant, chromosome karyotype, acute GVHD II-IV and poor risk cytogenetics all associated with the relapse rate and disease-free survival rate of CMML. The low intensity conditioning regimen was better than myeloablative conditioning regimen. Type of donor and source of stem cells did not statistically and significantly affect OS and RFS. The splenectomy before allo-HSCT as well as spleen size at time of the alloHSCT did not influence on posttransplantation outcome of JMML. However, cord blood HSCT for JMML patients delayed hematologic recovery as compared to that of bone marrow or peripheral blood HSCT. The age, GVHD, HbF level played an important role in leukemia replace. It is concluded that the allogeneic hematopoietic stem cell transplantation is a curative regimen for CMML and JMML, but there also is a serial problems to be resolved. PMID:25130828

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

    PubMed Central

    Zhou, Jianbiao; Chng, Wee-Joo

    2014-01-01

    Accumulating evidence support the notion that acute myeloid leukemia (AML) is organized in a hierarchical system, originating from a special proportion of leukemia stem cells (LSC). Similar to their normal counterpart, hematopoietic stem cells (HSC), LSC possess self-renewal capacity and are responsible for the continued growth and proliferation of the bulk of leukemia cells in the blood and bone marrow. It is believed that LSC are also the root cause for the treatment failure and relapse of AML because LSC are often resistant to chemotherapy. In the past decade, we have made significant advancement in identification and understanding the molecular biology of LSC, but it remains a daunting task to specifically targeting LSC, while sparing normal HSC. In this review, we will first provide a historical overview of the discovery of LSC, followed by a summary of identification and separation of LSC by either cell surface markers or functional assays. Next, the review will focus on the current, various strategies for eradicating LSC. Finally, we will highlight future directions and challenges ahead of our ultimate goal for the cure of AML by targeting LSC. PMID:25258669

  5. Eradication of Chronic Myeloid Leukemia Stem Cells: A Novel Mathematical Model Predicts No Therapeutic

    E-print Network

    Eradication of Chronic Myeloid Leukemia Stem Cells: A Novel Mathematical Model Predicts induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients B, Holyoake T, Michor F (2009) Eradication of Chronic Myeloid Leukemia Stem Cells: A Novel

  6. 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

  7. Leukemia . Author manuscript Sirolimus enhances the effect of apoptotic cell infusion on hematopoietic

    E-print Network

    Paris-Sud XI, Université de

    Leukemia . Author manuscript Page /1 6 Sirolimus enhances the effect of apoptotic cell infusion not candidate for standard myeloablative AHCT and diseases other than acute leukemia. However, and despite some

  8. Identification of cancer stem cells: from leukemia to solid cancers

    Microsoft Academic Search

    Yinghui Huang; Xiaoxue Qiu; Ji-Long Chen

    2010-01-01

    Cancer stem cells (CSCs) are widely considered to be a small cell population in leukemia and many solid cancers with the properties\\u000a including self-renewal and differentiation to non-tumorigenic cancer cells. Identification and isolation of CSCs significantly\\u000a depend on the special surface markers of CSCs. Aberrant gene expression and signal transduction contribute to malignancies\\u000a of CSCs, which result in cancer initiation,

  9. Surface Markers on Leukemia and Lymphoma Cells: Recent Advances

    Microsoft Academic Search

    Kenneth A. Foon; Robert W. Schroff; Robert Peter Gale; Wendell F. Rosse; Joseph Yourno; Peter Burkart; Walter Mastropaolo; Anthony Tartaglia; James D. Griffin; Richard P. Beveridge; Stuart F. Schlossman; Mark R. Wick; Chin-Yang Li; Robert V. Pierre; Carl G. Figdor; Willy S. Bont; Ivo Touw; Johan de Roos; Eddy E. Roosnek; Jan E. de Vries; Thomas J. Kunicki; Mary B. Koenig; Susan M. Kristopeit; Richard H. Aster; Paula B. Tracy; Lisa L. Eide; E. J. W. Bowie; Kenneth G. Mann

    1982-01-01

    Recent advances in immunology have led to important insights into leukocyte differentiation and the cellular on- gin of leukemia. It is now possible to precisely define stages of human lymphocyte and gnanulocyte differentiation uti- lizing highly specific monoclonal antibodies that define cell surface antigens in conjunction with more traditional markers such as surface and cytoplasmic immunoglobulin on B lymphocytes, sheep

  10. Natural killer cell lymphoma/leukemia: pathology and treatment.

    PubMed

    Kwong, Y L; Chan, A C; Liang, R H

    1997-05-01

    Malignancies arising from cells of putative natural killer (NK) cell origin have increasingly been recognized as distinct clinicopathological entities. These malignancies are marked by tumour cells with NK cell characteristics, including the immunophenotype of CD2+, surface CD3-, cytoplasmic CD3 epsilon+, CD7 +/-, and CD56+, and the genotype of germline T cell receptor gene. A consistent association with monoclonal Epstein-Barr virus infection in the tumour cell has been observed. These tumours are now regarded as putative NK cell lymphoma/leukemia. Pathologically, tumour cells show variable cytological appearances, with frequent angiocentricity and angioinvasion, associated with zonal necrosis. Clinically, most cases occur in the nasal area and upper aerodigestive tract. However, occurrence in non-nasal sites such as the skin, gastrointestinal tract and testis is also observed. A particularly aggressive form of NK lymphoma/leukemia presents fulminantly as disseminated disease sometimes with a leukemic phase. All types of NK lymphoma/leukemia have an extremely poor prognosis with a median survival of less than a year. New modalities of treatment, including the use of high dose chemotherapy and stem cell rescue may be needed to improve treatment outcome. PMID:9375032

  11. 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. ...

  12. B cell acute lymphocytic leukemia in pregnancy

    Microsoft Academic Search

    Justin Bottsford-Miller; Sina Haeri; Arthur M. Baker; Jeremiah Boles; Mark Brown

    2011-01-01

    Acute lymphocytic leukemia (ALL) is a rare occurrence in pregnancy and can be rapidly fatal if left untreated. The need for\\u000a immediate treatment of ALL, coupled with the maternal–fetal risks from the chemotherapy regimen render a therapeutic dilemma\\u000a in pregnant women with ALL. We report a case of ALL diagnosed in the 24th week of pregnancy to outline our management

  13. Megakaryoblastic leukemia cell line MOLM-16 derived from minimally differentiated acute leukemia with myeloid\\/NK precursor phenotype

    Microsoft Academic Search

    Yoshinobu Matsuo; Hans G. Drexler; Kinuyo Kaneda; Kensuke Kojima; Yuji Ohtsuki; Masamichi Hara; Masaki Yasukawa; Mitsune Tanimoto; Kunzo Orita

    2003-01-01

    The megakaryoblastic leukemia cell line MOLM-16 was established at relapse from the peripheral blood of a 77-year-old Japanese woman with minimally differentiated acute myeloid leukemia (AML-M0). Immunophenotyping of the fresh leukemic cells revealed a myeloid\\/NK precursor phenotype being positive for CD7, CD13, CD33, CD34, and CD56. In addition, megakaryocyte-associated antigens CD41 and CD61 were found to be positive. The established

  14. High frequencies of leukemia stem cells in poor-outcome childhood precursor-B acute lymphoblastic leukemias

    Microsoft Academic Search

    S Morisot; A S Wayne; O Bohana-Kashtan; I M Kaplan; C D Gocke; R Hildreth; M Stetler-Stevenson; R L Walker; S Davis; P S Meltzer; S J Wheelan; P Brown; R J Jones; L D Shultz; C I Civin

    2010-01-01

    In order to develop a xenograft model to determine the efficacy of new therapies against primary human precursor-B acute lymphoblastic leukemia (ALL) stem cells (LSCs), we used the highly immunodeficient non-obese diabetic (NOD).Cg-PrkdcscidIL2rgtmlWjl\\/SzJ (NOD-severe combined immune deficient (scid) IL2rg?\\/?) mouse strain. Intravenous transplantation of 2 of 2 ALL cell lines and 9 of 14 primary ALL cases generated leukemia-like proliferations

  15. Investigation of anti-leukemia molecular mechanism of ITR-284, a carboxamide analog, in leukemia cells and its effects in WEHI-3 leukemia mice.

    PubMed

    Wen, Yen-Fang; Yang, Jai-Sing; Kuo, Sheng-Chu; Hwang, Chrong-Shiong; Chung, Jing-Gung; Wu, Hsi-Chin; Huang, Wen-Wen; Jhan, Jia-Hua; Lin, Chung-Ming; Chen, Hui-Jye

    2010-02-01

    ITR-284, a potent anti-leukemia agent of carboxamide derivative, has been shown to inhibit the proliferation of leukemia cells. In this study, the underlying molecular mechanisms in vitro and anti-leukemia activity in vivo of ITR-284 were investigated. ITR-284 reduced the cell viability and induced apoptosis in HL-60 and WEHI-3 leukemia cells. Following exposure of cells to 30 nM of ITR-284, there is a time-dependent decrease in the mitochondrial membrane potential (DeltaPsi(m)) and an increase in the reactive oxygen species (ROS). ITR-284 treatment also caused a time-dependent increase of Fas/CD95, cytosolic cytochrome c, cytosolic active form of caspase-8/-9/-3, cytosolic Apaf-1 and Bax, and the decrease of Bcl-2. However, the ITR-284-induced caspase-8/-9 and -3 activities can be blocked by pan-caspase inhibitor (Z-VAD-FMK). In addition, the anti-leukemia effects of ITR-284 in vivo were further evaluated in BALB/c mice inoculated with WEHI-3 cells. Orally treatment with ITR-284 (2 and 10mg/kg/alternate day for 7 times) increased the survival rate and prevented the loss of body weight in leukemia mice. The enlargement of spleen and infiltration of immature myeloblastic cells into spleen red pulp were significantly reduced in ITR-284-treated mice compared with control mice. Moreover, ITR-284 application can enhance the anti-leukemia effect of all-trans retinoic acid (ATRA). These results revealed that ITR-284 acted against both HL-60 and WEHI-3 in vitrovia both intrinsic and extrinsic apoptotic signaling pathways, and exhibited an anti-leukemic effect in a WEHI-3 orthotopic mice model of leukemia. PMID:19765549

  16. 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.

  17. Impaired degradation of Ca(2+)-regulating second messengers in myeloid leukemia cells. Implications for the regulation of leukemia cell proliferation.

    PubMed

    Nye, K E; Riley, G A; Poulter, L W; Porfiri, E; Hoffbrand, A V; Wickremasinghe, R G

    1992-08-01

    Inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate are Ca(2+)-regulating second messenger molecules which are generated via the cleavage of inositol lipids. We have previously shown that these species are autonomously generated in HL60 myeloid leukemia cells and that they may play a role in signalling the continuous proliferation of this cell line. Here we show that the activity of the 5-phosphomonoesterase (5-PME) enzyme which cleaves and inactivates these second messengers was strikingly reduced in HL60 cells compared to normal granulocytes or macrophages. Induction of differentiation of HL60 cells along the monocyte/macrophage or granulocytic pathways did not result in a significant increase in 5-PME activity. The activity of this enzyme was also low in extracts of bone marrow mononuclear cells from four patients with myeloid leukemia. A lesion in the 5-PME pathway may therefore result in the conservation of Ca(2+)-regulating second messengers in the HL60 cell line and in some myeloid leukemia cells. It is plausible that this lesion may co-operate with the autonomous cleavage of inositol lipids in the signalling of leukemic cell proliferation. PMID:1640731

  18. Cancer Cell The Common Feature of Leukemia-Associated IDH1

    E-print Network

    Sharp, Kim

    Cancer Cell Article The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations of patients with cytogenetically normal acute myeloid leukemia (AML). Surprisingly, less than half of cases glioblastomas, and in 8.5% of acute myeloid leukemias (AML) (Mardis et al., 2009; Yan et al., 2009). Mutations

  19. Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia

    E-print Network

    Quake, Stephen R.

    Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia Max myeloid leukemia (AML). Using exome sequencing, we identified mutations present in individual AML patients-PAAuthorManuscriptNIH-PAAuthorManuscriptNIH-PAAuthorManuscript #12;INTRODUCTION Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic progenitor

  20. What Is Childhood Leukemia?

    MedlinePLUS

    ... key statistics for 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 ...

  1. Deregulated expression of TCL1 causes T cell leukemia in mice

    PubMed Central

    Virgilio, Laura; Lazzeri, Cristina; Bichi, Roberta; Nibu, Ken-ichi; Narducci, Maria Grazia; Russo, Giandomenico; Rothstein, Jay L.; Croce, Carlo M.

    1998-01-01

    The TCL1 oncogene on human chromosome 14q32.1 is involved in the development of T cell leukemia in humans. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age. The TCL1 oncogene is activated in these leukemias by juxtaposition to the ? or ? locus of the T cell receptor, caused by chromosomal translocations t(14:14)(q11:q32), t(7:14)(q35:q32), or by inversions inv(14)(q11:q32). To show that transcriptional alteration of TCL1 is causally involved in the generation of T cell neoplasia we have generated transgenic mice that carry the TCL1 gene under the transcriptional control of the p56lck promoter element. The lck-TCL1 transgenic mice developed mature T cell leukemias after a long latency period. Younger mice presented preleukemic T cell expansions expressing TCL1, and leukemias developed only at an older age. The phenotype of the murine leukemias is CD4?CD8+, in contrast to human leukemias, which are predominantly CD4+CD8?. These studies demonstrate that transcriptional activation of the TCL1 protooncogene can cause malignant transformation of T lymphocytes, indicating the role of TCL1 in the initiation of malignant transformation in T prolymphocytic leukemias and T chronic lymphocytic leukemias. PMID:9520462

  2. Monoclonal antibody therapy directed against human acute myeloid leukemia stem cells

    Microsoft Academic Search

    R Majeti

    2011-01-01

    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

  3. 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. PMID:25620649

  4. 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. PMID:25452033

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

    PubMed Central

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

    2013-01-01

    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 I?B kinases as well as expression of cytotoxic gene products such as granzyme B, perforin and IFN?. 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. PMID:24183305

  6. Insights into leukemia initiating cell frequency and self-renewal from a novel canine model of leukemia

    PubMed Central

    Imren, Suzan; Zhang, Xiao-Bing; Humphries, R. Keith; Kiem, Hans-Peter

    2011-01-01

    Objective Leukemia initiating cells (LICs) have been the subject of considerable investigation because of their ability to self-renew and maintain leukemia. Thus, selective targeting and killing of LIC would provide highly efficient and novel therapeutic strategies. Here we explored whether we could use a canine leukemia cell line (G374) derived from a dog that received HOXB4 transduced repopulating cells to study leukemia in the murine xenograft model and the dog. Materials and Methods G374 cells were infused in dogs intravenously (IV) and in NOD/SCID and NOD/SCID/IL2R?null mice either IV or directly into the bone cavity (IF). Animals were bled to track engraftment and proliferation of G374 cells, and were sacrificed when they appeared ill. Results We found that canine LICs are capable of sustained in vitro self-renewal while maintaining their ability to induce AML that resembles human disease in both dogs and mice. Furthermore, we developed a novel strategy for the quantification of LIC frequency in large animals and showed that this frequency was highly comparable to that determined by limited dilution in mouse xenotransplants. We also demonstrated, using single cell analysis, that LICs are heterogenous in their self-renewal capacity and regenerate a leukemic cell population consistent with a hierarchical leukemia model. Conclusions The availability of this novel framework should accelerate the characterization of LICs and the translation of animal studies into clinical trials. PMID:20933571

  7. Genetic aberrations and survival in plasma cell leukemia

    Microsoft Academic Search

    R E Tiedemann; N Gonzalez-Paz; R A Kyle; R Santana-Davila; T Price-Troska; S A Van Wier; W J Chng; R P Ketterling; M A Gertz; K Henderson; P R Greipp; A Dispenzieri; M Q Lacy; S V Rajkumar; P L Bergsagel; A K Stewart; R Fonseca

    2008-01-01

    Plasma cell leukemia (PCL) is an aggressive and rare hematological malignancy that originates either as primary disease (pPCL) or as a secondary leukemic transformation (sPCL) of multiple myeloma (MM). We report here the genetic aberrations and survival of 80 patients with pPCL or sPCL and make comparisons with 439 cases of MM. pPCL presents a decade earlier than sPCL (54.7

  8. Leukemia

    NSDL National Science Digital Library

    Patient Education Institute

    This patient education program explains what leukemia is and reviews the causes, symptoms, diagnosis, and treatment options. This resource is a MedlinePlus Interactive Health Tutorial from the National Library of Medicine, designed and developed by the Patient Education Institute. NOTE: This tutorial requires a special Flash plug-in, version 4 or above. If you do not have Flash, you will be prompted to obtain a free download of the software before you start the tutorial. You will also need an Acrobat Reader, available as a free download, in order to view the Reference Summary.

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

    Microsoft Academic Search

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

    2010-01-01

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

  10. Recent advances in acute myeloid leukemia stem cell biology

    PubMed Central

    Horton, Sarah J.; Huntly, Brian J.P.

    2012-01-01

    The existence of cancer stem cells has long been postulated, but was proven less than 20 years ago following the demonstration that only a small sub-fraction of leukemic cells from acute myeloid leukemia patients were able to propagate the disease in xenografts. These cells were termed leukemic stem cells since they exist at the apex of a loose hierarchy, possess extensive self-renewal and the ability to undergo limited differentiation into leukemic blasts. Acute myeloid leukemia is a heterogeneous condition at both the phenotypic and molecular level with a variety of distinct genetic alterations giving rise to the disease. Recent studies have highlighted that this heterogeneity extends to the leukemic stem cell, with this dynamic compartment evolving to overcome various selection pressures imposed upon it during disease progression. The result is a complex situation in which multiple pools of leukemic stem cells may exist within individual patients which differ both phenotypically and molecularly. Since leukemic stem cells are thought to be resistant to current chemotherapeutic regimens and mediate disease relapse, their study also has potentially profound clinical implications. Numerous studies have generated important recent advances in the field, including the identification of novel leukemic stem cell-specific cell surface antigens and gene expression signatures. These tools will no doubt prove invaluable for the rational design of targeted therapies in the future. PMID:22511496

  11. Vitamin D Control of Hematopoietic Cell Differentiation and Leukemia.

    PubMed

    Studzinski, George P; Harrison, Jonathan S; Wang, Xuening; Sarkar, Surojit; Kalia, Vandana; Danilenko, Michael

    2015-08-01

    It is now well known that in the mammalian body vitamin D is converted by successive hydroxylations to 1,25-dihydroxyvitamin D (1,25D), a steroid-like hormone with pleiotropic properties. These include important contributions to the control of cell proliferation, survival and differentiation, as well as the regulation of immune responses in disease. Here, we present recent advances in current understanding of the role of 1,25D in myelopoiesis and lymphopoiesis, and the potential of 1,25D and analogs (vitamin D derivatives; VDDs) for the control of hematopoietic malignancies. The reasons for the unimpressive results of most clinical studies of the therapeutic effects of VDDs in leukemia and related diseases may include the lack of a precise rationale for the conduct of these studies. Further, clinical trials to date have generally used extremely heterogeneous patient populations and, in many cases, small numbers of patients, generally without controls. Although low calcemic VDDs have been used and combined with agents that can increase the leukemia cell killing or differentiation effects in acute leukemias, the sequencing of agents used for combination therapy should to be more clearly delineated. Most importantly, it is recommended that in future clinical trials the rationale for the basis of the enhancing action of drug combinations should be clearly articulated and the effects on anticancer immunity should also be evaluated. J. Cell. Biochem. 116: 1500-1512, 2015. © 2015 Wiley Periodicals, Inc. PMID:25694395

  12. Cluster of differentiation 96 as a leukemia stem cell-specific marker and a factor for prognosis evaluation in leukemia

    PubMed Central

    DU, WEN; HU, YANJIE; LU, CONG; LI, JUAN; LIU, WEI; HE, YANLI; WANG, PING; CHENG, CHEN; HU, YU; HUANG, SHIANG; YAO, JUNXIA; ZHENG, JIN'E

    2015-01-01

    Resistance to chemotherapy is a major challenge for leukemia treatment. It has been suggested that leukemia stem cells (LSCs), a small pool of self-renewing leukemic cells, play important roles in development of chemotherapy resistance. The expression of cluster of differentiation 96 (CD96), a potential marker for LSCs, was investigated in CD34+CD38? cells of 105 acute leukemia (AL) patients by flow cytometry. The data showed that all the CD34+, CD34+CD38? and CD34+CD38?CD96+ proportions were much higher in AL compared to the normal control (P<0.01), while a clear difference was identified in the CD34+CD38? and CD34+CD38?CD96+ proportions between acute lymphoid leukemia and acute myeloid leukemia (AML). However, all the AML patients with >15% CD34+CD38? cells achieved complete remission (CR), suggesting that as an LSC-rich population, the amount of CD34+CD38? cells may not be positively associated with the proportion of refractory LSCs. The mean percentage of the co-presence of CD96 expression itself was similar in AML patients with CR and non-CR (P>0.05). However, the CR rate was significantly higher in the AML population with <10% CD96 expressed, which indicated that a distinct sub-group of CD34+CD38?CD96+ cells may still contribute to the drug resistance or poor prognosis. PMID:26171191

  13. Precursor NK cell lymphoblastic leukemia/lymphoma-report of a case with literature review.

    PubMed

    Jain, Sonal; Kumar, Rajiv; Purohit, Abhishek; Pati, Hara Prasad

    2014-09-01

    Precursor Natural Killer (NK) cell lymphoblastic leukemia/lymphoma is a rare entity defined clearly by WHO (2008 WHO classification). However, the pathobiology of this subset of neoplasms is not clearly defined. There is wide disparity in the literature regarding the nomenclature and diagnostic criteria used to diagnose and characterize acute leukemias of presumed NK cell origin. In the present article we report a case of Precursor NK cell lymphoblastic leukemia/lymphoma and review the cases reported after 2008 WHO classification came into vogue, as acute leukemias of NK cell origin. PMID:25332598

  14. Cancer stem cells: lessons from leukemia

    Microsoft Academic Search

    Jean C. Y. Wang; John E. Dick

    2005-01-01

    A fundamental problem in cancer research is identifi- cation of the cell type capable of initiating and sustaining growth of the tumor - the cancer stem cell (CSC). While the existence of CSCs was first proposed over 40 years ago, only in the past decade have these cells been identified and characterized in hematological malignancies. Recent studies have now described

  15. Ultrastructure of adult T-cell leukemia\\/lymphoma

    Microsoft Academic Search

    Tadaaki Eimoto; Tetsuji Mitsui; Masahiro Kikuchi

    1981-01-01

    Summary  Eighteen cases of adult T-cell leukemia\\/lymphoma (ATLL) in Japan were analyzed by electron microscopy and compared with 5\\u000a cases of B-lymphoma and well-established groups of T-lymphomas (4 cases of T-lymphoblastic lymphoma and 2 cases of Sézary\\u000a syndrome). Five hundred cells in each case, categorized ultrastructurally as to the cellular size and nuclear shape, showed\\u000a an essentially pleomorphic cellular distribution in

  16. 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

    2015-06-15

    Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent 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; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  17. Selected epidemiological observations of cell-specific leukemia mortality in the USA, 1969-1977

    SciTech Connect

    Selvin, S.; Levin, L.I.; Merrill, D.W.; Winkelstein, W. Jr.

    1982-03-01

    Utilizing a newly available data set which includes for the first time cell-specific leukemia mortality rates for the USA during the period 1969-1977, age and sex distributions, time trends and geographic patterns have been analyzed. Four major cell types of leukemia were considered. Acute lymphatic leukemia had a bimodal distribution with the first peak in the 5 to 9 year age group and lowest rates in age group 35 to 44 after which rates rose geometrically. Acute myeloid leukemia had only a very small childhood peak with a low in the age group 5 to 9, after which the rates also rose geometrically. For both chronic lymphatic and myeloid leukemia the rates rose geometrically after age 15. Rates among females were consistently lower for each age group. The highest sex ratio was found for chronic lymhatic leukemia and is proposed to be the result of a lag period between male and female rates. During the period under study acute lymphatic leukemia mortality in adults declined by almost 10% while acute myeloid leukemia mortality increased by almost 20%. Analysis of the geographic variation of the four major cell types revealed a geographic association between acute lymphatic and acute myeloid leukemia in children, a lack of association between childhood and adult cell types and an association of acute and chronic cell types in adults.

  18. Selected epidemiologic observations of cell-specific leukemia mortality in the United States, 1969-1977

    SciTech Connect

    Selvin, S.; Levin, L.I.; Merrill, D.W.; Winkelstein, W. Jr.

    1983-01-01

    Utilizing a newly available data set which includes for the first time cell-specific leukemia mortality rates for the United States during 1969-1977, age and sex distributions, time trends and geographic patterns were analyzed. Four major cell types of leukemia were considered. Acute lymphatic leukemia had a bimodal distribution with the first peak in the 5-9-year age group and lowest rates in age group 35-44, after which rates rose geometrically. Acute myeloid leukemia had only a very small childhood peak with a low in the age group 5-9, after which the rates also rose geometrically. For both chronic lymphatic and myeloid leukemia the rates rose geometrically after age 15. Rates among females were consistently lower for each age group. The highest sex ratio was found for chronic lymphatic leukemia and is proposed to be the result of a lag period between male and female rates. During the period under study acute lymphatic leukemia mortality in adults declined by almost 10% while acute myeloid leukemia mortality increased by almost 20%. Analysis of the geographic variation of the four major cell types revealed a geographic association between acute lymphatic and acute myeloid leukemia in children, a lack of association between childhood and adult cell types, and an association of acute and chronic cell types in adults.

  19. Oncogenic Kras Initiates Leukemia in Hematopoietic Stem Cells

    PubMed Central

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

    2009-01-01

    How oncogenes modulate the self-renewal properties of cancer-initiating cells is incompletely understood. Activating KRAS and NRAS mutations are among the most common oncogenic lesions detected in human cancer, and occur in myeloproliferative disorders (MPDs) and leukemias. We investigated the effects of expressing oncogenic KrasG12D from its endogenous locus on the proliferation and tumor-initiating properties of murine hematopoietic stem and progenitor cells. MPD could be initiated by KrasG12D expression in a highly restricted population enriched for hematopoietic stem cells (HSCs), but not in common myeloid progenitors. KrasG12D HSCs demonstrated a marked in vivo competitive advantage over wild-type cells. KrasG12D expression also increased the fraction of proliferating HSCs and reduced the overall size of this compartment. Transplanted KrasG12D HSCs efficiently initiated acute T-lineage leukemia/lymphoma, which was associated with secondary Notch1 mutations in thymocytes. We conclude that MPD-initiating activity is restricted to the HSC compartment in KrasG12D mice, and that distinct self-renewing populations with cooperating mutations emerge during cancer progression. PMID:19296721

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

    ClinicalTrials.gov

    2015-06-19

    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

  1. CD5-positive B-cell acute lymphoblastic leukemia.

    PubMed

    Peterson, Michael R; Noskoviak, Kyle J; Newbury, Robert

    2007-01-01

    CD5-positive B-cell acute lymphoblastic leukemia (ALL) is an exceedingly rare entity, with only a single case report in the literature. We report 2 additional cases of CD5-positive B-cell ALL in a 16-year-old male and a 15-year-old female. The 1st case was initially misdiagnosed as Ewing sarcoma due to a lack of CD45 expression and weak expression of CD99. Cytogenetic analysis of the 2nd case revealed trisomy 22, the 1st time this finding has been reported in ALL. Both patients had poor outcomes, as did the patient in the previously published case report. We conclude that CD5-positive B-cell ALL is a rare, aggressive malignancy with a poor prognosis that presents in adolescence. Pathologists and clinicians should be aware of this entity to avoid confusion with other small blue-cell tumors. PMID:17378623

  2. Human T-cell leukemia virus type I (HTLV-I) infection and the onset of adult T-cell leukemia (ATL)

    Microsoft Academic Search

    Masao Matsuoka

    2005-01-01

    The clinical entity of adult T-cell leukemia (ATL) was established around 1977, and human T-cell leukemia virus type 1 (HTLV-I) was subsequently identified in 1980. In the 25 years since the discovery of HTLV-I, HTLV-I infection and its associated diseases have been extensively studied, and many of their aspects have been clarified. However, the detailed mechanism of leukemogenesis remains unsolved

  3. Inhibition of tumor cell proliferation and induction of apoptosis in human lung carcinoma 95-D cells by a new sesquiterpene from hairy root cultures of Artemisia annua.

    PubMed

    Zhai, D-D; Supaibulwatana, K; Zhong, J-J

    2010-09-01

    Artemisia annua is a rich source of many bioactive substances, and in our recent work, a new sesquiterpene, (Z)-7-acetoxy-methyl-11-methyl-3-methylene-dodeca-1,6,10-triene (AMDT), was isolated and identified from hairy roots culture of A. annua, and its bioactivity was characterized in this work. AMDT showed moderate cytotoxic activities against the human tumor cell lines of HO8910 (ovary), 95-D (lung), QGY (liver) and HeLa (cervix) by MTT assay, whose IC(50) values were ranged within 52.44-73.3 microM. As lung cancer is the No. 1 killer of global cancer patients, our interest is to investigate the ability of AMDT in inducing apoptosis of 95-D tumor cells. The 95-D cell growth was inhibited by AMDT, and the flow cytometry analysis showed its cell cycle was arrested in the G1 phase. The apoptotic rate of the cells increased in a dose-dependent manner. AMDT lowered the mitochondrial membrane potential and increased the expression of caspase-9 and -3. These results revealed that AMDT could efficiently induce 95-D cell apoptosis through mitochondrial dependent pathway, and it may be a potential chemotherapeutic agent. PMID:20362422

  4. Current status of haploidentical stem cell transplantation for leukemia

    PubMed Central

    Huang, Xiao-jun

    2008-01-01

    Haploidentical hematopoietic stem cell transplantation has made tremendous progress over the past 20 years and has become a feasible option for leukemia patients without a HLA identical sibling donor. The early complications of severe graft-versus-host disease (GVHD), graft failure and delayed engraftment, as well as disease recurrence have limited the use of this approach. Newer strategies have been applied and overcome some of the problems, including the use of T-cell depleted graft, "mega" dose of stem cells, intensive post-transplant immunosuppression and manipulation of the graft. These have decreased the transplant related mortality and GVHD associated with haploidentical transplantation, however, the major problems of disease relapse and infection, which related to late immune reconstitution, limit the development of haploidentical HSCT. Future challenges remain in improving post-transplant immune reconstitution and finding the best approach to reduce the incidence and severity of GVHD, while preserving graft-versus-leukemia effect to prevent the recurrence of underlying malignancy. PMID:19117511

  5. Biological activity of DC-CIK cells and its effect against leukemia cells in vitro.

    PubMed

    Wei, Xu-Cang; Zhai, Xin-Hui; Han, Xiu-Rui; Yang, Di-Di; Zhao, Wen-Li

    2008-10-01

    This study was aimed to investigate the effect of dendritic cells (DC) on the proliferation capability, immunophenotype changes, level of secreted cytokines and activity against leukemia of cytokine-induced killer (CIK) cells in vitro. DCs and CIK cells were induced from peripheral blood mononuclear cells of healthy volunteers. They were co-cultured meanwhile CIK cells were cultured alone as controls. Increased number of cells were counted by trypan-blue staining; the killing activity was detected by MTT assay; immunophenotype changes were analyzed by flow cytometry; the IL-12 and INF-gamma levels of the cultured supernatants were detected by ELISA kits. The results showed that the proliferation capability of DC-CIK cells was significantly higher than that of CIK cells (p < 0.05). Under the same condition, the ratio of double positive cells such as CD3(+) CD8(+), CD3(+) CD56(+) in CIK cells was significantly enhanced by co-cultured with DC cells (p < 0.05). The levels of IL-12 and INF-gamma in cultured supernatants of DC-CIK cells increased noticeably on day 3 as compared with CIK cells cultured alone (p < 0.01, p < 0.05). Within the effector-target ratio range between 5:1 to 40:1, the activity of DC-CIK cells against leukemia cells were much higher than that of CIK cells (p < 0.05), and this effect showed a positive correlation with the effector-target ratio. It is concluded that the proliferation capability of DC-CIK cells, the level of their secreted cytokines and their activity against leukemia cells are significantly higher than those of CIK cells. This research may suggest an approach for clinical immunotherapy against leukemia with DC-CIK cells. PMID:18928615

  6. Origin of leukemic cells in mouse leukemia induced by N-butylnitrosourea.

    PubMed

    Shisa, H; Matsudaira, Y; Hiai, H; Nishizuka, Y

    1975-02-01

    Administration of N-butylnitrosourea (BNU) induces leukemia in thymectomized C57BL/6J and C3Hf/Bi mice with almost the same high frequency as in non-thymectomized mice. Thymectomized and BNU-treated (C3Hf/Bi times CBA/H-T6T6)F1 mice receiving neonatal thymus tissues from C3Hf donors developed leukemias with or without marked enlargement of the grafts. The origin of leukemic cells was analysed by T6 marker chromosome and thymus allo-antigen theta in this hybrid system. Cells from leukemia with enlarged thymus grafts possessed the sigma-antigen detected by cytotoxicity tests. Cells from leukemia without thymus involvement had no sigma antigen. The leukemic cells arising at the site of thymus grafts were derived from the graft itself (C3Hf) or from the host (C3Hf times CBA/H-T6T6)F1 cells, most probably bone marrow cells which are repopulating into the graft. When the mice were treated with BNU after the lymphoid elements in the grafted thymus had been replaced by host cells, leukemia mainly composed of host-origin cells developed. Leukemia in which neoplastic cells in the thymus grafts were of donor origin and those in other hematopoietic tissues were of host origin was found not infrequently. The present results mean that the target cells in BNU leukemogenesis are distributed within and outside the thymus and that some leukemias are of multifocal tissue origin. PMID:1150001

  7. Review: Diagnostic and therapeutic applications of rat basophilic leukemia cells.

    PubMed

    Rashid, Amir; Sadroddiny, Esmaeil; Ye, Hong Tu; Vratimos, Athanassios; Sabban, Sari; Carey, Eric; Helm, Birgit

    2012-10-01

    The research into understanding of the immunological processes is often difficult due to several factors complicating the isolation and culturing of primary degranulating cells like mast cells and basophils. The establishment of rat basophilic leukemia (RBL) cell line as an efficient and reliable experimental research tool was considered a major advance toward the understanding of the wild-type mast cell population's biology. The development of sub-clone RBL-IV (HR+) led to the isolation of histamine-secreting RBL-2H3 cell line. Since then, RBL-2H3 cells have been extensively used for studying the IgE high affinity receptor (Fc?RI) interactions with their ligand, the IgE antibody. This cell line has been employed for generating human and more recently canine and equine Fc?RI?-transfected RBL cell lines facilitating an assessment of the residues involved in the complementary interaction between the IgE molecules from these species and their cognate high affinity receptor. A proteomics-based approach to the definition of IgE-receptor-mediated signaling pathways was also carried out using this cell line. Furthermore, RBL-2H3 cells have the potential of being used to assess the potential allergenicity of antigens to humans and other animals like dogs and horses which are known to suffer from similar allergic manifestations. PMID:22750069

  8. B cell receptor signaling in chronic lymphocytic leukemia

    PubMed Central

    Burger, Jan A.; Chiorazzi, Nicholas

    2013-01-01

    BCR signaling plays an important pathogenic role in chronic lymphocytic leukemia (CLL) and B cell lymphomas, based on structural restrictions of the BCR, and BCR-dependent survival and growth of the malignant B cells. In CLL and lymphoma subtypes, ligand-independent (“tonic”) and ligand-dependent BCR signaling have been characterized, which can involve mutations of BCR pathway components or be triggered by (auto-) antigens present in the tissue microenvironment. In CLL, based on high response rates and durable remissions in early-stage clinical trials, there is rapid clinical development of inhibitors targeting BCR-associated kinases (BTK, PI3K?), which will change treatment paradigms in CLL and other B cell malignancies. Here, we discuss the evolution of this field, from BCR-related prognostic markers, to mechanisms of BCR activation, and targeting of BCR-associated kinases, the emerging Achilles’ heel in CLL pathogenesis. PMID:23928062

  9. Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells

    PubMed Central

    Liu, Ting; Men, Qiuxu; Wu, Guixian; Yu, Chunrong; Huang, Zan; Liu, Xin; Li, Wenhua

    2015-01-01

    All-trans retinoic acid (ATRA) is a differentiating agent for the treatment of acute promyelocytic leukemia (APL). However, the therapeutic efficacy of ATRA has limitations. Tetrandrine is a traditional Chinese medicinal herb extract with antitumor effects. In this study, we investigated the effects of tetrandrine on human PML-RAR?-positive acute promyelocytic leukemia cells. Tetrandrine inhibited tumors in vivo. It induced autophagy and differentiation by triggering ROS generation and activating Notch1 signaling. Tetrandrine induced autophagy and differentiation in M5 type patient primary leukemia cells. The in vivo results indicated that low concentrations of tetrandrine inhibited leukemia cells proliferation and induced autophagy and then facilitated their differentiation, by activating ROS and Notch1 signaling. We suggest that tetrandrine is a potential agent for the treatment of APL by inducing differentiation of leukemia cells. PMID:25797266

  10. Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells.

    PubMed

    Liu, Ting; Men, Qiuxu; Wu, Guixian; Yu, Chunrong; Huang, Zan; Liu, Xin; Li, Wenhua

    2015-04-10

    All-trans retinoic acid (ATRA) is a differentiating agent for the treatment of acute promyelocytic leukemia (APL). However, the therapeutic efficacy of ATRA has limitations. Tetrandrine is a traditional Chinese medicinal herb extract with antitumor effects. In this study, we investigated the effects of tetrandrine on human PML-RAR?-positive acute promyelocytic leukemia cells. Tetrandrine inhibited tumors in vivo. It induced autophagy and differentiation by triggering ROS generation and activating Notch1 signaling. Tetrandrine induced autophagy and differentiation in M5 type patient primary leukemia cells. The in vivo results indicated that low concentrations of tetrandrine inhibited leukemia cells proliferation and induced autophagy and then facilitated their differentiation, by activating ROS and Notch1 signaling. We suggest that tetrandrine is a potential agent for the treatment of APL by inducing differentiation of leukemia cells. PMID:25797266

  11. Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia.

    PubMed

    Fiorcari, Stefania; Martinelli, Silvia; Bulgarelli, Jenny; Audrito, Valentina; Zucchini, Patrizia; Colaci, Elisabetta; Potenza, Leonardo; Narni, Franco; Luppi, Mario; Deaglio, Silvia; Marasca, Roberto; Maffei, Rossana

    2015-02-01

    Lenalidomide is an immunomodulatory agent clinically active in chronic lymphocytic leukemia patients. The specific mechanism of action is still undefined, but includes modulation of the microenvironment. In chronic lymphocytic leukemia patients, nurse-like cells differentiate from CD14(+) mononuclear cells and protect chronic lymphocytic leukemia cells from apoptosis. Nurse-like cells resemble M2 macrophages with potent immunosuppressive functions. Here, we examined the effect of lenalidomide on the monocyte/macrophage population in chronic lymphocytic leukemia patients. We found that lenalidomide induces high actin polymerization on CD14(+) monocytes through activation of small GTPases, RhoA, Rac1 and Rap1 that correlated with increased adhesion and impaired monocyte migration in response to CCL2, CCL3 and CXCL12. We observed that lenalidomide increases the number of nurse-like cells that lost the ability to nurture chronic lymphocytic leukemia cells, acquired properties of phagocytosis and promoted T-cell proliferation. Gene expression signature, induced by lenalidomide in nurse-like cells, indicated a reduction of pivotal pro-survival signals for chronic lymphocytic leukemia, such as CCL2, IGF1, CXCL12, HGF1, and supported a modulation towards M1 phenotype with high IL2 and low IL10, IL8 and CD163. Our data provide new insights into the mechanism of action of lenalidomide that mediates a pro-inflammatory switch of nurse-like cells affecting the protective microenvironment generated by chronic lymphocytic leukemia into tissues. PMID:25398834

  12. Functional and phenotypic studies of Japanese adult T cell leukemia cells.

    PubMed Central

    Morimoto, C; Matsuyama, T; Oshige, C; Tanaka, H; Hercend, T; Reinherz, E L; Schlossman, S F

    1985-01-01

    The cell surface marker profile and functional analysis of peripheral blood lymphocytes from 11 Japanese adult T cell leukemia patients were studied. The phenotypic analysis of Japanese adult T cell leukemia (ATL) cells by a series of 13 monoclonal antibodies showed that all ATL cells are anti-T4 reactive but some differ in their expression of T3, T11, and T12 antigens. Thus, considerable phenotypic heterogeneity exists in these populations of leukemia cells. When analyzed in functional assays, ATL cells were suppressive when added to a pokeweed mitogen- (PWM) driven Ig synthesis system. However, the suppression mechanism seemed to be more complex than originally conceived. ATL cells examined in this study seem to function mainly as an inducer of suppressor cells, and as such, activate normal T8 precursors of suppressor cells rather than function as suppressor effector cells. In addition, no evidence was obtained to suggest that suppression of PWM-stimulated IgG synthesis was mediated by natural killer (NK) activity of ATL cells. Rather, ATL cells seem to be markedly deficient in NK activity. These studies suggest that the majority of ATL cells tested are representative of and seem to be the leukemic counterparts of the T4+ suppressor inducer subset. PMID:2858496

  13. Cell fusion induced by the murine leukemia virus envelope glycoprotein.

    PubMed Central

    Jones, J S; Risser, R

    1993-01-01

    To determine whether ecotropic murine leukemia virus (MuLV) envelope glycoproteins are sufficient to cause cell-to-cell fusion when expressed in the absence of virus production, we used an ecotropic MuLV, AKV, to construct env expression vectors that lack the gag and pol genes. The rat cell line XC, which undergoes cell-to-cell fusion upon infection with ecotropic MuLV, was transfected with wild-type env expression vectors, and high levels of syncytium formation resulted. Transfection of the murine cell line NIH 3T3 with expression vectors containing the wild-type or mutated env region did not result in syncytium formation. Immunoprecipitation analysis of the envelope glycoproteins expressed in NIH 3T3 and XC cells showed that the mature surface glycoprotein expressed in XC cells was of a much lower apparent molecular weight than that expressed in NIH 3T3 cells. Further characterization showed that most if not all of this difference was the result of differences in glycosylation. Finally, site-directed mutagenesis was used to introduce several conservative and nonconservative changes into the amino-terminal region of the transmembrane protein. Analysis of the effect of these mutations confirmed that this region is a fusion domain. Images PMID:8416389

  14. Expression Profiling of Murine Acute Promyelocytic Leukemia Cells Reveals Multiple Model-Dependent Progression Signatures†

    PubMed Central

    Walter, Matthew J.; Park, John S.; Lau, Steven K. M.; Li, Xia; Lane, Andrew A.; Nagarajan, Rakesh; Shannon, William D.; Ley, Timothy J.

    2004-01-01

    Leukemia results from the expansion of self-renewing hematopoietic cells that are thought to contain mutations that contribute to disease initiation and progression. Studies of the gene expression profiles of human acute myeloid leukemia samples has allowed their classification based on the presence of translocations and French-American-British subtypes, but it is not yet clear whether their molecular signatures reflect the initiating mutations or mutations acquired during progression. To begin to address this question, we examined the expression profiles of normal murine promyelocyte-enriched samples, nontransformed murine promyelocytes expressing human promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR?) fusion gene, and primary acute promyelocytic leukemia cells. The expression profile of nontransformed cells expressing PML-RAR? was remarkably similar to that of wild-type promyelocytes. In contrast, the expression profiles of fully transformed cells from three acute promyelocytic leukemia model systems were all different, suggesting that the expression signature of acute promyelocytic leukemia cells reflects the genetic changes that contributed to progression. To further evaluate these progression events, we compared two high-penetrance acute promyelocytic leukemia models that both commonly acquire an interstitial deletion of chromosome 2 during progression. The two models exhibited distinct gene expression profiles, suggesting that the dominant molecular signatures of murine acute promyelocytic leukemia can be influenced by several independent progression events. PMID:15572690

  15. T-cell Depletion of HLA-Identical Transplants in Leukemia

    Microsoft Academic Search

    Alberto M. Marmont; Mary M. Horowitz; Robert Peter Gale; Kathleen Sobocinski; Robert C. Ash; Dirk W. van Bekkum; Richard E. Champlin; Karel A. Dicke; John M. Goldman; Robert A. Good; Roger H. Herzig; Richard Hong; Tohru Masaoka; Alfred A. Rimm; Olle Ringdh; Bruno Speck; Roy S. Weiner; Mortimer M. Bortin

    1991-01-01

    We analyzed the effects of T-cell depletion on the outcome of HLA-identical sibling bone marrow transplants for leukemia by comparing 731 T-cell-depleted transplants with 2,480 non-T-cell-depleted transplants. T-cell depletion decreased acute graft-versus-host disease (GVHD) (relative risk (RR) 0.45; P < .Mol) and chronic GVHD (RR 0.56; P < .Mol). However, it increased graft failure (RR 9.29; P < .OOOl). Leukemia

  16. The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic chemotherapy

    Microsoft Academic Search

    MV Blagosklonny; T Fojo; KN Bhalla; J-S Kim; JB Trepel; WD Figg; Y Rivera; LM Neckers

    2001-01-01

    The Bcr-Abl fusion protein drives leukemogenesis and can render leukemia cells resistant to conventional chemotherapy. Geldanamycin (GA), a drug which destabilizes Hsp90-associated proteins, depletes cells of Bcr-Abl, an Hsp90 client, but not of Abl. Both HL60 cells transfected with Bcr-Abl and naturally Ph1-positive K562 leukemia cells are resistant to most cytotoxic drugs, but were found to be sensitive to GA.

  17. Cochlear implantation in a patient with acute myelomonocytic leukemia before allogeneic peripheral blood stem cell transplantation.

    PubMed

    Cho, Hyong-Ho; Lee, Sungsu; Cho, Yong-Beom

    2014-08-01

    Bilateral deafness can occur in patients with acute leukemia and it can cause communication problems and depressed mood during the treatment of leukemia. Cochlear implantation (CI) is the choice of hearing rehabilitation; however, there is scarce information about the safety of CI during the treatment of leukemia. A 50-year-old female leukemia patient was successfully implanted with a Nucleus cochlear implant while in complete remission before peripheral blood stem cell transplantation. Until now, with a follow-up of 4 years, the patient has useful hearing perception without any complications. To our knowledge, this is the first reported case of a successful CI in a patient with acute leukemia during the treatment of leukemia. PMID:24560096

  18. BOVINE LEUKEMIA VIRUS (BLV) SPECIFIC RNA IN INFECTED CELLS T. ASTIER R. MAMOUN B. GUILLEMAIN J.F. DUPLAN

    E-print Network

    Paris-Sud XI, Université de

    BOVINE LEUKEMIA VIRUS (BLV) SPECIFIC RNA IN INFECTED CELLS T. ASTIER R. MAMOUN B. GUILLEMAIN J and Baumgartener, 1976). The so-called bovine leukemia virus (BLV) displays morphological and biochemical and virus Fetal lamb kidney cells chronically infected with bovine leukemia virus (FLK-BLV) were kindly

  19. FES/FER kinase signaling in hematopoietic cells and leukemias.

    PubMed

    Craig, Andrew W B

    2012-01-01

    FES and FES-related (FER) comprise a unique subfamily of protein-tyrosine kinases (PTKs) that signal downstream of several classes of receptors involved in regulating hematopoietic cell development, survival, migration, and inflammatory mediator release. Activated alleles of FES are potent inducers of myeloid differentiation, however FES-deficient mice have only subtle differences in hematopoiesis. This may reflect overlapping function of other kinases such as FER. Studies of FES- and FER-deficient mice have revealed more prominent roles in regulating the activation of mature innate immune cells, including macrophages and mast cells. Recently, new insights into regulation of FES/FER kinases has emerged with the characterization of their N-terminal phospholipid-binding and membrane targeting FER/CIP4 homology-Bin/Amphyphysin/Rvs (F-BAR) and F-BAR extension (FX) domains. The F-BAR/FX domains regulate subcellular localization and FES/FER kinase activation. FES kinase activity is also enhanced upon ligand binding to its SH2 domain, which may lead to further phosphorylation of the same ligand, or other ligand-associated proteins. In mast cells, SH2 ligands of FES/FER include KIT receptor PTK, and the high affinity IgE receptor (FceRI) that trigger rapid activation of FES/FER and signaling to regulators of the actin cytoskeleton and membrane trafficking. Recently, FES/FER have also been implicated in growth and survival signaling in leukemias driven by oncogenic KIT and FLT3 receptors. With further definition of their roles in immune cells and their progenitors, FES/FER may emerge as relevant therapeutic targets in inflammatory diseases and leukemias. PMID:22201778

  20. Acquired amegakaryocytic thrombocytopenia and pure red cell aplasia associated with an occult large granular lymphocyte leukemia.

    PubMed

    Lai, Dominic W; Loughran, Thomas P; Maciejewski, Jaroslaw P; Sasu, Sebastian; Song, Sophie X; Epling-Burnette, P K; Paquette, Ronald L

    2008-05-01

    Acquired amegakaryocytic thrombocytopenia and pure red cell aplasia rarely occur concurrently. We report a case in which these disorders were associated with an occult large granular lymphocyte leukemia. The peripheral blood cytopenias improved after glucocorticoids and intravenous immunoglobulin were administered, and response was maintained with cyclosporine. Large granular lymphocyte leukemia should be suspected in the setting of unexplained bone marrow failure. PMID:17915315

  1. Acquired amegakaryocytic thrombocytopenia and pure red cell aplasia associated with an occult large granular lymphocyte leukemia

    Microsoft Academic Search

    Dominic W. Lai; Thomas P. Loughran Jr.; Jaroslaw P. Maciejewski; Sebastian Sasu; Sophie X. Song; P. K. Epling-Burnette; Ronald L. Paquette

    2008-01-01

    Acquired amegakaryocytic thrombocytopenia and pure red cell aplasia rarely occur concurrently. We report a case in which these disorders were associated with an occult large granular lymphocyte leukemia. The peripheral blood cytopenias improved after glucocorticoids and intravenous immunoglobulin were administered, and response was maintained with cyclosporine. Large granular lymphocyte leukemia should be suspected in the setting of unexplained bone marrow

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

    Microsoft Academic Search

    E J Dettman; S J Simko; B Ayanga; B L Carofino; J F Margolin; H C Morse; M J Justice

    2011-01-01

    Understanding the heterogeneous genetic mechanisms of tumor initiation in lymphoid leukemias (LL) will lead to improvements in prognostic classification and treatment regimens. In previous studies of mouse leukemias, we showed that retroviral insertion at the ecotropic viral insertion site 32 locus leads to increased expression of Prdm14, a pluripotency gene implicated in the self-renewal capacity of embryonic stem cells and

  3. 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.

  4. Childhood Cancer: Leukemia (For Parents)

    MedlinePLUS

    About Leukemia The term leukemia refers to cancers of the white blood cells (also called leukocytes or WBCs). When ... the disease without it coming back. Types of Leukemia In general, leukemias are classified into acute (rapidly ...

  5. Involvement of tumor necrosis factor (TNF-?) in arsenic trioxide induced apoptotic cell death of murine myeloid leukemia cells

    Microsoft Academic Search

    N. K Mak; R. N. S Wong; K. N Leung; M. C Fung

    2002-01-01

    Arsenic trioxide (As2O3) has recently been shown to be effective to inhibit the growth and to induce apoptosis in acute promyelocytic leukemia (APL) but not in acute myeloid leukemia (AML) cells. Recently, we have isolated an As2O3 sensitive subclone JCS-16 from the murine myeloid leukemia WEHI 3B (JCS). At the concentrations of 0.3–3 ?M, As2O3 induces a dose-dependent cytotoxicity and

  6. Targeting acute myeloid leukemia stem cells: a review and principles for the development of clinical trials

    PubMed Central

    Pollyea, Daniel A.; Gutman, Jonathan A.; Gore, Lia; Smith, Clayton A.; Jordan, Craig T.

    2014-01-01

    Despite an increasingly rich understanding of its pathogenesis, acute myeloid leukemia remains a disease with poor outcomes, overwhelmingly due to disease relapse. In recent years, work to characterize the leukemia stem cell population, the disease compartment most difficult to eliminate with conventional therapy and most responsible for relapse, has been undertaken. This, in conjunction with advances in drug development that have allowed for increasingly targeted therapies to be engineered, raises the hope that we are entering an era in which the leukemia stem cell population can be eliminated, resulting in therapeutic cures for acute myeloid leukemia patients. For these therapies to become available, they must be tested in the setting of clinical trials. A long-established clinical trials infrastructure has been employed to shepherd new therapies from proof-of-concept to approval. However, due to the unique features of leukemia stem cells, drugs that are designed to specifically eliminate this population may not be adequately tested when applied to this model. Therefore, in this review article, we seek to identify the relevant features of acute myeloid leukemia stem cells for clinical trialists, discuss potential strategies to target leukemia stem cells, and propose a set of guidelines outlining the necessary elements of clinical trials to allow for the successful testing of stem cell-directed therapies. PMID:25082785

  7. Targeting acute myeloid leukemia stem cells: a review and principles for the development of clinical trials.

    PubMed

    Pollyea, Daniel A; Gutman, Jonathan A; Gore, Lia; Smith, Clayton A; Jordan, Craig T

    2014-08-01

    Despite an increasingly rich understanding of its pathogenesis, acute myeloid leukemia remains a disease with poor outcomes, overwhelmingly due to disease relapse. In recent years, work to characterize the leukemia stem cell population, the disease compartment most difficult to eliminate with conventional therapy and most responsible for relapse, has been undertaken. This, in conjunction with advances in drug development that have allowed for increasingly targeted therapies to be engineered, raises the hope that we are entering an era in which the leukemia stem cell population can be eliminated, resulting in therapeutic cures for acute myeloid leukemia patients. For these therapies to become available, they must be tested in the setting of clinical trials. A long-established clinical trials infrastructure has been employed to shepherd new therapies from proof-of-concept to approval. However, due to the unique features of leukemia stem cells, drugs that are designed to specifically eliminate this population may not be adequately tested when applied to this model. Therefore, in this review article, we seek to identify the relevant features of acute myeloid leukemia stem cells for clinical trialists, discuss potential strategies to target leukemia stem cells, and propose a set of guidelines outlining the necessary elements of clinical trials to allow for the successful testing of stem cell-directed therapies. PMID:25082785

  8. Acute Myeloid Leukemia

    MedlinePLUS

    ... myeloblasts or myeloid blasts. These cells do not mature into healthy blood cells. Instead, they develop into ... types of leukemia cells or help leukemia cells mature into white blood cells. These drugs are used ...

  9. Combinatorial Targeting of the Macropinocytotic Pathway in Leukemia and Lymphoma Cells*

    PubMed Central

    Nishimura, Shinpei; Takahashi, Shunsuke; Kamikatahira, Hiromi; Kuroki, Yuko; Jaalouk, Diana E.; O’Brien, Susan; Koivunen, Erkki; Arap, Wadih; Pasqualini, Renata; Nakayama, Hitoshi; Kuniyasu, Akihiko

    2008-01-01

    Ligand-directed delivery of agents to leukemia and lymphoma cells has the potential to yield new mechanistic disease insights and targeted therapies. Here we set out to target the macropinocytotic pathway with a combinatorial approach. From the screening of acute T-lymphoblastic leukemia Molt-4 cells with a random phage-display peptide library, we isolated a phage displaying the sequence CAYHRLRRC. This peptide contains a lymph node-homing motif (Cys-Ala-Tyr) and a cell-penetrating motif (Arg-Leu-Arg-Arg). Binding of this ligand-directed phage to a large panel of leukemia/lymphoma cells and to patient-derived samples was much higher than to non-leukemia control cells. CAYHRLRRC phage internalization into Molt-4 cells is both energy- and temperature-dependent. Flow cytometry with fluorescein-labeled peptide and endocytosis blocking with specific inhibitors revealed that CAYHRLRRC is indeed taken up through macropinocytosis in Molt-4 and K562 human leukemia cells. Unexpectedly, the cell surface receptor for the CAYHRLRRC peptide is not a heparan sulfate proteoglycan as it would be predicted for other cell-penetrating peptides. Confirming this interpretation, a CAYHRLRRC-directed peptidomimetic-induced cell death in all the leukemia and lymphoma cells was evaluated, whereas a control transactivator of transcription protein (tat)-directed proapoptotic peptidomimetic was non-selective. In summary, the targeting peptide CAYHRLRRC is selectively internalized through macropinocytosis in leukemia and lymphoma cells and has potential as a drug lead for ligand-directed anti-leukemia therapies. PMID:18292083

  10. Evidence for monoclonal proliferation in prolymphocytic leukemia of T- cell origin

    Microsoft Academic Search

    E. Thiel; M. Bauchinger; H. Rodt; D. Huhn; H. Theml; S. Thierfelder

    1977-01-01

    Summary B- and T-cell markers were studied in a patient with prolymphocytic leukemia, a rare variant of chronic lymphocytic leukemia. Thymus-derived features were identified on the membrane of the neoplastic lymphocytes using the following cellsurface markers: Heterologous T-cell antigen, sheep erythrocyte receptor, surface immunoglobulin, complement receptor, Fc receptor and mouse erythrocyte receptor. Cytogenetic studies of leukemic cells from unstimulated and

  11. Role of tumor suppressor genes in the development of adult T cell leukemia\\/lymphoma (ATLL)

    Microsoft Academic Search

    Y Hatta; HP Koeffler

    2002-01-01

    Adult T cell leukemia\\/lymphoma (ATLL) is one of the peripheral T cell malignant neoplasms strongly associated with human T cell leukemia virus type-I (HTLV-I). Although the viral transactivating protein Tax has been proposed to play a critical role in leukemogeneis as shown by its transforming activity in various experimental systems, additional cellular events are required for the development of ATLL.

  12. Immunostimulatory oligodeoxynucleotides induce apoptosis of B cell chronic lymphocytic leukemia cells

    Microsoft Academic Search

    Bernd Jahrsdorfer; James E. Wooldridge; Sue E. Blackwell; Christiana M. Taylor; Thomas S. Griffith; Brian K. Link; George J. Weiner

    2004-01-01

    Immunostimulatory oligodeoxynucle- otides (IS ODN) can mediate a number of immu- nologic effects. We previously demonstrated that treatment of B cell chronic lymphocytic leukemia (B-CLL) cells with one class of IS ODN, CpG ODN, alters their phenotype and increases their immuno- genicity. Here, we demonstrate that in contrast to the classic understanding of CpG ODN as inhibitors of B cell

  13. Essential role of PU.1 in maintenance of mixed lineage leukemia-associated leukemic stem cells.

    PubMed

    Aikawa, Yukiko; Yamagata, Kazutsune; Katsumoto, Takuo; Shima, Yutaka; Shino, Mika; Stanley, E Richard; Cleary, Michael L; Akashi, Koichi; Tenen, Daniel G; Kitabayashi, Issay

    2015-03-01

    Acute myeloid leukemia is a clonal malignant disorder derived from a small number of leukemic stem cells (LSCs). Rearrangements of the mixed lineage leukemia (MLL) gene are found in acute myeloid leukemia associated with poor prognosis. The upregulation of Hox genes is critical for LSC induction and maintenance, but is unlikely to support malignancy and the high LSC frequency observed in MLL leukemias. The present study shows that MLL fusion proteins interact with the transcription factor PU.1 to activate the transcription of CSF-1R, which is critical for LSC activity. Acute myeloid leukemia is cured by either deletion of PU.1 or ablation of cells expressing CSF-1R. Kinase inhibitors specific for CSF-1R prolong survival time. These findings indicate that PU.1-mediated upregulation of CSF-1R is a critical effector of MLL leukemogenesis. PMID:25529853

  14. Flavopiridol in Treating Patients With Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2013-01-16

    B-cell Chronic Lymphocytic 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

  15. 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 [Department of Hematology/Oncology, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8606 (Japan)] [Department of Hematology/Oncology, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8606 (Japan); Shirafuji, Naoki, E-mail: ramuji@med.teikyo-u.ac.jp [Department of Hematology/Oncology, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8606 (Japan)] [Department of Hematology/Oncology, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8606 (Japan)

    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.

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

    SciTech Connect

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

    2012-11-09

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

  17. Alisertib and Romidepsin in Treating Patients With Relapsed or Refractory B-Cell or T-Cell Lymphomas

    ClinicalTrials.gov

    2015-07-03

    Adult B Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Intraocular Lymphoma; 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 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; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  18. Alisertib and Romidepsin in Treating Patients With Relapsed or Refractory B-Cell or T-Cell Lymphomas

    ClinicalTrials.gov

    2015-04-09

    Adult B Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Intraocular Lymphoma; 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 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; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  19. Leukemia among participants in military maneuvers at a nuclear bomb test. [Plumbbob Project

    SciTech Connect

    Caldwell, G.G.; Kelley, D.B.; Heath, C.W. Jr.

    1980-10-03

    Preliminary studies indicate that nine cases of leukemia have occurred among 3224 men who participated in military maneuvers during the 1957 nuclear test explosion Smoky. This represents a significant increase over the expected incidence of 3.5 cases. They included four cases of acute myelocytic leukemia, three of chronic myelocytic leukemia, and one each of hairy cell and acute lymphocytic leukemia. At time of diagnosis, patient ages ranged from 21 to 60 years (mean, 41.8 years) and the interval from time of nuclear test to diagnosis from two to 19 years (mean, 14.2 years). Film-badge records, which are available for eight of the nine men, indicated gamma radiation exposure levels ranging from 0 to 2977 mrem (mean, 1033 mrem). Mean film-badge gamma dose for the entire Smoky cohort was 466.2 mrem.

  20. Myeloid Derived Suppressor Cells in Chronic Myeloid Leukemia

    PubMed Central

    Giallongo, Cesarina; Parrinello, Nunziatina; Brundo, Maria Violetta; Raccuia, Salvatore Antonino; Di Rosa, Michelino; La Cava, Piera; Tibullo, Daniele

    2015-01-01

    The suppression of the immune system creates a permissive environment for development and progression of cancer. One population of immunosuppressive cells that have become the focus of intense study is myeloid derived suppressor cells (MDSCs), immature myeloid cells able to induce immune-escape, angiogenesis, and tumor progression. Two different subpopulations have been identified and studied: granulocytic and monocytic MDSCs, with a different immunophenotype and immunosuppressive properties. Recently, an accumulation of both Gr-MDSCs and Mo-MDSCs cells has been found in the peripheral blood of chronic myeloid leukemia (CML) patients. They are part of the tumor clone showing BCR/ABL expression. Imatinib therapy decreases both MDSCs and arginase 1 levels to normal ones. This review will focus on actual knowledge for human MDSCs and their immunosuppressive activity in CML patients, with a critical attention to comparison of Gr-MDSCs and polymorphonuclear cells (PMNs). We will then suggest the monitoring of MDSCs in patients who have discontinued tyrosine kinase inhibitors (TKIs) therapy to evaluate if their increase could correlate with disease relapse. PMID:26029664

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

    PubMed

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

    2013-11-22

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

  2. Pterostilbene induces cell cycle arrest and apoptosis in MOLT4 human leukemia cells.

    PubMed

    Siedlecka-Kroplewska, Kamila; Jozwik, Agnieszka; Kaszubowska, Lucyna; Kowalczyk, Anna; Boguslawski, Wojciech

    2012-01-01

    Pterostilbene, a polyphenolic compound present in grapes and other fruits, has been demonstrated to inhibit growth and induce apoptosis and autophagy in some cancer cell types. We found that pterostilbene at the IC(90) concentration of 44 µM inhibited proliferation and induced apoptosis in MOLT4 human leukemia cells. Treatment with pterostilbene resulted in a transient accumulation of cells in the G(0)/G(1)-cell cycle phase followed by the S-phase arrest. Pterostilbene-induced apoptotic death of MOLT4 cells was mediated by caspase-3 activation and was accompanied by the disruption of mitochondrial membrane potential, phosphatidylserine externalization and internucleosomal DNA fragmentation. Our results suggest that pterostilbene could serve as a potential additional chemotherapeutic agent for the treatment of leukemia. PMID:23264221

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

    ClinicalTrials.gov

    2015-01-05

    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

  4. Alternative Donor Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia.

    PubMed

    Kanakry, Christopher G; de Lima, Marcos J; Luznik, Leo

    2015-07-01

    Allogeneic hematopoietic cell transplantation (alloHCT) provides a potentially curative therapy for patients with high-risk or chemorefractory acute myeloid leukemia (AML). Historically, the applicability of alloHCT has been limited as only 30%-35% of patients have human leukocyte antigen (HLA)-matched siblings and outcomes using other donor types have been markedly inferior due to excess toxicity, graft failure, graft-versus-host disease (GVHD), and consequently non-relapse mortality. Advances in HLA typing, GVHD prophylactic approaches, and other transplantation techniques have successfully addressed these historical challenges. Herein, we review recent alloHCT studies using volunteer unrelated donors, umbilical cord blood units, or HLA-haploidentical donors, specifically focusing on studies that compared outcomes between donor sources. Although none are randomized and most are retrospective, these analyses suggest that current outcomes for AML patients using most alternative donor types are comparable to those seen using HLA-matched siblings. PMID:26111471

  5. T memory stem cells are the hierarchical apex of adult T-cell leukemia.

    PubMed

    Nagai, Yuya; Kawahara, Masahiro; Hishizawa, Masakatsu; Shimazu, Yayoi; Sugino, Noriko; Fujii, Sumie; Kadowaki, Norimitsu; Takaori-Kondo, Akifumi

    2015-06-01

    Adult T-cell leukemia (ATL) is a peripheral CD4(+) T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). Despite several investigations using human specimens and mice models, the exact origin of ATL cells remains unclear. Here we provide a new insight into the hierarchical architecture of ATL cells. HTLV-1-infected cells and dominant ATL clones are successfully traced back to CD45RA(+) T memory stem (TSCM) cells, which were recently identified as a unique population with stemlike properties, despite the fact that the majority of ATL cells are CD45RA(-)CD45RO(+) conventional memory T cells. TSCM cells from ATL patients are capable of both sustaining themselves in less proliferative mode and differentiating into other memory T-cell populations in the rapidly propagating phase. In a xenograft model, a low number of TSCM cells efficiently repopulate identical ATL clones and replenish downstream CD45RO(+) memory T cells, whereas other populations have no such capacities. Taken together, these findings demonstrate the phenotypic and functional heterogeneity and the hierarchy of ATL cells. TSCM cells are identified as the hierarchical apex capable of reconstituting identical ATL clones. Thus, this is the first report to demonstrate the association of a T-cell malignancy with TSCM cells. PMID:25847015

  6. Gold nanoparticle-enhanced electroporation for leukemia cell transfection.

    PubMed

    Huang, Shuyan; Zu, Yingbo; Wang, Shengnian

    2014-01-01

    Electroporation serves as an attractive nonviral gene delivery approach for its effectiveness, operational simplicity, and no restrictions of probe or cell type. The commercial electroporation systems have been widely adopted in research and clinics with protocols usually compromising appropriate transfection efficiency and cell viability. By introducing gold nanoparticles (AuNPs), we demonstrated greatly enhanced performance of electroporation from two aspects: the highly conductive, naked AuNPs help reduce the potential drop consumed by the electroporation solution so that the majority of the applied voltage of an electric pulse is truly imposed on cells with enhanced field strength; AuNPs with targeting ligands (e.g., transferrin-AuNPs or Tf-AuNPs) are bound to the cell membrane, working as virtual microelectrodes to create pores on cells with limited opening area while from many different sites. The addition of AuNPs during electroporation therefore benefits not only quicker recovery and better survival of cells but also more efficient uptake of the subjected probes. Such enhancement was successfully confirmed on a chronic myeloid leukemia cell line (i.e., K562 cells) in both a commercial batch electroporation system and a homemade flow system with pWizGFP plasmid DNA probes. The efficiency was found to be dependent on the size, concentration, and mixing ratio of free AuNPs/Tf-AuNPs. An equivalent mixture of free AuNPs and Tf-AuNPs exhibited the best enhancement with the transfection efficiency increase of two to threefold at a minimum sacrifice of the cell viability. PMID:24510813

  7. Detection of NOTCH1 Mutations in Adult T-cell Leukemia\\/Lymphoma and Peripheral T-Cell Lymphoma

    Microsoft Academic Search

    Daisuke Shimizu; Tomohiko Taki; Atae Utsunomiya; Hitoshi Nakagawa; Kenichi Nomura; Yosuke Matsumoto; Kazuhiro Nishida; Shigeo Horiike; Masafumi Taniwaki

    2007-01-01

    We analyzedNOTCH1 gene mutation in 53 adults with mature T-cell leukemia\\/lymphoma: 21 patients with adult T-cell leukemia (ATL), 25 with T-cell\\u000a non-Hodgkin’s lymphoma (T-NHL), and 7 with T-cell prolymphocytic leukemia. We detected a nonsense mutation, C7249T (resulting\\u000a in Q2417X, where X is a termination codon) in the PEST domain ofNOTCH1 in an ATL patient and detected a 3-bp deletion (positions

  8. Specific reactivity of leukemia cells to polyclonal anti-PCB antibodies.

    PubMed

    Harper, D M; Flessas, D A; Reinisch, C L

    1994-11-01

    Bivalve molluscs such as the soft shell clam (Mya arenaria) develop leukemias in the hemolymph which are fatal. The prevalence of leukemia in Mya was evaluated using a murine monoclonal antibody which recognizes a leukemia-specific protein expressed by tumor cells. The reactivity with a polyclonal antibody to polychlorinated biphenyls (PCBs) of both normal circulating cells and tumor cells was also determined. Both leukemia prevalence and PCB reactivity were ascertained by flow cytometry. Analytical chemistry was used to quantitate the amount of Aroclor per tumor cell population and compared directly to flow cytometric results. Our results show that the prevalence of leukemia consistently exceeds 60% when clams are retrieved from New Bedford Harbor, a site heavily contaminated with PCBs. Both normal circulating cells and tumor cells are extremely reactive with the PCB antibody. When clams from two other sites were compared with clams from New Bedford Harbor, both disease prevalence and cell reactivity to the PCB antibody were reduced. Our experiments are the first which use the flow cytometer to demonstrate PCBs in cell populations of marine invertebrates. Our results further demonstrate that the presence of polychlorinated biphenyls in vivo is directly correlated with environmentally linked leukemia. PMID:7806895

  9. Changes in ligno-suberization of cell walls of tomato hairy roots produced by salt treatment: the relationship with the release of a basic peroxidase.

    PubMed

    Talano, Melina Andrea; Agostini, Elizabeth; Medina, María I; Reinoso, Herminda; Tordable, María del Carmen; Tigier, Horacio A; de Forchetti, Silvia Milrad

    2006-05-01

    A highly basic peroxidase isoenzyme was shown to be released to the culture medium of tomato (Lycopersicon esculentum) hairy roots grown in Murashige-Skoog (MS) liquid medium when it was supplemented with 100 mM NaCl. In this paper we demonstrate that this enzyme is ionically bound to cell walls and that the release was a consequence of the continuous agitation of the tissue in a high ionic strength medium with salt addition. In order to establish the physiological role of this isoenzyme we partially purified it, and we analysed its kinetic properties as coniferyl alcohol peroxidase. The peroxidase isoenzyme showed a high catalytic efficiency for this substrate, which suggests that it would be associated with the ligno-suberization process. To confirm the involvement of this isoenzyme in that process, we studied the pattern of ligno-suberization of the tissue under different conditions of growth. Our results suggest that this basic peroxidase would be indeed involved in ligno-suberization since its leakage from cell walls, induced by 100 mM NaCl in liquid MS, caused less ligno-suberization of exo and endodermis. On the contrary, more ligno-suberization was seen in cell walls when the hairy roots were grown in a salt-supplemented MS solid medium without contact with it, a condition in which the release of the isoenzyme would be avoided. Thus, through the changes produced by the release of the enzyme from its site of action, we could demonstrate the physiological role of this peroxidase in the processing of root cell walls, being part of control mechanisms of ion and water fluxes through the root. PMID:16616585

  10. A COMPARISON OF THE BOVINE LEUKEMIA AND BOVINE SYNCYTIAL VIRUS STATUS IN UTERO-TUBAL CELLS RECOVERED FROM FLUIDS USED

    E-print Network

    Paris-Sud XI, Université de

    A COMPARISON OF THE BOVINE LEUKEMIA AND BOVINE SYNCYTIAL VIRUS STATUS IN UTERO-TUBAL CELLS) (Samagh et al 1977, Serological diagno- sis of bovine leukemia virus infection using dual (glycoprotein, Rotterdam, Aug 29ih-30th ; pp 69-77) that both bovine leukemia virus (BLV) and bovine syncytial virus (BSV

  11. Free radical production and labile iron pool decrease triggered by subtoxic concentration of aclarubicin in human leukemia cell lines

    E-print Network

    Boyer, Edmond

    of aclarubicin in human leukemia cell lines Doriane Richard, Hamid Morjani, Benoît Chénais* Unité MéDIAN, CNRS manuscript, published in "Leukemia Research 26, 10 (2002) 927-31" #12;2 Abstract Aclarubicin (ACLA), which agent for a broad range of human solid tumors and leukemia. By using dihydroethidium as a fluorescent

  12. In Vivo Imaging Enables High Resolution Preclinical Trials on Patients’ Leukemia Cells Growing in Mice

    PubMed Central

    Terziyska, Nadia; Alves, Catarina Castro; Groiss, Volker; Schneider, Katja; Farkasova, Katarina; Ogris, Manfred; Wagner, Ernst; Ehrhardt, Harald; Brentjens, Renier J.; zur Stadt, Udo; Horstmann, Martin; Quintanilla-Martinez, Leticia; Jeremias, Irmela

    2012-01-01

    Background Xenograft mouse models represent helpful tools for preclinical studies on human tumors. For modeling the complexity of the human disease, primary tumor cells are by far superior to established cell lines. As qualified exemplary model, patients’ acute lymphoblastic leukemia cells reliably engraft in mice inducing orthotopic disseminated leukemia closely resembling the disease in men. Unfortunately, disease monitoring of acute lymphoblastic leukemia in mice is hampered by lack of a suitable readout parameter. Design and Methods Patients’ acute lymphoblastic leukemia cells were lentivirally transduced to express the membrane-bound form of Gaussia luciferase. In vivo imaging was established in individual patients’ leukemias and extensively validated. Results Bioluminescence in vivo imaging enabled reliable and continuous follow-up of individual mice. Light emission strictly correlated to post mortem quantification of leukemic burden and revealed a logarithmic, time and cell number dependent growth pattern. Imaging conveniently quantified frequencies of leukemia initiating cells in limiting dilution transplantation assays. Upon detecting a single leukemia cell within more than 10,000 bone marrow cells, imaging enabled monitoring minimal residual disease, time to tumor re-growth and relapse. Imaging quantified therapy effects precisely and with low variances, discriminating treatment failure from partial and complete responses. Conclusions For the first time, we characterized in detail how in vivo imaging reforms preclinical studies on patient-derived tumors upon increasing monitoring resolution. In the future, in vivo imaging will enable performing precise preclinical studies on a broad range of highly demanding clinical challenges, such as treatment failure, resistance in leukemia initiating cells, minimal residual disease and relapse. PMID:23300782

  13. Digital gene expression profiling of primary acute lymphoblastic leukemia cells.

    PubMed

    Nordlund, J; Kiialainen, A; Karlberg, O; Berglund, E C; Göransson-Kultima, H; Sønderkær, M; Nielsen, K L; Gustafsson, M G; Behrendtz, M; Forestier, E; Perkkiö, M; Söderhäll, S; Lönnerholm, G; Syvänen, A-C

    2012-06-01

    We determined the genome-wide digital gene expression (DGE) profiles of primary acute lymphoblastic leukemia (ALL) cells from 21 patients taking advantage of 'second-generation' sequencing technology. Patients included in this study represent four cytogenetically distinct subtypes of B-cell precursor (BCP) ALL and T-cell lineage ALL (T-ALL). The robustness of DGE combined with supervised classification by nearest shrunken centroids (NSC) was validated experimentally and by comparison with published expression data for large sets of ALL samples. Genes that were differentially expressed between BCP ALL subtypes were enriched to distinct signaling pathways with dic(9;20) enriched to TP53 signaling, t(9;22) to interferon signaling, as well as high hyperdiploidy and t(12;21) to apoptosis signaling. We also observed antisense tags expressed from the non-coding strand of ~50% of annotated genes, many of which were expressed in a subtype-specific pattern. Antisense tags from 17 gene regions unambiguously discriminated between the BCP ALL and T-ALL subtypes, and antisense tags from 76 gene regions discriminated between the 4 BCP subtypes. We observed a significant overlap of gene regions with alternative polyadenylation and antisense transcription (P<1 × 10(-15)). Our study using DGE profiling provided new insights into the RNA expression patterns in ALL cells. PMID:22173241

  14. Asymptomatic T-cell large granular lymphocyte leukemia with an unusual immunophenotype

    PubMed Central

    Petsa, Panagiota K.; Karamoutsios, Achilleas; Dova, Lefkothea; Benetatos, Leonidas; Petsiou, Asimina; Kolaitis, Nikolaos; Georgopoulos, Antonis; Vartholomatos, Georgios

    2012-01-01

    T-cell large granular lymphocyte (T-LGL) leukemia represents a clonal proliferation of cytotoxic T-cells which etiology has not been entirely elucidated. However, CD4+, CD4?, CD8?, CD4+, CD8+ cases have been described. The disease is usually characterized by cytopenias and a modest lymphocytosis. The majority of patients with T-LGL leukemia remains asymptomatic for a long period and will require treatment later during the course of their disease. Hereby we describe a case of T-LGL leukemia diagnosed by flow cytometry, which presented indolent course and required no treatment so far. PMID:24765467

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

    ClinicalTrials.gov

    2014-12-02

    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

  16. A hairy situation.

    PubMed

    Ibrahim, Nader; Wooles, Nicola Rachel; Elloy, Marianne; Da Forno, Philip

    2015-01-01

    A 2-day-old neonate was transferred to a specialist paediatric otolaryngology centre with stridor at rest, feeding difficulties and an apparent mass in the oropharynx. The newborn displayed evidence of respiratory distress, however, she remained self-ventilating. MRI highlighted a fat-containing lesion in the postnasal space with no intracranial extension. A CT scan under general anaesthesia showed no underlying bony abnormality, and hence an examination of the nasopharynx, oropharynx and microlaryngoscopy and bronchoscopy were performed. The macroscopically hairy lesion arising from the superior aspect of the soft palate was resected. Histology displayed a benign growth measuring 28×17×12?mm in keeping with a hairy polyp. This is one of very few cases, to the best of our knowledge, in which a hairy polyp (bigerminal choristomas) has resulted in stridor in the first few days of life. Nasal masses in neonates, although a rare phenomenon, remain clinically important as they are obligate nasal breathers. PMID:26055604

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

    ClinicalTrials.gov

    2009-01-29

    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)

  18. Adult T-Cell Leukemia: A Review of Epidemiological Evidence

    PubMed Central

    Iwanaga, Masako; Watanabe, Toshiki; Yamaguchi, Kazunari

    2012-01-01

    Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type I (HTLV-1) infection and often occurs in HTLV-1-endemic areas, such as southwestern Japan, the Caribbean islands, Central and South America, Intertropical Africa, and Middle East. To date, many epidemiological studies have been conducted to investigate the incidence of ATL among general population or HTLV-1 carriers and to identify a variety of laboratory, molecular, and host-specific markers to be possible predictive factors for developing ATL because HTLV-1 infection alone is not sufficient to develop ATL. This literature review focuses on the epidemiology of ATL and the risk factors for the development of ATL from HTLV-1 carriers, while keeping information on the epidemiology of HTLV-1 to a minimum. The main lines of epidemiological evidence are: (1) ATL occurs mostly in adults, at least 20–30?years after the HTLV-1 infection, (2) age at onset differs across geographic areas: the average age in the Central and South America (around 40?years old) is younger than that in Japan (around 60?years old), (3) ATL occurs in those infected in childhood, but seldom occurs in those infected in adulthood, (4) male carriers have about a three- to fivefold higher risk of developing ATL than female, (5) the estimated lifetime risk of developing ATL in HTLV-1 carriers is 6–7% for men and 2–3% for women in Japan, (6) a low anti-Tax reactivity, a high soluble interleukin-2 receptor level, a high anti-HTLV-1 titer, and high levels of circulating abnormal lymphocytes and white blood cell count are accepted risk factors for the development of ATL, and (7) a higher proviral load (more than 4 copies/100 peripheral blood mononuclear cells) is an independent risk factor for progression of ATL. Nevertheless, the current epidemiological evidence is insufficient to fully understand the oncogenesis of ATL. Further well-designed epidemiological studies are needed. PMID:22973265

  19. Efficient Expression and Rapid Purification of Human T-Cell Leukemia Virus Type 1 Protease

    Microsoft Academic Search

    Y. SHIRLEY DING; SHERRY M. OWEN; RENU B. LAL; RICHARD A. IKEDA

    1998-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) is an oncovirus that is clinically associated with adult T-cell leukemia. We report here the construction of a pET19-based expression clone containing HTLV-1 protease fused to a decahistidine-containing leader peptide. The recombinant protein is efficiently expressed in Esch- erichia coli, and the fusion protein can be easily purified by affinity chromatography. Active mature

  20. Malignant lymphomas in Japan: Epidemiological analysis of adult T-cell leukemia\\/lymphoma (ATL)

    Microsoft Academic Search

    Kazuo Tajima

    1988-01-01

    The incidence of malignant lymphomas in Japan is relatively low compared to that in western European countries and the United States. However, in limited areas in Japan a specific type of lymphoid malignancy called adult T-cell leukemia\\/lymphoma (ATL), which is caused by human T-cell leukemia virus type I (HTLV-I), is highly prevalent, and there are also many healthy carriers of

  1. Pathogenesis and treatment of human T-cell leukemia virus infection

    Microsoft Academic Search

    Lee Ratner

    2005-01-01

    The pathogenesis of human T-cell leukemia virus (HTLV)-induced adult T-cell leukemia-lymphoma (ATLL) was explored using an\\u000a infectious molecular viral clone and a transgenic mouse model. Activation of nuclear factor-?B by the HTLV transcriptional\\u000a transactivator protein Tax was found to be important for lymphocyte immortalization and tumorigenesis. Interferon-? regulates\\u000a tumor development owing primarily to angiostatic effects. Translational clinical studies of chemotherapy,

  2. 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. ...

  3. 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. ...

  4. [Analysis of expression of mitosis checkpoint gene chfr in bone marrow cells of acute leukemia patients].

    PubMed

    Gong, Hui; Liu, Wen-Li; Zhou, Jian-Feng; Ran, Dan; Xu, Hui-Zhen

    2006-02-01

    This study was purposed to investigate the significance of mitosis checkpoint gene chfr expression in acute leukemia (AL). 2 ml of bone marrow were extracted from each of 46 AL patients and 10 normal donors as control and their mononuclear cells were isolated. Then, their chfr expression was detected by using RT-PCR and immunohistochemistry. Normal control blood samples were also analyzed. The results showed that in 15 out of 28 cases of acute non-lymphocytic leukemia and 13 out of 18 cases of acute lymphocytic leukemia expression of chfr gene mRNA and protein significantly decreased as compared with control. The cytogenetic analysis of patients with a decreased Chfr expression revealed abnormal chromosome. In conclusion, Chfr gene is a leukemia-related gene and may play an important role in leukemia pathogenesis. PMID:16584586

  5. Scalarized hairy black holes

    NASA Astrophysics Data System (ADS)

    Kleihaus, Burkhard; Kunz, Jutta; Yazadjiev, Stoytcho

    2015-05-01

    In the presence of a complex scalar field scalar-tensor theory allows for scalarized rotating hairy black holes. We exhibit the domain of existence for these scalarized black holes, which is bounded by scalarized rotating boson stars and hairy black holes of General Relativity. We discuss the global properties of these solutions. Like their counterparts in general relativity, their angular momentum may exceed the Kerr bound, and their ergosurfaces may consist of a sphere and a ring, i.e., form an ergo-Saturn.

  6. Scalarized Hairy Black Holes

    E-print Network

    Kleihaus, Burkhard; Yazadjiev, Stoytcho

    2015-01-01

    In the presence of a complex scalar field scalar-tensor theory allows for scalarized rotating hairy black holes. We exhibit the domain of existence for these scalarized black holes, which is bounded by scalarized rotating boson stars and ordinary hairy black holes. We discuss the global properties of these solutions. Like their counterparts in general relativity, their angular momentum may exceed the Kerr bound, and their ergosurfaces may consist of a sphere and a ring, i.e., form an ergo-Saturn.

  7. Scalarized Hairy Black Holes

    E-print Network

    Burkhard Kleihaus; Jutta Kunz; Stoytcho Yazadjiev

    2015-03-05

    In the presence of a complex scalar field scalar-tensor theory allows for scalarized rotating hairy black holes. We exhibit the domain of existence for these scalarized black holes, which is bounded by scalarized rotating boson stars and ordinary hairy black holes. We discuss the global properties of these solutions. Like their counterparts in general relativity, their angular momentum may exceed the Kerr bound, and their ergosurfaces may consist of a sphere and a ring, i.e., form an ergo-Saturn.

  8. Stem cell transplantation for chronic myeloid leukemia in children.

    PubMed

    Cwynarski, Kate; Roberts, Irene A G; Iacobelli, Simona; van Biezen, Anja; Brand, Ronald; Devergie, Agnes; Vossen, Jaak M; Aljurf, Mahmoud; Arcese, William; Locatelli, Franco; Dini, Giorgio; Niethammer, Dietrich; Niederwieser, Dietger; Apperley, Jane F

    2003-08-15

    Hematopoietic stem cell transplantation (SCT) is the only proven cure for chronic myeloid leukemia (CML), a rare disease in childhood. We report outcomes of 314 children with Philadelphia-chromosome-positive (Ph+) CML undergoing SCT from HLA-matched siblings (n = 182) or volunteer-unrelated donors (VUD; n = 132). Three-year overall survival (OS) and leukemia-free survival (LFS) rates were 66% and 55% (n = 314). For 156 children in first chronic phase (CP1) who underwent transplantation from HLA-identical siblings, OS and LFS rates were 75% and 63%. For 97 children who underwent SCT in CP1 from VUD, 3-year OS and LFS rates were 65% and 56%, reflecting higher transplantation-related mortality (TRM) after VUD SCT (35% vs 20%; multivariate hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.0-3.5; P =.05). In a multivariate model for OS and LFS, outcomes were superior in CP1 than in advanced phase (AP/CP1) (OS HR, 2.0; 95% CI, 1.3-3; P =.001; LFS HR, 1.8; 95% CI, 1.2-2.6; P =.003). For relapse, donor source (VUD/sibling) (HR, 0.38; 95% CI, 0.19-0.76; P =.006) and disease stage (AP/CP1) (HR, 2.4; 95% CI, 1.36-4.3; P =.003) were significant. This is the first large series to show that SCT confers long-term LFS in most children with CML and helps assess alternative therapy, including tyrosine kinase inhibitors. PMID:12714525

  9. Musashi2 sustains the mixed-lineage leukemia–driven stem cell regulatory program

    PubMed Central

    Park, Sun-Mi; Gönen, Mithat; Vu, Ly; Minuesa, Gerard; Tivnan, Patrick; Barlowe, Trevor S.; Taggart, James; Lu, Yuheng; Deering, Raquel P.; Hacohen, Nir; Figueroa, Maria E.; Paietta, Elisabeth; Fernandez, Hugo F.; Tallman, Martin S.; Melnick, Ari; Levine, Ross; Leslie, Christina; Lengner, Christopher J.; Kharas, Michael G.

    2015-01-01

    Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Leukemia cells exhibit a dysregulated developmental program as the result of genetic and epigenetic alterations. Overexpression of the RNA-binding protein Musashi2 (MSI2) has been previously shown to predict poor survival in leukemia. Here, we demonstrated that conditional deletion of Msi2 in the hematopoietic compartment results in delayed leukemogenesis, reduced disease burden, and a loss of LSC function in a murine leukemia model. Gene expression profiling of these Msi2-deficient animals revealed a loss of the hematopoietic/leukemic stem cell self-renewal program and an increase in the differentiation program. In acute myeloid leukemia patients, the presence of a gene signature that was similar to that observed in Msi2-deficent murine LSCs correlated with improved survival. We determined that MSI2 directly maintains the mixed-lineage leukemia (MLL) self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc, and Ikzf2 mRNAs. Moreover, depletion of MLL target Ikzf2 in LSCs reduced colony formation, decreased proliferation, and increased apoptosis. Our data provide evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and suggest MSI2 as a potential therapeutic target for myeloid leukemia. PMID:25664853

  10. Tartrate-resistant Acid Phosphatase (Acp 5): Identification in Diverse Human Tissues and Dendritic Cells

    Microsoft Academic Search

    Alison R. Hayman; Paul Macary; Paul J. Lehner; Timothy M. Cox

    2001-01-01

    SUMMARY Histochemical demonstration of tartrate-resistant acid phosphatase (TRAP) is used for the specific identification of osteoclasts. The enzyme, which we have shown to be critical for normal bone development in mice, is also characteristic of monohistiocytes, in- cluding alveolar macrophages, and is associated with diverse pathological conditions such as Gaucher's disease and hairy cell leukemia. TRAP activity is enhanced in

  11. IgE synthesis by chronic lymphocytic leukemia cells

    PubMed Central

    1989-01-01

    The present results indicate that B cells isolated from chronic lymphocytic leukemia (B-CLL) from 11 of 14 patients are capable of specifically producing IgE upon costimulation with IL-4 and hydrocortisone (HC). IgE is detected by intracytoplasmic fluorescence staining and by RIA. Clinical, hematological, and immunological parameters (including Rai stage, WBC, Lc, sIg kappa/lambda, CD5, and CD23 expression) cannot distinguish the IgE responder from the nonresponder patients. IL-4 alone is a potent inducer of human IgE synthesis by normal PBMC and we show here that its effect is strikingly enhanced by HC. The IgE produced by B-CLLs are monoclonal since they display the same L chain type as the freshly isolated CD5+ B-CLLs. We, therefore, conclude that the combination of IL-4 and HC can abrogate the maturation arrest of CD5+ B-CLLs by inducing their differentiation into IgE-producing cells. The present data provide a unique model to study the isotype switching to IgE and the regulation of human IgE synthesis by monoclonal human B cells. PMID:2478656

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

    PubMed Central

    2013-01-01

    Background The role of IGF binding protein 2 (IGFBP2) in cancer development is intriguing. Previously we identified IGFBP2 as an extrinsic factor that supports the activity of hematopoietic stem cells (HSCs). Methods and results Here we investigated the role of IGFBP2 in in human leukemia cells and in the retroviral AML1-ETO9a transplantation acute myeloid leukemia (AML) mouse model. Results IGFBP2 is highly expressed in certain human AML and acute lymphoblastic leukemia (ALL) cells. Inhibition of expression of endogenous IGFBP2 in human leukemia cells led to elevated apoptosis and decreased migration and, consistently, to decreased activation of AKT and other signaling molecules. We also studied the effects of IGFBP2 knockout in the retroviral AML1-ETO9a transplantation AML mouse model. The deletion of IGFBP2 in donor AML cells significantly decreased leukemia development in transplanted mice. Lack of IGFBP2 resulted in upregulation of PTEN expression and downregulation of AKT activation, in the mouse AML cells. The treatment of IGFBP2 deficient AML cells with a PTEN inhibitor restored the wild-type colony forming ability. The deletion of IGFBP2 also led to decreased AML infiltration into peripheral organs and tissues, suggesting that IGFBP2 is required for the migration of AML cells out of bone marrow. Conclusion IGFBP2 is a critical cell-autonomous factor that promotes the survival and migration of acute leukemia cells. PMID:24191913

  13. [Lymphomas and lymphatic leukemias in the bone marrow].

    PubMed

    Adam, P; Quintanilla-Fend, L; Fend, F

    2012-11-01

    A bone marrow biopsy in a patient with a diagnosis of lymphoma is often performed as part of the staging procedures, i.e. to find out whether or not the bone marrow harbors infiltrates of an already diagnosed tumor. On the other hand, occasionally changes in the peripheral blood count or an M-protein in the serum lead to a bone marrow biopsy in which the first diagnosis of a malignant lymphoma is established. In either case, the diagnosis of lymphomas and lymphatic leukemias in the bone marrow requires an integration of clinical data, cytomorphology, the topographic distribution of the infiltrate and immunohistochemical as well as molecular techniques, where required. This may particularly be the case when confirmation or exclusion of conventionally barely detectable infiltrates (e.g. hairy cell leukemia, hepatosplenic T-cell lymphoma, plasma cell infiltrates) is required. PMID:23085695

  14. 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

  15. Kinase-Independent Mechanisms of Resistance of Leukemia Stem Cells to Tyrosine Kinase Inhibitors

    PubMed Central

    2014-01-01

    Summary Tyrosine kinase inhibitors such as imatinib mesylate have changed the clinical course of chronic myeloid leukemia; however, the observation that these inhibitors do not target the leukemia stem cell implies that patients need to maintain lifelong therapy. The mechanism of this phenomenon is unclear: the question of whether tyrosine kinase inhibitors are inactive inside leukemia stem cells or whether leukemia stem cells do not require breakpoint cluster region (Bcr)-Abl signaling is currently under debate. Herein, I propose an alternative model: perhaps the leukemia stem cell requires Bcr-Abl, but is dependent on its kinase-independent functions. Kinases such as epidermal growth factor receptor and Janus kinase 2 possess kinase-independent roles in regulation of gene expression; it is worth investigating whether Bcr-Abl has similar functions. Mechanistically, Bcr-Abl is able to activate the Ras, phosphatidylinositol 3-kinase/Akt, and/or the Src-kinase Hck/Stat5 pathways in a scaffolding-dependent manner. Whereas the scaffolding activity of Bcr-Abl with Grb2 is dependent on autophosphorylation, kinases such as Hck can use Bcr-Abl as substrate, inducing phosphorylation of Y177 to enable scaffolding ability in the absence of Bcr-Abl catalytic activity. It is worth investigating whether leukemia stem cells exclusively express kinases that are able to use Bcr-Abl as substrate. A kinase-independent role for Bcr-Abl in leukemia stem cells would imply that drugs that target Bcr-Abl’s scaffolding ability or its DNA-binding ability should be used in conjunction with current therapeutic regimens to increase their efficacy and eradicate the stem cells of chronic myeloid leukemia PMID:24598782

  16. Oncogenic NRAS Primes Primary Acute Myeloid Leukemia Cells for Differentiation

    PubMed Central

    Millahn, Axel; Stiewe, Thorsten; Krause, Michael; Stabla, Kathleen; Ross, Petra; Huynh, Minh; Illmer, Thomas; Mernberger, Marco; Barckhausen, Christina; Neubauer, Andreas

    2015-01-01

    RAS mutations are frequently found among acute myeloid leukemia patients (AML), generating a constitutively active signaling protein changing cellular proliferation, differentiation and apoptosis. We have previously shown that treatment of AML patients with high-dose cytarabine is preferentially beneficial for those harboring oncogenic RAS. On the basis of a murine AML cell culture model, we ascribed this effect to a RAS-driven, p53-dependent induction of differentiation. Hence, in this study we sought to confirm the correlation between RAS status and differentiation of primary blasts obtained from AML patients. The gene expression signature of AML blasts with oncogenic NRAS indeed corresponded to a more mature profile compared to blasts with wildtype RAS, as demonstrated by gene set enrichment analysis (GSEA) and real-time PCR analysis of myeloid ecotropic viral integration site 1 homolog (MEIS1) in a unique cohort of AML patients. In addition, in vitro cell culture experiments with established cell lines and a second set of primary AML cells showed that oncogenic NRAS mutations predisposed cells to cytarabine (AraC) driven differentiation. Taken together, our findings show that AML with inv(16) and NRAS mutation have a differentiation gene signature, supporting the notion that NRAS mutation may predispose leukemic cells to AraC induced differentiation. We therefore suggest that promotion of differentiation pathways by specific genetic alterations could explain the superior treatment outcome after therapy in some AML patient subgroups. Whether a differentiation gene expression status may generally predict for a superior treatment outcome in AML needs to be addressed in future studies. PMID:25901794

  17. Metabolism of arsenic trioxide in acute promyelocytic leukemia cells.

    PubMed

    Khaleghian, Ali; Ghaffari, Seyed H; Ahmadian, Shahin; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir

    2014-10-01

    Arsenic trioxide (As2O3) effectively induces complete clinical and molecular remissions in acute promyelocytic leukemia (APL) patients and triggers apoptosis in APL cells. The effect induced by As2O3 is also associated with extensive genomic-wide epigenetic changes with large-scale alterations in DNA methylation. We investigated the As2O3 metabolism in association with factors involved in the production of its methylated metabolites in APL-derived cell line, NB4. We used high performance liquid chromatography (HPLC) technique to detect As2O3 metabolites in NB4 cells. The effects of As2O3 on glutathione level, S-Adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels were investigated. Also, we studied the expression levels of arsenic methyltransferase (AS3MT) and DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) by real-time PCR. Our results show that after As2O3 entry into the cell, it was converted into methylated metabolites, mono-methylarsenic (MMA) and dimethylarsenic (DMA). The glutathione (GSH) production was increased in parallel with the methylated metabolites formations. As2O3 treatment inhibited DNMTs (DNMT1, DNMT3a, and DNMT3b) in dose- and time-dependent manners. The SAH levels in As2O3-treated cells were increased; however, the SAM level was not affected. The present study shows that APL cell is capable of metabolizing As2O3. The continuous formation of intracellular methylated metabolites, the inhibition of DNMTs expression levels and the increase of SAH level by As2O3 biotransformation would probably affect the DNMTs-methylated DNA methylation in a manner related to the extent of DNA hypomethylation. Production of intracellular methylated metabolites and epigenetic changes of DNA methylation during As2O3 metabolism may contribute to the therapeutic effect of As2O3 in APL. PMID:24819152

  18. Targeting B cell leukemia with highly specific allogeneic T cells with a public recognition motif.

    PubMed

    Abrahamsen, I W; Stronen, E; Wälchli, S; Johansen, J N; Kjellevoll, S; Kumari, S; Komada, M; Gaudernack, G; Tjonnfjord, G; Toebes, M; Schumacher, T N; Lund-Johansen, F; Olweus, J

    2010-11-01

    The possibility that allogeneic T cells may be targeted to leukemia has important therapeutic implications. As most tumor antigens represent self-proteins, high-avidity tumor-specific T cells are largely deleted from the repertoire of the patient. In contrast, T cells from major histocompatibility complex (MHC)-mismatched donors provide naïve repertoires wherein such cells have not been systematically eliminated. Yet, evidence for peptide degeneracy or poly-specificity warrants caution in the use of foreign human leukocyte antigen (HLA) or peptide complexes as therapeutic targets. Here, we cocultured HLA-A(*)0201-negative T cells with autologous dendritic cells engineered to present HLA-A(*)0201 complexed with a peptide from the B cell antigen CD20 (CD20p). HLA-A(*)0201/CD20p pentamer-reactive CD8(+) T cells were readily obtained from all donors. The polyclonal cells showed exquisite peptide and MHC specificity, and efficiently killed HLA-A(*)0201-positive B cells, including primary chronic lymphocytic leukemia cells. The T cell receptor (TCR) sequences displayed a novel type of conservation, with extensive homology in the TCR ? chain complementarity-determining region 3 and in J, but not V, region. This is surprising, as the donors were HLA disparate and their TCR repertoires are expected to show little overlap. The results demonstrate the first public recognition motif for an allogeneic HLA/peptide complex. The allo-restricted T cells or TCRs could provide graft-versus-leukemia in the absence of graft-versus-host disease. PMID:20844564

  19. 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. PMID:24698102

  20. Therapeutic options for adult T-cell leukemia/lymphoma.

    PubMed

    Marçais, Ambroise; Suarez, Felipe; Sibon, David; Frenzel, Laurent; Hermine, Olivier; Bazarbachi, Ali

    2013-10-01

    Adult T-cell leukemia/lymphoma (ATL) is the first human malignancy associated with a retroviral infection and occurs in approximately 5 % of the 15 million to 20 million people infected by human T-cell lymphotropic virus 1. In general, ATL is resistant to chemotherapy, and while awaiting new therapeutics, patients commonly face a detrimental progress of the disease and death. The viral oncoprotein Tax is a key player in the cause of ATL and acts by interfering with DNA repair, cell cycle, apoptosis, and proliferative cellular programs. The Shimoyama classification describes four different subtypes (acute, lymphoma, chronic, and smoldering) associated with different outcomes, and that require different treatment strategies tailored to the clinical presentation. In aggressive ATL (acute and lymphoma subtypes), clinical trials, mostly from Japan, have demonstrated that combinations of chemotherapy can induce acceptable response rates, especially in the lymphoma subtype. However, the overall outcome remains extremely poor owing to a high rate of relapse. Similarly, the so-called indolent forms (smoldering and chronic subtypes) have a poor outcome whether they are managed with watching and waiting or treated with chemotherapy. We recently realized a worldwide meta-analysis and showed that the combination of zidovudine and interferon alpha is highly effective in the leukemic subtypes of ATL and should be considered as standard first-line therapy in that setting. This combination has changed the natural history of the disease through achievement of significantly improved long-term survival in patients with smoldering and chronic ATL as well as a subset of patients with acute ATL. Patients with lymphoma-type ATL still benefit from chemotherapy induction with concurrent or sequential antiretroviral therapy with zidovudine and interferon alpha. Allogeneic stem cell transplantation is a promising option but has several barriers. New drugs such as the new antibody anti-CXCR4 show promising results. Prospective trials testing maintenance therapy in order to avoid relapse are warranted when the patient cannot undergo allogeneic stem cell transplantation. PMID:23943384

  1. Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse

    PubMed Central

    Clappier, Emmanuelle; Gerby, Bastien; Sigaux, François; Delord, Marc; Touzri, Farah; Hernandez, Lucie; Ballerini, Paola; Baruchel, André

    2011-01-01

    Genomic studies in human acute lymphoblastic leukemia (ALL) have revealed clonal heterogeneity at diagnosis and clonal evolution at relapse. In this study, we used genome-wide profiling to compare human T cell ALL samples at the time of diagnosis and after engraftment (xenograft) into immunodeficient recipient mice. Compared with paired diagnosis samples, the xenograft leukemia often contained additional genomic lesions in established human oncogenes and/or tumor suppressor genes. Mimicking such genomic lesions by short hairpin RNA–mediated knockdown in diagnosis samples conferred a selective advantage in competitive engraftment experiments, demonstrating that additional lesions can be drivers of increased leukemia-initiating activity. In addition, the xenograft leukemias appeared to arise from minor subclones existing in the patient at diagnosis. Comparison of paired diagnosis and relapse samples showed that, with regard to genetic lesions, xenograft leukemias more frequently more closely resembled relapse samples than bulk diagnosis samples. Moreover, a cell cycle– and mitosis-associated gene expression signature was present in xenograft and relapse samples, and xenograft leukemia exhibited diminished sensitivity to drugs. Thus, the establishment of human leukemia in immunodeficient mice selects and expands a more aggressive malignancy, recapitulating the process of relapse in patients. These findings may contribute to the design of novel strategies to prevent or treat relapse. PMID:21464223

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

    PubMed Central

    Eriksson, A; Österroos, A; Hassan, S; Gullbo, J; Rickardson, L; Jarvius, M; Nygren, P; Fryknäs, M; Höglund, M; Larsson, R

    2015-01-01

    To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 ?M drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug–drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis. PMID:25885427

  3. Epigenetic therapy overcomes treatment resistance in T cell prolymphocytic leukemia.

    PubMed

    Hasanali, Zainul S; Saroya, Bikramajit Singh; Stuart, August; Shimko, Sara; Evans, Juanita; Vinod Shah, Mithun; Sharma, Kamal; Leshchenko, Violetta V; Parekh, Samir; Loughran, Thomas P; Epner, Elliot M

    2015-06-24

    T cell prolymphocytic leukemia (T-PLL) is a rare, mature T cell neoplasm with distinct features and an aggressive clinical course. Early relapse and short overall survival are commonplace. Use of the monoclonal anti-CD52 antibody alemtuzumab has improved the rate of complete remission and duration of response to more than 50% and between 6 and 12 months, respectively. Despite this advance, without an allogeneic transplant, resistant relapse is inevitable. We report seven complete and one partial remission in eight patients receiving alemtuzumab and cladribine with or without a histone deacetylase inhibitor. These data show that administration of epigenetic agents can overcome alemtuzumab resistance. We also report epigenetically induced expression of the surface receptor protein CD30 in T-PLL. Subsequent treatment with the anti-CD30 antibody-drug conjugate brentuximab vedotin overcame organ-specific (skin) resistance to alemtuzumab. Our findings demonstrate activity of combination epigenetic and immunotherapy in the incurable illness T-PLL, particularly in the setting of previous alemtuzumab therapy. PMID:26109102

  4. Dose-dependent killing of leukemia cells by low-temperature plasma

    NASA Astrophysics Data System (ADS)

    Barekzi, N.; Laroussi, M.

    2012-10-01

    The effect of low-temperature atmospheric pressure plasma towards the progression of cancerous human T-cell leukemia cells was investigated. The plasma pencil, which utilizes short duration high voltage pulses, was used to generate a low-temperature plasma (LTP) plume in ambient air. Our data showed that cell morphology and cell viability were affected in a dose-dependent manner after treatment with LTP. The outcome of this study revealed that the effect of plasma exposure was not immediate, but had a delayed effect and increasing the time of plasma exposure resulted in increased leukemia cell death.

  5. Cytotoxicity of CD56-positive lymphocytes against autologous B-cell precursor acute lymphoblastic leukemia cells.

    PubMed

    Fei, F; Lim, M; George, A A; Kirzner, J; Lee, D; Seeger, R; Groffen, J; Abdel-Azim, H; Heisterkamp, N

    2015-04-01

    Precursor B-lineage acute lymphoblastic leukemia (pre-B ALL) affects hematopoietic development and therefore is associated with immune deficiencies that can be further exacerbated by chemotherapy. It is unclear if and when monoclonal antibodies (mAbs) that stimulate antibody-mediated cellular cytotoxicity (ADCC) can be used for treatment because this depends on the presence of functional effector cells. Here, we used flow cytometry to determine that patient samples at diagnosis, post-induction and relapse contain detectable numbers of CD56+ cells. We were able to selectively expand CD56+ immune effector cells from bone marrow and peripheral blood samples at diagnosis and at various stages of treatment by co-culture with artificial antigen-presenting K562 clone 9.mbIL-21 cells. Amplified CD56+CD3- cells had spontaneous and anti-B cell-activating factor receptor mAb-stimulated ADCC activity against allogeneic ALL cells, which could be further enhanced by IL-15. Importantly, matched CD56+ effector cells also killed autologous ALL cells grown out from leukemia samples of the same patient, through both spontaneous as well as antibody-dependent cellular cytotoxicity. Since autologous cell therapy will not be complicated by graft-versus-host disease, our results show that expanded CD56+ cells could be applied for treatment of pre-B ALL without transplantation, or for purging of bone marrow in the setting of autologous bone marrow transplants. PMID:25134458

  6. Radotinib Induces Apoptosis of CD11b+ Cells Differentiated from Acute Myeloid Leukemia Cells

    PubMed Central

    Heo, Sook-Kyoung; Noh, Eui-Kyu; Yoon, Dong-Joon; Jo, Jae-Cheol; Choi, Yunsuk; Koh, SuJin; Baek, Jin Ho; Park, Jae-Hoo; Min, Young Joo; Kim, Hawk

    2015-01-01

    Radotinib, developed as a BCR/ABL tyrosine kinase inhibitor (TKI), is approved for the second-line treatment of chronic myeloid leukemia (CML) in South Korea. However, therapeutic effects of radotinib in acute myeloid leukemia (AML) are unknown. In the present study, we demonstrate that radotinib significantly decreases the viability of AML cells in a dose-dependent manner. Kasumi-1 cells were more sensitive to radotinib than NB4, HL60, or THP-1 cell lines. Furthermore, radotinib induced CD11b expression in NB4, THP-1, and Kasumi-1 cells either in presence or absence of all trans-retinoic acid (ATRA). We found that radotinib promoted differentiation and induced CD11b expression in AML cells by downregulating LYN. However, CD11b expression induced by ATRA in HL60 cells was decreased by radotinib through upregulation of LYN. Furthermore, radotinib mainly induced apoptosis of CD11b+ cells in the total population of AML cells. Radotinib also increased apoptosis of CD11b+ HL60 cells when they were differentiated by ATRA/dasatinib treatment. We show that radotinib induced apoptosis via caspase-3 activation and the loss of mitochondrial membrane potential (??m) in CD11b+ cells differentiated from AML cells. Our results suggest that radotinib may be used as a candidate drug in AML or a chemosensitizer for treatment of AML by other therapeutics. PMID:26065685

  7. Cardiopulmonary Failure Requiring ECMO Bypass Resulting from Leukemia Cell Lysis in a Patient with Childhood Acute Myelomonocytic Leukemia

    PubMed Central

    Huang, Michael; Owen, Erin; Myers, Scott; Raj, Ashok

    2015-01-01

    Background. Childhood AML patients are at increased risk for early fatal pulmonary complications. Pulmonary leukostasis and systemic inflammatory response syndrome (SIRS) following leukemia cell lysis are the likely etiologies. Observation. Soon after initiation of AML chemotherapy, an 18-month-old female who met SIRS criteria sustained cardiopulmonary failure requiring ECMO support. Upon recovery, the patient went on to complete therapy and remains in remission without permanent neurologic or cardiac sequelae. Conclusion. Cytokine release syndrome from rapid cell lysis was the likely cause as infectious workup failed to reveal a definitive etiology and drug hypersensitivity testing to the chemotherapy agents was negative.

  8. Establishment of hairy root cultures of Ammi majus.

    PubMed

    Królicka, A; Staniszewska, I; Bielawski, K; Malinski, E; Szafranek, J; L&z shtsls;ojkowska, E

    2001-01-01

    Axenically grown Ammi majus plantlets were inoculated with seven different Agrobacterium rhizogenes strains. Hairy root lines were established only after inoculation with the two agropine strains: A4 and LBA9402. The growth rate of hairy root cultures was about thirty times faster than that of callus and cell suspension cultures. Polymerase chain reaction with primers for the genes rolB and rolC confirmed the integration of the T-DNA fragment of Ri plasmid of A. rhizogenes to the genome of hairy roots obtained after transformation by both Agrobacterium strains. The furanocoumarins (psoralen, xanthotoxine, bergapten and imperatorin) usually found in seeds of A. majus were not detected in callus, cell suspension and hairy root cultures using Gas chromatography-mass spectrometry (GC-MS). However, umbelliferone, a precursor of furanocoumarins, was detected in callus, cell suspension and hairy root cultures. The umbelliferone content in extracts of hairy root cultures, obtained after transformation by A4, was similar to that determined in A. majus seeds (19 µg/g DW) and higher than those obtained for cell suspension and callus cultures (2 and 9 µg/g DW, respectively). PMID:11164597

  9. ASB-2 inhibits growth and promotes commitment in myeloid leukemia cells.

    PubMed

    Guibal, Florence C; Moog-Lutz, Christel; Smolewski, Piotr; Di Gioia, Yolande; Darzynkiewicz, Zbigniew; Lutz, Pierre G; Cayre, Yvon E

    2002-01-01

    In acute promyelocytic leukemia (APL) cells harboring the promyelocytic leukemia retinoic acid receptor alpha (PML-RARalpha) chimeric protein, retinoic acid (RA)-induced differentiation is triggered through a PML-RARalpha signaling resulting in activation of critical target genes. Induced differentiation of APL cells is always preceded by withdrawal from the cell cycle and commitment events leading to terminal differentiation. Here we have identified the human ankyrin repeat-containing protein with a suppressor of cytokine signaling box-2 (ASB-2) cDNA, as a novel RA-induced gene in APL cells. PML-RARalpha strongly enhanced RA-induced ASB-2 mRNA expression. In myeloid leukemia cells, ASB-2 expression induced growth inhibition and chromatin condensation recapitulating early events critical to RA-induced differentiation of APL cells. PMID:11682484

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

    SciTech Connect

    Nonaka, Mizuho [Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Bunkyo-ku, Tokyo 113-8510 (Japan); Retrovirus Research Unit, RIKEN, Saitama (Japan); Uota, Shin; Saitoh, Yasunori [Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Bunkyo-ku, Tokyo 113-8510 (Japan); Takahashi, Mayumi [Department of Hematology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo (Japan); Sugimoto, Haruyo; Amet, Tohti [Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Bunkyo-ku, Tokyo 113-8510 (Japan); Arai, Ayako; Miura, Osamu [Department of Hematology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo (Japan); Yamamoto, Naoki [Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Bunkyo-ku, Tokyo 113-8510 (Japan); AIDS Research Center, National Institute of Infectious Diseases, Tokyo (Japan); Yamaoka, Shoji [Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Bunkyo-ku, Tokyo 113-8510 (Japan)], E-mail: shojmmb@tmd.ac.jp

    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.

  11. 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 ...

  12. Leukemia stem cells in T-ALL require active Hif1? and Wnt signaling.

    PubMed

    Giambra, Vincenzo; Jenkins, Catherine E; Lam, Sonya H; Hoofd, Catherine; Belmonte, Miriam; Wang, Xuehai; Gusscott, Sam; Gracias, Deanne; Weng, Andrew P

    2015-06-18

    The Wnt signaling pathway has been shown to play important roles in normal hematopoietic stem cell biology and in the development of both acute and chronic myelogenous leukemia. Its role in maintaining established leukemia stem cells, which are more directly relevant to patients with disease, however, is less clear. To address what role Wnt signaling may play in T-cell acute lymphoblastic leukemia (T-ALL), we used a stably integrated fluorescent Wnt reporter construct to interrogate endogenous Wnt signaling activity in vivo. In this study, we report that active Wnt signaling is restricted to minor subpopulations within bulk tumors, that these Wnt-active subsets are highly enriched for leukemia-initiating cells (LICs), and that genetic inactivation of ?-catenin severely reduces LIC frequency. We show further that ?-catenin transcription is upregulated by hypoxia through hypoxia-inducible factor 1? (Hif1?) stabilization, and that deletion of Hif1? also severely reduces LIC frequency. Of note, the deletion of ?-catenin or Hif1? did not impair the growth or viability of bulk tumor cells, suggesting that elements of the Wnt and Hif pathways specifically support leukemia stem cells. We also confirm the relevance of these findings to human disease using cell lines and patient-derived xenografts, suggesting that targeting these pathways could benefit patients with T-ALL. PMID:25934477

  13. Acute myeloid leukemia of donor origin after allogeneic bone marrow transplantation for precursor T-cell acute lymphoblastic leukemia: case report and review of the literature.

    PubMed

    Reichard, Kaaren K; Zhang, Qian-Yun; Sanchez, Lorraine; Hozier, John; Viswanatha, David; Foucar, Kathryn

    2006-03-01

    We report a case of donor-derived acute myeloid leukemia (AML) occurring in a 33-year-old man after allogeneic bone marrow transplantation (BMT) for precursor T-cell acute lymphoblastic -leukemia (T-ALL). The cells for BMT were from his human leukocyte antigen (HLA)-matched sister. Fluorescence in-situ hybridization (FISH) analysis showed the AML to be of donor origin (i.e., karyotypically female) with an 11q23 (mixed lineage leukemia (MLL) gene) translocation, while the original T-ALL exhibited a male karyotype with abnormalities of chromosomes 6, 8, and a t(10;14)(q24;q11.2). Subsequent molecular short tandem repeat studies confirmed the AML to be of donor origin. Donor-cell leukemia (DCL) after allogeneic BMT is a rare, yet well-documented, event. Our report presents clinicopathologic information about a case of DCL and a review of the recent literature. PMID:16493618

  14. Antiproliferative effects of 4',5'-unsaturated adenine nucleosides on leukemia L1210 cells in vitro.

    PubMed

    Sheid, B; Lerner, L M; Gaetjens, E

    1989-08-15

    Several 4',5'-unsaturated adenine nucleosides were shown to have antiproliferative activity against L1210 leukemia cells in vitro. The active nucleosides were cytotoxic to the L1210 cells as demonstrated by Trypan Blue uptake. The cytotoxicity was not induced by alterations in the ribonucleoside and deoxyribonucleoside triphosphate levels of the L1210 cells. PMID:2759202

  15. Chimeric antigen receptor T cells: power tools to wipe out leukemia and lymphoma.

    PubMed

    Riet, Tobias; Abken, Hinrich

    2015-08-01

    Adoptive cell therapy for malignant diseases is showing promise in recent early-phase trials in the treatment of B cell leukemia/lymphoma. Genetically engineered with a tumor-specific chimeric antigen receptor, patient's T cells produce lasting and complete leukemia regression. However, treatment is associated with some toxicity which needs our attention and the field still faces some hurdles at the scientific, technologic and clinical levels. Surmounting these obstacles will establish chimeric antigen receptor T cell therapy as a powerful approach to cure hematologic malignancies, paving the way for the treatment of other common types of cancer in the future. PMID:25946901

  16. [Epidemiological analysis of adult T-cell leukemia].

    PubMed

    Tajima, K

    1983-02-01

    Adult T-cell leukemia (ATL) is prevalent in the rural coastal areas of southwestern part of Japan. The geographical distribution of persons with antibody to ATLV which seems to be the decisive causal agent of ATL is very similar to that of ATL patients. The positive rate of anti-ATLA among healthy inhabitants older than 50 years was 32% (21% in males and 39% in females) in Goto Islands in Nagasaki Prefecture. However, positive rates are only 15% in the age group of 30 to 49 years and 4% under 29 years in the same area. From the epidemiological analyses of the mode of anti-ATLA reactivity among married couples and family members with positive and negative anti-ATLA, two routes of transmission of ATLV were suspected. One route is from parents to children and another is the horizontal transmission from new family to woman after marriage. The environmental and socioeconomic factors which had changed remarkably after the World War II and may have influenced the characteristic distribution of ATLV carriers by age and sex in these areas are discussed as the modifying factors for ATLV infection and ATL manifestation from the epidemiological view point. PMID:6603823

  17. Stereotyped B-cell receptors in chronic lymphocytic leukemia.

    PubMed

    Agathangelidis, Andreas; Vardi, Anna; Baliakas, Panagiotis; Stamatopoulos, Kostas

    2014-10-01

    Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IGs) has proved to be a particularly fruitful field in chronic lymphocytic leukemia (CLL), not only for understanding disease pathogenesis but also for discriminating clinical subgroups with markedly distinct course and outcome. Of utmost importance was the identification of quasi-identical BcR IGs among unrelated patients with CLL, fittingly coined as "stereotypy," that set the wheels in motion for unraveling the role of antigen(s) in the selection and expansion of the leukemic clones. The categorization of CLL clones into "subsets" according to shared BcR IG structural characteristics provided a compartmentalized view of this otherwise heterogeneous disease, which eventually led to defining strikingly homogeneous groups of patients in terms of: (i) functional properties of the clonal BcR IGs, e.g. BcR reactivity and signaling; (ii) clonal genetic landscape, e.g. genomic aberrations, gene expression/methylation profiles, microRNA signatures; and (iii) clinical course and outcome. The remarkable restriction of the CLL IG gene repertoire, resulting to a great degree from the high impact of BcR IG stereotypy, may also prompt speculations regarding CLL ontogenesis. Overall, the BcR IG molecule justifiably lies at the heart of CLL clinical research, holding the promise of subset-tailored therapies. PMID:24397617

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

    ClinicalTrials.gov

    2015-06-22

    Accelerated Phase Chronic Myelogenous Leukemia; 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); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; 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 Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; 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; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent 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; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

  19. Induction by Bufalin of Differentiation of Human Leukemia Cells HL60, U937, and ML1 toward Macrophage\\/Monocyte-like Cells and Its Potent Synergistic Effect on the Differentiation of Human Leukemia Cells in Combination with Other Inducers

    Microsoft Academic Search

    Lisha Zhang; Takemi Yoshida; Yukio Kuroiwa

    We have recently demonstrated that bufalin is a new potent inducer of the differentiation of human myeloid leukemia cells. The present work was carried out to examine further the effect of bufalin on the growth and characteristics of human leukemia-derived cell lines U937, Mil. and HL60. At concentrations of 5-10 IIM,bufalin decreased the growth of Mil cells preferentially at the

  20. Senescence effects of Angelica sinensis polysaccharides on human acute myelogenous leukemia stem and progenitor cells.

    PubMed

    Liu, Jun; Xu, Chun-Yan; Cai, Shi-Zhong; Zhou, Yue; Li, Jing; Jiang, Rong; Wang, Ya-Ping

    2014-01-01

    Leukemia stem cells (LSCs) play important roles in leukemia initiation, progression and relapse, and thus represent a critical target for therapeutic intervention. Hence, it is extremely urgent to explore new therapeutic strategies directly targeting LSCs for acute myelogenous leukemia (AML) therapy. We show here that Angelica sinensis polysaccharide (ASP), a major active component in Dong quai (Chinese Angelica sinensis), effectively inhibited human AML CD34+CD38? cell proliferation in vitro culture in a dose-dependent manner while sparing normal hematopoietic stem and progenitor cells at physiologically achievable concentrations. Furthermore, ASP exerted cytotoxic effects on AML K562 cells, especially LSC-enriched CD34+CD38? cells. Colony formation assays further showed that ASP significantly suppressed the formation of colonies derived from AML CD34+CD38? cells but not those from normal CD34+CD38? cells. Examination of the underlying mechanisms revealed that ASP induced CD34+CD38? cell senescence, which was strongly associated with a series of characteristic events, including up-regulation of p53, p16, p21, and Rb genes and changes of related cell cycle regulation proteins P16, P21, cyclin E and CDK4, telomere end attrition as well as repression of telomerase activity. On the basis of these findings, we propose that ASP represents a potentially important agent for leukemia stem cell-targeted therapy. PMID:24377566

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

    ClinicalTrials.gov

    2015-06-01

    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

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

    ClinicalTrials.gov

    2015-06-09

    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

  3. CXCL12-Producing Vascular Endothelial Niches Control Acute T Cell Leukemia Maintenance.

    PubMed

    Pitt, Lauren A; Tikhonova, Anastasia N; Hu, Hai; Trimarchi, Thomas; King, Bryan; Gong, Yixiao; Sanchez-Martin, Marta; Tsirigos, Aris; Littman, Dan R; Ferrando, Adolfo A; Morrison, Sean J; Fooksman, David R; Aifantis, Iannis; Schwab, Susan R

    2015-06-01

    The role of the microenvironment in T cell acute lymphoblastic leukemia (T-ALL), or any acute leukemia, is poorly understood. Here we demonstrate that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Cxcl12 deletion from vascular endothelial, but not perivascular, cells impeded tumor growth, suggesting a vascular niche for T-ALL. Moreover, genetic targeting of Cxcr4 in murine T-ALL after disease onset led to rapid, sustained disease remission, and CXCR4 antagonism suppressed human T-ALL in primary xenografts. Loss of CXCR4 targeted key T-ALL regulators, including the MYC pathway, and decreased leukemia initiating cell activity in vivo. Our data identify a T-ALL niche and suggest targeting CXCL12/CXCR4 signaling as a powerful therapeutic approach for T-ALL. PMID:26058075

  4. CD317 is over-expressed in B-cell chronic lymphocytic leukemia, but not B-cell acute lymphoblastic leukemia

    PubMed Central

    Gong, Shunyou; Osei, Ebenezer S; Kaplan, David; Chen, Youhai H; Meyerson, Howard

    2015-01-01

    CD317 was first identified as a multiple myeloma-associated antigen. Here we report the expression of CD317 in normal B cells and B-cell malignancies. In normal bone marrow, CD317 demonstrates a biphasic expression pattern, with higher expression on stage 1 and stage 3 hematogones, but not on stage 2 hematogones. CD317 is over-expressed in B-cell chronic lymphocytic leukemia, and appears associated with negative CD38 expression. Moreover, CD317 is barely detectable in B-cell acute lymphoblastic leukemia. Our results suggest that CD317 expression might be of prognostic significance for B-CLL, and CD317 could be used as a new marker for minimal residual disease detection in B-ALL. PMID:25973046

  5. 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

  6. Recent developments in the management of T-cell precursor acute lymphoblastic leukemia/lymphoma.

    PubMed

    Fielding, Adele K; Banerjee, Lalita; Marks, David I

    2012-06-01

    T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma are uncommon disorders classified together by the World Health Organization classification as "T-lymphoblastic leukemia/lymphoma." This review gives an overview on the treatment of these aggressive but curable T cell malignancies in adult patients, in order to highlight current developments. The most interesting and relevant developments are in our understanding of the genetics of T-ALL/LBL and how the genetics relate to clinical outcome. These studies will inform clinicians as to which targeted novel agents may be of value and how patients may be best risk-stratified to receive them. PMID:22476945

  7. Metabolic Effects of Acute Thiamine Depletion Are Reversed by Rapamycin in Breast and Leukemia Cells

    PubMed Central

    Liu, Shuqian; Miriyala, Sumitra; Keaton, Mignon A.; Jordan, Craig T.; Wiedl, Christina; Clair, Daret K. St.; Moscow, Jeffrey A.

    2014-01-01

    Thiamine-dependent enzymes (TDEs) control metabolic pathways that are frequently altered in cancer and therefore present cancer-relevant targets. We have previously shown that the recombinant enzyme thiaminase cleaves and depletes intracellular thiamine, has growth inhibitory activity against leukemia and breast cancer cell lines, and that its growth inhibitory effects were reversed in leukemia cell lines by rapamycin. Now, we first show further evidence of thiaminase therapeutic potential by demonstrating its activity against breast and leukemia xenografts, and against a primary leukemia xenograft. We therefore further explored the metabolic effects of thiaminase in combination with rapamycin in leukemia and breast cell lines. Thiaminase decreased oxygen consumption rate and increased extracellular acidification rate, consistent with the inhibitory effect of acute thiamine depletion on the activity of the TDEs pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes; these effects were reversed by rapamycin. Metabolomic studies demonstrated intracellular thiamine depletion and the presence of the thiazole cleavage product in thiaminase-treated cells, providing validation of the experimental procedures. Accumulation of ribose and ribulose in both cell lines support the thiaminase-mediated suppression of the TDE transketolase. Interestingly, thiaminase suppression of another TDE, branched chain amino ketoacid dehydrogenase (BCKDH), showed very different patterns in the two cell lines: in RS4 leukemia cells it led to an increase in BCKDH substrates, and in MCF-7 breast cancer cells it led to a decrease in BCKDH products. Immunoblot analyses showed corresponding differences in expression of BCKDH pathway enzymes, and partial protection of thiaminase growth inhibition by gabapentin indicated that BCKDH inhibition may be a mechanism of thiaminase-mediated toxicity. Surprisingly, most of thiaminase-mediated metabolomic effects were also reversed by rapamycin. Thus, these studies demonstrate that acute intracellular thiamine depletion by recombinant thiaminase results in metabolic changes in thiamine-dependent metabolism, and demonstrate a previously unrecognized role of mTOR signaling in the regulation of thiamine-dependent metabolism. PMID:24454921

  8. Metabolic effects of acute thiamine depletion are reversed by rapamycin in breast and leukemia cells.

    PubMed

    Liu, Shuqian; Miriyala, Sumitra; Keaton, Mignon A; Jordan, Craig T; Wiedl, Christina; Clair, Daret K St; Moscow, Jeffrey A

    2014-01-01

    Thiamine-dependent enzymes (TDEs) control metabolic pathways that are frequently altered in cancer and therefore present cancer-relevant targets. We have previously shown that the recombinant enzyme thiaminase cleaves and depletes intracellular thiamine, has growth inhibitory activity against leukemia and breast cancer cell lines, and that its growth inhibitory effects were reversed in leukemia cell lines by rapamycin. Now, we first show further evidence of thiaminase therapeutic potential by demonstrating its activity against breast and leukemia xenografts, and against a primary leukemia xenograft. We therefore further explored the metabolic effects of thiaminase in combination with rapamycin in leukemia and breast cell lines. Thiaminase decreased oxygen consumption rate and increased extracellular acidification rate, consistent with the inhibitory effect of acute thiamine depletion on the activity of the TDEs pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes; these effects were reversed by rapamycin. Metabolomic studies demonstrated intracellular thiamine depletion and the presence of the thiazole cleavage product in thiaminase-treated cells, providing validation of the experimental procedures. Accumulation of ribose and ribulose in both cell lines support the thiaminase-mediated suppression of the TDE transketolase. Interestingly, thiaminase suppression of another TDE, branched chain amino ketoacid dehydrogenase (BCKDH), showed very different patterns in the two cell lines: in RS4 leukemia cells it led to an increase in BCKDH substrates, and in MCF-7 breast cancer cells it led to a decrease in BCKDH products. Immunoblot analyses showed corresponding differences in expression of BCKDH pathway enzymes, and partial protection of thiaminase growth inhibition by gabapentin indicated that BCKDH inhibition may be a mechanism of thiaminase-mediated toxicity. Surprisingly, most of thiaminase-mediated metabolomic effects were also reversed by rapamycin. Thus, these studies demonstrate that acute intracellular thiamine depletion by recombinant thiaminase results in metabolic changes in thiamine-dependent metabolism, and demonstrate a previously unrecognized role of mTOR signaling in the regulation of thiamine-dependent metabolism. PMID:24454921

  9. Central nervous system acute lymphoblastic leukemia: role of natural killer cells.

    PubMed

    Frishman-Levy, Liron; Shemesh, Avishai; Bar-Sinai, Allan; Ma, Chao; Ni, Zhenya; Frenkel, Shahar; Muench, Vera; Bruckmueller, Hilke; Vokuhl, Christian; Debatin, Klaus-Michael; Eckert, Cornelia; Stanulla, Martin; Schrappe, Martin; Campbell, Kerry S; Loewenthal, Ron; Schewe, Denis M; Hochman, Jacob; Meyer, Lueder H; Kaufman, Dan; Cario, Gunnar; Porgador, Angel; Izraeli, Shai

    2015-05-28

    Central nervous system acute lymphoblastic leukemia (CNS-ALL) is a major clinical problem. Prophylactic therapy is neurotoxic, and a third of the relapses involve the CNS. Increased expression of interleukin 15 (IL-15) in leukemic blasts is associated with increased risk for CNS-ALL. Using in vivo models for CNS leukemia caused by mouse T-ALL and human xenografts of ALL cells, we demonstrate that expression of IL-15 in leukemic cells is associated with the activation of natural killer (NK) cells. This activation limits the outgrowth of leukemic cells in the periphery, but less in the CNS because NK cells are excluded from the CNS. Depletion of NK cells in NOD/SCID mice enabled combined systemic and CNS leukemia of human pre-B-ALL. The killing of human leukemia lymphoblasts by NK cells depended on the expression of the NKG2D receptor. Analysis of bone marrow (BM) diagnostic samples derived from children with subsequent CNS-ALL revealed a significantly high expression of the NKG2D and NKp44 receptors. We suggest that the CNS may be an immunologic sanctuary protected from NK-cell activity. CNS prophylactic therapy may thus be needed with emerging NK cell-based therapies against hematopoietic malignancies. PMID:25896649

  10. Vaccine Therapy in Preventing Cytomegalovirus Infection in Patients With Hematological Malignancies Undergoing Donor Stem Cell Transplant

    ClinicalTrials.gov

    2015-06-01

    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); Adult Acute Promyelocytic Leukemia (M3); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Nodular Lymphocyte Predominant Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; B-cell Adult Acute Lymphoblastic Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cytomegalovirus Infection; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Isolated Plasmacytoma of Bone; Monoclonal Gammopathy of Undetermined Significance; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously 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; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cu

  11. The Role of B Cells for in Vivo T Cell Responses to a Friend Virus-Induced Leukemia

    NASA Astrophysics Data System (ADS)

    Schultz, Kirk R.; Klarnet, Jay P.; Gieni, Randall S.; Hayglass, Kent T.; Greenberg, Philip D.

    1990-08-01

    B cells can function as antigen-presenting cells and accessory cells for T cell responses. This study evaluated the role of B cells in the induction of protective T cell immunity to a Friend murine leukemia virus (F-MuLV)-induced leukemia (FBL). B cell-deficient mice exhibited significantly reduced tumor-specific CD4^+ helper and CD8^+ cytotoxic T cell responses after priming with FBL or a recombinant vaccinia virus containing F-MuLV antigens. Moreover, these mice had diminished T cell responses to the vaccinia viral antigens. Tumor-primed T cells transferred into B cell-deficient mice effectively eradicated disseminated FBL. Thus, B cells appear necessary for efficient priming but not expression of tumor and viral T cell immunity.

  12. The role of B cells for in vivo T cell responses to a Friend virus-induced leukemia.

    PubMed

    Schultz, K R; Klarnet, J P; Gieni, R S; HayGlass, K T; Greenberg, P D

    1990-08-24

    B cells can function as antigen-presenting cells and accessory cells for T cell responses. This study evaluated the role of B cells in the induction of protective T cell immunity to a Friend murine leukemia virus (F-MuLV)-induced leukemia (FBL). B cell-deficient mice exhibited significantly reduced tumor-specific CD4+ helper and CD8+ cytotoxic T cell responses after priming with FBL or a recombinant vaccinia virus containing F-MuLV antigens. Moreover, these mice had diminished T cell responses to the vaccinia viral antigens. Tumor-primed T cells transferred into B cell-deficient mice effectively eradicated disseminated FBL. Thus, B cells appear necessary for efficient priming but not expression of tumor and viral T cell immunity. PMID:2118273

  13. Reverse signaling from LIGHT promotes pro-inflammatory responses in the human monocytic leukemia cell line, THP-1

    E-print Network

    Lee, Won-Ha

    Reverse signaling from LIGHT promotes pro-inflammatory responses in the human monocytic leukemia in co-stim- ulation of T cells or apoptosis in tumors. In this study, the possibility of LIGHT-mediated reverse signaling was tested in the human monocytic leukemia cell line, THP-1. For stimulation of LIGHT

  14. Induction of apoptosis in acute lymphoblastic leukemia cells by isolated fractions from strawberries

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Strawberries contain phytochemicals that have anti-inflammatory and anti-cancer activity. We investigated the ability of isolated fractions from strawberry extracts to induce apoptotic cell death in three pre-B acute lymphoblastic leukemia (ALL) lines, including SEM and RS4;11 cell lines derived fr...

  15. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus

    Microsoft Academic Search

    P Dreger; P Corradini; E Kimby; M Michallet; D Milligan; J Schetelig; W Wiktor-Jedrzejczak; D Niederwieser; M Hallek; E Montserrat

    2007-01-01

    The aim of this project was to identify situations where allogeneic stem cell transplantation (allo-SCT) might be considered as a preferred treatment option for patients with B-cell chronic lymphocytic leukemia (CLL). Based on a MEDLINE search and additional sources, a consented proposal was drafted, refined and approved upon final discussion by an international expert panel. Key elements of the consensus

  16. Induction of Differentiation in Human Promyelocytic Leukemia Cells by Tumor Promoters

    Microsoft Academic Search

    Giovanni Rovera; Thomas G. O'Brien; Leila Diamond

    1979-01-01

    Phorbol diester tumor promoters and the promoter mezerein convert human promyelocytic leukemia cells in culture into adherent, nonproliferating cells with many of the characteristics of macrophages. Other types of promoters such as anthralin, phenobarbital, and saccharin do not have this effect. Various compounds that can inhibit some of the biological and biochemical effects of tumor promoters do not interfere with

  17. Reproductive fitness advantage of BCRABL expressing leukemia cells Arne Traulsen a

    E-print Network

    Traulsen, Arne

    Reproductive fitness advantage of BCR­ABL expressing leukemia cells Arne Traulsen a , Jorge M Keywords: Cancer evolution Oncogenes Mutation fitness BCR­ABL Cancer dynamics a b s t r a c t Mutations in oncogenes and tumor suppressor genes confer a fitness advantage to cells that can lead to cancer. The tumor

  18. Vorinostat Induces Reactive Oxygen Species and DNA Damage in Acute Myeloid Leukemia Cells

    Microsoft Academic Search

    Luca A. Petruccelli; Daphné Dupéré-Richer; Filippa Pettersson; Hélène Retrouvey; Sophia Skoulikas; Wilson H. Miller

    2011-01-01

    Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, however, their mechanisms of action remain unclear. In acute myeloid leukemia (AML) cells, HDACi have been reported to arrest growth and induce apoptosis. In this study, we elucidate details of the DNA damage induced by the HDACi vorinostat in AML cells. At clinically relevant concentrations, vorinostat induces double-strand breaks and oxidative DNA

  19. Leukemia inhibitory factor blocks early differentiation of skeletal muscle cells by activating ERK

    Microsoft Academic Search

    Chulman Jo; Hyuck Kim; Inho Jo; Insun Choi; Sung-Chul Jung; Joon Kim; Sung Soo Kim; Sangmee Ahn Jo

    2005-01-01

    Leukemia inhibitory factor (LIF) is a multifunctional cytokine belonging to the interleukin-6 family and has been shown to stimulate regeneration of injured skeletal muscle. Although LIF has been shown to stimulate muscle cell proliferation, its precise role in differentiation is unclear. Thus, we examined the effect of LIF on the differentiation of cultured C2C12 myoblast cells. In this study, we

  20. Genetic aberrations and survival in plasma cell leukemia.

    PubMed

    Tiedemann, R E; Gonzalez-Paz, N; Kyle, R A; Santana-Davila, R; Price-Troska, T; Van Wier, S A; Chng, W J; Ketterling, R P; Gertz, M A; Henderson, K; Greipp, P R; Dispenzieri, A; Lacy, M Q; Rajkumar, S V; Bergsagel, P L; Stewart, A K; Fonseca, R

    2008-05-01

    Plasma cell leukemia (PCL) is an aggressive and rare hematological malignancy that originates either as primary disease (pPCL) or as a secondary leukemic transformation (sPCL) of multiple myeloma (MM). We report here the genetic aberrations and survival of 80 patients with pPCL or sPCL and make comparisons with 439 cases of MM. pPCL presents a decade earlier than sPCL (54.7 vs 65.3 years) and is associated with longer median overall survival (11.1 vs 1.3 months; P<0.001). 14q32 (IgH) translocations are highly prevalent in both sPCL and pPCL (82-87%); in pPCL IgH translocations almost exclusively involve 11q13 (CCND1), supporting a central etiological role, while in sPCL multiple partner oncogenes are involved, including 11q13, 4p16 (FGFR3/MMSET) and 16q23 (MAF), recapitulating MM. Both show ubiquitous inactivation of TP53 (pPCL 56%; sPCL 83%) by coding mutation or 17p13 deletion; complemented by p14ARF epigenetic silencing in sPCL (29%). Both show frequent N-RAS or K-RAS mutation. Poor survival in pPCL was predicted by MYC translocation (P=0.006). Survival in sPCL was consistently short. Overall pPCL and sPCL are different disorders with distinct natural histories, genetics and survival. PMID:18216867

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

    SciTech Connect

    Sumi, Daigo, E-mail: sdaigo@ph.bunri-u.ac.j [Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180, Yamashiro-cho, Tokushima-city, Tokushima 770-8514 (Japan); Shinkai, Yasuhiro; Kumagai, Yoshito [Doctoral Program in Life System Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575 (Japan)

    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.

  2. Leukemia mortality by cell type in petroleum workers with potential exposure to benzene.

    PubMed Central

    Raabe, G K; Wong, O

    1996-01-01

    Workers in the petroleum industry are potentially exposed to a variety of petrochemicals, including benzene or benzene-containing liquids. Although a large number of studies of petroleum workers have been conducted to examine leukemia and other cancer risks, few existing studies have investigated cell-type-specific leukemias. One of the major reasons for the lack of cell-type-specific analysis was the small number of deaths by cell type in individual studies. In the present investigation, all cohort studies of petroleum workers in the United States and the United Kingdom were combined into a single database for cell-type-specific leukemia analysis. The majority of these workers were petroleum refinery employees, but production, pipeline, and distribution workers in the petroleum industry were also included. The combined cohort consisted of more than 208,000 petroleum workers, who contributed more than 4.6 million person-years of observation. Based on a meta-analysis of the combined data, cell-type-specific leukemia risks were expressed in terms of standardized mortality ratios (meta-SMRs). The meta-SMR for acute myeloid leukemia was 0.96. The lack of an increase of acute myeloid leukemia was attributed to the low levels of benzene exposure in the petroleum industry, particularly in comparison to benzene exposure levels in some previous studies of workers in other industries, who had been found to experience an increased risk of acute myeloid leukemia. Similarly, no increase in chronic myeloid, acute lymphocytic, or chronic lymphocytic leukemias was found in petroleum workers (meta-SMRs of 0.89, 1.16, and 0.84, respectively). Stratified meta-analyses restricted to refinery studies or to studies with at least 15 years of follow-up yielded similar results. The findings of the present investigation are consistent with those from several recent case-control studies of cell-type-specific leukemia. Patterns and levels of benzene exposure in the petroleum industry are reviewed. The results of the present epidemiologic investigation are discussed in conjunction with recent advances in leukemogenesis from other scientific disciplines. PMID:9118924

  3. -Arrestin2 mediates the initiation and progression of myeloid leukemia

    E-print Network

    -Arrestin2 mediates the initiation and progression of myeloid leukemia Mark Fereshteha leukemia (CML). These defects are linked to a re- duced frequency, as well as defective self maintenance. chronic myeloid leukemia | leukemia stem cell | hematopoiesis Chronic myelogenous leukemia (CML

  4. Stereotypical Chronic Lymphocytic Leukemia B-Cell Receptors Recognize Survival Promoting Antigens on Stromal Cells

    PubMed Central

    Binder, Mascha; Léchenne, Barbara; Ummanni, Ramesh; Scharf, Christan; Balabanov, Stefan; Trusch, Maria; Schlüter, Hartmut; Braren, Ingke; Spillner, Edzard; Trepel, Martin

    2010-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion molecules. Since CLL survival may also be driven by antigenic stimulation through the B-cell antigen receptor (BCR), we explored the hypothesis that these processes may be linked to each other. We tested if stromal cells could serve as an antigen reservoir for CLL cells, thus promoting CLL cell survival by stimulation through the BCR. As a proof of principle, we found that two CLL BCRs with a common stereotyped heavy chain complementarity-determining region 3 (previously characterized as “subset 1”) recognize antigens highly expressed in stromal cells – vimentin and calreticulin. Both antigens are well-documented targets of autoantibodies in autoimmune disorders. We demonstrated that vimentin is displayed on the surface of viable stromal cells and that it is present and bound by the stereotyped CLL BCR in CLL-stroma co-culture supernatant. Blocking the vimentin antigen by recombinant soluble CLL BCR under CLL-stromal cell co-culture conditions reduces stroma-mediated anti-apoptotic effects by 20–45%. We therefore conclude that CLL BCR stimulation by stroma-derived antigens can contribute to the protective effect that the stroma exerts on CLL cells. This finding sheds a new light on the understanding of the pathobiology of this so far mostly incurable disease. PMID:21209908

  5. Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity

    PubMed Central

    Velu, Chinavenmeni S.; Chaubey, Aditya; Phelan, James D.; Horman, Shane R.; Wunderlich, Mark; Guzman, Monica L.; Jegga, Anil G.; Zeleznik-Le, Nancy J.; Chen, Jianjun; Mulloy, James C.; Cancelas, Jose A.; Jordan, Craig T.; Aronow, Bruce J.; Marcucci, Guido; Bhat, Balkrishen; Gebelein, Brian; Grimes, H. Leighton

    2013-01-01

    Acute myelogenous leukemia (AML) subtypes that result from oncogenic activation of homeobox (HOX) transcription factors are associated with poor prognosis. The HOXA9 transcription activator and growth factor independent 1 (GFI1) transcriptional repressor compete for occupancy at DNA-binding sites for the regulation of common target genes. We exploited this HOXA9 versus GFI1 antagonism to identify the genes encoding microRNA-21 and microRNA-196b as transcriptional targets of HOX-based leukemia oncoproteins. Therapeutic inhibition of microRNA-21 and microRNA-196b inhibited in vitro leukemic colony forming activity and depleted in vivo leukemia-initiating cell activity of HOX-based leukemias, which led to leukemia-free survival in a murine AML model and delayed disease onset in xenograft models. These data establish microRNA as functional effectors of endogenous HOXA9 and HOX-based leukemia oncoproteins, provide a concise in vivo platform to test RNA therapeutics, and suggest therapeutic value for microRNA antagonists in AML. PMID:24334453

  6. Radiolabeled Monoclonal Antibody and Combination Chemotherapy Before Stem Cell Transplant in Treating Patients With High-Risk Lymphoid Malignancies

    ClinicalTrials.gov

    2015-06-22

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; 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; 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 Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

  7. The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy

    PubMed Central

    Packham, Graham; Krysov, Serge; Allen, Alex; Savelyeva, Natalia; Steele, Andrew J.; Forconi, Francesco; Stevenson, Freda K.

    2014-01-01

    Biologists and clinicians agree that the B-cell receptor influences the behavior of chronic lymphocytic leukemia, and promising new drugs are aimed at receptor-associated kinases. Engagement of surface immunoglobulin by antigen is a key driver of malignant cells with outcome influenced by the nature of the cell, the level of stimulation and the microenvironment. Analysis of surface immunoglobulin-mediated signaling in the two major disease subsets defined by IGHV mutational status reveals bifurcation of responses toward proliferation or anergy. Mutated chronic lymphocytic leukemia, generally of relatively good prognosis, is mainly, but not exclusively, driven towards anergy in vivo. In contrast, unmutated chronic lymphocytic leukemia shows less evidence for anergy in vivo retaining more responsiveness to surface immunoglobulin M-mediated signaling, possibly explaining increased tumor progression. Expression and function of surface immunoglobulin M in unmutated chronic lymphocytic leukemia appear rather homogeneous, but mutated chronic lymphocytic leukemia exhibits a highly heterogeneous profile that may relate to further variable clinical behavior within this subset. Anergy should increase susceptibility to apoptosis but, in leukemic cells, this may be countered by overexpression of the B-cell lymphoma-2 survival protein. Maintained anergy spreads to chemokines and adhesion molecules, restraining homing and migration. However, anergy is not necessarily completely benign, being able to reverse and regenerate surface immunoglobulin M-mediated responses. A two-pronged attack on proliferative and anti-apoptotic pathways may succeed. Increased understanding of how chronic lymphocytic leukemia cells are driven to anergy or proliferation should reveal predictive biomarkers of progression and of likely response to kinase inhibitors, which could assist therapeutic decisions. PMID:24986876

  8. Nicotinamide Cooperates with Retinoic Acid and 1,25-Dihydroxyvitamin D3 to Regulate Cell Differentiation and Cell Cycle Arrest of Human Myeloblastic Leukemia Cells

    Microsoft Academic Search

    Miaoqing Shen; Andrew Yen

    2009-01-01

    Nicotinamide, the amide derivative of vitamin B3, cooperates with retinoic acid (RA), a form of vitamin A, and 1,25-dihydroxyvitamin D3 (D3), to regulate cell differentiation and proliferation of human myeloblastic leukemia cells. In human myeloblastic leukemia cells, RA or D3 are known to cause MAPK signaling leading to myeloid or monocytic differentiation and G0 cell cycle arrest. In this process,

  9. Hairy Root Transformation Using Agrobacterium rhizogenes as a Tool for Exploring Cell Type-Specific Gene Expression and Function Using Tomato as a Model1[W][OPEN

    PubMed Central

    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.

    2014-01-01

    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. PMID:24868032

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

    PubMed

    Nicolini, Franck Emmanuel; Basak, Grzegorz W; Soverini, Simona; Martinelli, Giovanni; Mauro, Michael J; Müller, Martin C; Hochhaus, Andreas; Chuah, Charles; Dufva, Inge H; Rege-Cambrin, Giovanna; Saglio, Giuseppe; Michallet, Mauricette; Labussière, Hélène; Morisset, Stéphane; Hayette, Sandrine; Etienne, Gabriel; Olavarria, Eduardo; Zhou, Wei; Peter, Senaka; Apperley, Jane F; Cortes, Jorge

    2011-11-17

    T315I(+) Philadelphia chromosome-positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited. We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABL(T315I) mutations. Median follow-up was 52 months from mutation detection and 26 months from transplantation. At transplantation, 51.5% of patients with chronic myeloid leukemia were in the chronic phase and 4.5% were in advanced phases. Median overall survival after transplantation was 10.3 months (range 5.7 months to not reached [ie, still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome-positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic myeloid leukemia. The occurrence of chronic GVHD had a positive impact on overall survival (P = .047). Transplant-related mortality rates were low. Multivariate analysis identified only blast phase at transplantation (hazard ratio 3.68, P = .0011) and unrelated stem cell donor (hazard ratio 2.98, P = .011) as unfavorable factors. We conclude that allogeneic stem cell transplantation represents a valuable therapeutic tool for eligible patients with BCR-ABL(T315I) mutation, a tool that may or may not be replaced by third-generation tyrosine kinase inhibitors. PMID:21926354

  11. Natural killer cell neoplasms: a distinctive group of highly aggressive lymphomas\\/leukemias

    Microsoft Academic Search

    Michael M. C Cheung; John K. C Chan; Kit-Fai Wong

    2003-01-01

    Natural killer (NK) cell neoplasms, which include extranodal NK\\/T-cell lymphoma (nasal and extranasal) and aggressive NK cell leukemia, are generally rare, but they are more common in people of Oriental, Mexican and South American descent. These neoplasms are highly aggressive, and show a strong association with Epstein-Barr virus. Extranodal NK\\/T-cell lymphoma most commonly affects the nasal cavity and other mucosal

  12. [Expression of CD133 in bone marrow cells of patients with leukemia and myelodysplastic syndrome].

    PubMed

    Wang, Wei; Wang, Hong-Yi; Zhao, Hui-Xia; Cui, Zhong-Guang; Li, Guang-Lun

    2007-06-01

    To explore the relationship between the expression of CD133 and pathogenesis of leukemia and MDS, immunocytochemistry method was used to examine the expression of CD133 in bone marrow cells of patients with leukemia and MDS. The results showed that the positive rate of CD133 in 41 acute leukemia patients was 51.2%. The expression of CD133 in AML patients (16/29, 55.2%) was significantly higher than that in control group (2/15, 13.3%). There was no significant difference in CD133 expression between CML and control group. The positive rate of CD133 in 9 patients with MDS was 55.56% (5/9). There was no significant difference between MDS and normal control. The expression of CD133 in all leukemia cells with CD34(+) was higher than that in leukemia cells with CD34(-), and there was significant difference in expression of CD133 between them (P < 0.05). The expression of CD133 had no relationship with the clinical prognostic factors such as sex, age, the percentage of leukemic cells in peripheral blood and in bone marrow, WBC counts, hemoglobin concentration, platelet counts and LDH level. It is concluded that the expression of CD133 in bone marrow cells of patients with AML is higher than that in control group. The expression of CD133 is significantly correlated with the expression of CD34. The high expression of CD133 may be an adverse prognostic factor in acute leukemia. PMID:17605847

  13. Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed Standard-Risk Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2015-05-01

    B-cell Childhood Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  14. Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44.

    PubMed

    Zhang, Suping; Wu, Christina C N; Fecteau, Jessie-F; Cui, Bing; Chen, Liguang; Zhang, Ling; Wu, Rongrong; Rassenti, Laura; Lao, Fitzgerald; Weigand, Stefan; Kipps, Thomas J

    2013-04-01

    Chronic lymphocytic leukemia (CLL) cells express high levels of CD44, a cell-surface glycoprotein receptor for hyaluronic acid. We found that a humanized mAb specific for CD44 (RG7356) was directly cytotoxic for leukemia B cells, but had little effect on normal B cells. Moreover, RG7356 could induce CLL cells that expressed the zeta-associated protein of 70 kDa (ZAP-70) to undergo caspase-dependent apoptosis, independent of complement or cytotoxic effector cells. The cytotoxic effect of this mAb was not mitigated when the CLL cells were cocultured with mesenchymal stromal cells (MSCs) or hyaluronic acid or when they were stimulated via ligation of the B-cell receptor with anti-µ. RG7356 induced rapid internalization of CD44 on CLL cells at 37 °C, resulting in reduced expression of ZAP-70, which we found was complexed with CD44. Administration of this mAb at a concentration of 1 mg/kg to immune-deficient mice engrafted with human CLL cells resulted in complete clearance of engrafted leukemia cells. These studies indicate that this mAb might have therapeutic activity, particularly in patients with CLL that express ZAP-70. PMID:23530247

  15. Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44

    PubMed Central

    Zhang, Suping; Wu, Christina C. N.; Fecteau, Jessie-F.; Cui, Bing; Chen, Liguang; Zhang, Ling; Wu, Rongrong; Rassenti, Laura; Lao, Fitzgerald; Weigand, Stefan; Kipps, Thomas J.

    2013-01-01

    Chronic lymphocytic leukemia (CLL) cells express high levels of CD44, a cell-surface glycoprotein receptor for hyaluronic acid. We found that a humanized mAb specific for CD44 (RG7356) was directly cytotoxic for leukemia B cells, but had little effect on normal B cells. Moreover, RG7356 could induce CLL cells that expressed the zeta-associated protein of 70 kDa (ZAP-70) to undergo caspase-dependent apoptosis, independent of complement or cytotoxic effector cells. The cytotoxic effect of this mAb was not mitigated when the CLL cells were cocultured with mesenchymal stromal cells (MSCs) or hyaluronic acid or when they were stimulated via ligation of the B-cell receptor with anti-µ. RG7356 induced rapid internalization of CD44 on CLL cells at 37 °C, resulting in reduced expression of ZAP-70, which we found was complexed with CD44. Administration of this mAb at a concentration of 1 mg/kg to immune-deficient mice engrafted with human CLL cells resulted in complete clearance of engrafted leukemia cells. These studies indicate that this mAb might have therapeutic activity, particularly in patients with CLL that express ZAP-70. PMID:23530247

  16. Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells.

    PubMed

    Welner, Robert S; Amabile, Giovanni; Bararia, Deepak; Czibere, Akos; Yang, Henry; Zhang, Hong; Pontes, Lorena Lobo De Figueiredo; Ye, Min; Levantini, Elena; Di Ruscio, Annalisa; Martinelli, Giovanni; Tenen, Daniel G

    2015-05-11

    Leukemic cells disrupt normal patterns of blood cell formation, but little is understood about the mechanism. We investigated whether leukemic cells alter functions of normal hematopoietic stem and progenitor cells. Exposure to chronic myelogenous leukemia (CML) caused normal mouse hematopoietic progenitor cells to divide more readily, altered their differentiation, and reduced their reconstitution and self-renewal potential. Interestingly, the normal bystander cells acquired gene expression patterns resembling their malignant counterparts. Therefore, much of the leukemia signature is mediated by extrinsic factors. Indeed, IL-6 was responsible for most of these changes. Compatible results were obtained when human CML were cultured with normal human hematopoietic progenitor cells. Furthermore, neutralization of IL-6 prevented these changes and treated the disease. PMID:25965572

  17. An unusual root tip formation in hairy root culture of Hyoscyamus muticus

    Microsoft Academic Search

    Mondher Jaziri; Jacques Homes; Koichiro Shimomura

    1994-01-01

    Summary  Hairy root cultures of Hyoscyamus muticus were established using Agrobacterium rhizogenes ATCC 15834. In one out of 8 clones established, an unusual root tip formation was observed after transfer of cultures from half-strength Murashige and Skoog (1962) to White's medium (1939). This phenomenon was associated with the production of a fine brownish cell suspension culture. Hairy root development resumed after

  18. COX2 independent induction of apoptosis by etodolac in leukemia cells in vitro and growth inhibition of leukemia cells in vivo

    Microsoft Academic Search

    Satoki Nakamura; Miki Kobayashi; Kiyoshi Shibata; Naohi Sahara; Kazuyuki Shigeno; Kaori Shinjo; Kensuke Naito; Kazunori Ohnishi

    2004-01-01

    Summary Cyclooxygenase-2 (COX-2) has been reported to regulate apoptosis and influence the growth of malignancies. In this study, we demonstrated that etodolac, a COX-2 inhibitor, inhibited proliferation and induced apoptosis in leukemia K562, NB4, U937, HL60, and CEM cells via a COX-2 independent pathway. Etodolac induced apoptosis in a dose-dependent manner, which was associated with i) down-regulation of anti-apoptotic bcl-2,

  19. Iodine I 131 Monoclonal Antibody BC8 Before Autologous Stem Cell Transplant in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma or Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2015-04-14

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; 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; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell 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 Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

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

    ClinicalTrials.gov

    2013-10-16

    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

  1. Amino-functionalized nanoparticles as inhibitors of mTOR and inducers of cell cycle arrest in leukemia cells.

    PubMed

    Loos, Cornelia; Syrovets, Tatiana; Musyanovych, Anna; Mailänder, Volker; Landfester, Katharina; Simmet, Thomas

    2014-02-01

    Activation of the mammalian target of rapamycin (mTOR) has been implicated in anticancer drug resistance, type 2 diabetes, and aging. Here, we show that surface functionalization of polystyrene nanoparticles with amino groups (PS-NH2), but not with carboxyl groups (PS-COOH), induces G2 cell-cycle arrest and inhibition of proliferation in three leukemia cell lines. Besides, PS-NH2 inhibit angiogenesis and proliferation of leukemia cells xenografted onto the chick chorioallantoic membrane. At the molecular level, PS-NH2 inhibit, whereas PS-COOH activate mTOR signaling in leukemia cells. Consistently, PS-NH2 block activation of the mTOR downstream targets, Akt and p70 ribosomal S6 kinase 1, and induce overexpression of the cell-cycle regulator p21(Cip1/Waf1) and degradation of cyclin B1. After addition, both types of particles rapidly induce autophagy in leukemia cells. Yet, only in PS-NH2-treated cells, acidic vesicular organelles show elevated pH and impaired processing of procathepsin B. Moreover, solely in PS-NH2-treated cells, autophagy is followed by permeabilization of acidic vesicular organelles and induction of apoptosis. By contrast, primary macrophages, which do not exhibit activated mTOR signaling, proved relatively resistant to PS-NH2-induced toxicity. These data indicate that functionalized nanoparticles can be used to control activation of mTOR signaling pathways, and to influence proliferation and viability of malignant cells. PMID:24331713

  2. The conformational alteration of the mutated extracellular domain of Fas in an adult T cell leukemia cell line

    Microsoft Academic Search

    Takahiro Maeda; Susumu Nakayama; Yasuaki Yamada; Kazuyuki Sugahara; Hajime Isomoto; Masayuki Tawara; Reishi Yamasaki; Yasuyuki Onimaru; Tetsuro Matsushita; Yoshiyuki Ohzono; Shimeru Kamihira

    2002-01-01

    Fas (APO-1\\/CD95) is a cell surface receptor involved in apoptosis. Almost all adult T cell leukemia (ATL) cells express abundant Fas antigen and show apoptosis induced by IgM anti-Fas monoclonal antibody (mAb). We established the ATL cell line, RSO4, which was obtained from Fas-sensitive ATL cell line SO4 and showed resistance to apoptosis induced by the mAb. By sequencing analysis

  3. Transformation of Human Umbilical Cord Blood T Cells by Human T-Cell Leukemia\\/Lymphoma Virus

    Microsoft Academic Search

    Mikulas Popovic; Gunhild Lange-Wantzin; Prem S. Sarin; Dean Mann; Robert C. Gallo

    1983-01-01

    Several isolates of human T-cell leukemia\\/lymphoma virus (HTLV) were transmitted to normal human T cells obtained from the umbilical cord blood of newborns. T cells from seven specimens were immortalized by infection with different HTLV isolates and their properties were compared with those of activated uninfected normal T cells grown in the presence of T-cell growth factor (TCGF) and with

  4. 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

    2015-07-02

    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

  5. 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

    2015-05-15

    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

  6. Infection Prophylaxis and Management in Treating Cytomegalovirus (CMV) Infection in Patients With Hematologic Malignancies Previously Treated With Donor Stem Cell Transplant

    ClinicalTrials.gov

    2015-06-03

    Hematopoietic/Lymphoid Cancer; Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated 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); Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Aplastic Anemia; Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Cytomegalovirus Infection; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Primary Systemic Amyloidosis; 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 Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Secondary Myelofibrosis; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lympho

  7. The role of the segmentation gene hairy in Tribolium.

    PubMed

    Aranda, Manuel; Marques-Souza, Henrique; Bayer, Till; Tautz, Diethard

    2008-09-01

    Hairy stripes in Tribolium are generated during blastoderm and germ band extension, but a direct role for Tc-h in trunk segmentation was not found. We have studied here several aspects of hairy function and expression in Tribolium, to further elucidate its role. First, we show that there is no functional redundancy with other hairy paralogues in Tribolium. Second, we cloned the hairy orthologue from Tribolium confusum and show that its expression mimics that of Tribolium castaneum, implying that stripe expression should be functional in some way. Third, we show that the dynamics of stripe formation in the growth zone is not compatible with an oscillatory mechanism comparable to the one driving the expression of hairy homologues in vertebrates. Fourth, we use parental RNAi experiments to study Tc-h function and we find that mandible and labium are particularly sensitive to loss of Tc-h, reminiscent of a pair-rule function in the head region. In addition, lack of Tc-h leads to cell death in the gnathal region at later embryonic stages, resulting in a detachment of the head. Cell death patterns are also altered in the midline. Finally, we have analysed the effect of Tc-h knockdown on two of the target genes of hairy in Drosophila, namely fushi tarazu and paired. We find that the trunk expression of Tc-h is required to regulate Tc-ftz, although Tc-ftz is itself also not required for trunk segmentation in Tribolium. Our results imply that there is considerable divergence in hairy function between Tribolium and Drosophila. PMID:18679713

  8. CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia

    Microsoft Academic Search

    Sherif Ibrahim; Michael Keating; Susan O'Brien; Yang O. Huh; Iman Jilani; Susan Lerner; Hagop M. Kantarjian; Maher Albitar

    CD38 is a transmembrane glycoprotein ex- pressed on the surface of leukemic cells in a significant percentage of patients with B- cell chronic lymphocytic leukemia (B-CLL). A recent study suggested that CD38 expres- sion has prognostic value in CLL. Peripheral blood samples from 218 patients with B-CLL were analyzed by flow cytometry for CD38 expression on CD5\\/191 leukemic cells. Vari-

  9. Melittin activates endogenous phospholipase D during cytolysis of human monocytic leukemia cells

    Microsoft Academic Search

    Shamsher S. Saini; Ashok K. Chopra; Johnny W. Peterson

    1999-01-01

    Human monocytic leukemia cells (U937) were challenged with synthetic melittin, and arachidonic acid (AA)\\/acylated lipids from both cells (pellet) and media (supernatant) were analyzed by thin layer chromatography (TLC). From these data, melittin-mediated activation\\/inhibition of major phospholipases in U937 cells was related to pore formation, permeabilization and cytolysis as determined by light microscopy. Also, the effect of melittin on acylhydrolase

  10. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia

    Microsoft Academic Search

    Adolfo A. Ferrando; Donna S. Neuberg; Jane Staunton; Mignon L. Loh; Christine Huard; Susana C. Raimondi; Fred G. Behm; Ching-Hon Pui; James R. Downing; D. Gary Gilliland; Eric S. Lander; Todd R. Golub; A. Thomas Look

    2002-01-01

    Human T cell leukemias can arise from oncogenes activated by specific chromosomal translocations involving the T cell receptor genes. Here we show that five different T cell oncogenes (HOX11, TAL1, LYL1, LMO1, and LMO2) are often aberrantly expressed in the absence of chromosomal abnormalities. Using oligonucleotide microarrays, we identified several gene expression signatures that were indicative of leukemic arrest at

  11. Deciphering the Evolution of Leukemia-Initiating Cells | Physical Sciences in Oncology

    Cancer.gov

    Cancer is a genetic disease, and a major focus in cancer research today is to tease out the details of how cancer cells evolve from a normal cell. Now, an international team of investigators has found that defective genes and the individual leukemia cells that carry them are organized in a more complex way than previously thought. These findings, which were published in the journal Nature, challenge the conventional scientific view that cancer progresses as a linear series of genetic events.

  12. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines

    Microsoft Academic Search

    S Yokota; H Kiyoi; M Nakao; T Iwai; S Misawa; T Okuda; Y Sonoda; T Abe; K Kahsima; Y Matsuo; T Naoe

    1997-01-01

    In this study, we examined a large number of patients to clarify the distribution and frequency of a recently described FLT3 tandem duplication among hematopoietic malignancies, including 112 acute myelocytic leukemia (AML), 55 acute lymphoblastic leukemia (ALL), 37 myelodysplastic syndrome (MDS), 20 chronic myelogenous leukemia (CML), 30 non-Hodgkin’s lymphoma (NHL), 14 adult T cell leukemia, 15 chronic lymphocytic leukemia (CLL)

  13. Glucocorticoid-induced cell death is mediated through reduced glucose metabolism in lymphoid leukemia cells.

    PubMed

    Buentke, E; Nordström, A; Lin, H; Björklund, A-C; Laane, E; Harada, M; Lu, L; Tegnebratt, T; Stone-Elander, S; Heyman, M; Söderhäll, S; Porwit, A; Ostenson, C-G; Shoshan, M; Tamm, K Pokrovskaja; Grandér, D

    2011-07-01

    Malignant cells are known to have increased glucose uptake and accelerated glucose metabolism. Using liquid chromatography and mass spectrometry, we found that treatment of acute lymphoblastic leukemia (ALL) cells with the glucocorticoid (GC) dexamethasone (Dex) resulted in profound inhibition of glycolysis. We thus demonstrate that Dex reduced glucose consumption, glucose utilization and glucose uptake by leukemic cells. Furthermore, Dex treatment decreased the levels of the plasma membrane-associated glucose transporter GLUT1, thus revealing the mechanism for the inhibition of glucose uptake. Inhibition of glucose uptake correlated with induction of cell death in ALL cell lines and in leukemic blasts from ALL patients cultured ex vivo. Addition of di-methyl succinate could partially overcome cell death induced by Dex in RS4;11 cells, thereby further supporting the notion that inhibition of glycolysis contributes to the induction of apoptosis. Finally, Dex killed RS4;11 cells significantly more efficiently when cultured in lower glucose concentrations suggesting that modulation of glucose levels might influence the effectiveness of GC treatment in ALL. In summary, our data show that GC treatment blocks glucose uptake by leukemic cells leading to inhibition of glycolysis and that these effects play an important role in the induction of cell death by these drugs. PMID:22829187

  14. CRIF1 Interacting with CDK2 Regulates Bone Marrow Microenvironment-Induced G0/G1 Arrest of Leukemia Cells

    PubMed Central

    Xiao, Yanni; Xiang, Lixing; Ye, Xingde; Deng, Xiaojun; Zhao, Jiang; Li, Zhongjun

    2014-01-01

    Background To assess the level of CR6-interacting factor 1 (CRIF1), a cell cycle negative regulator, in patients with leukemia and investigate the role of CRIF1 in regulating leukemia cell cycle. Methods We compared the CRIF1 level in bone marrow (BM) samples from healthy and acute myeloid leukemia (AML), iron deficiency anemia (IDA) and AML-complete remission (AML-CR) subjects. We also manipulated CRIF1 level in the Jurkat cells using lentivirus-mediated overexpression or siRNA-mediated depletion. Co-culture with the BM stromal cells (BMSCs) was used to induce leukemia cell cycle arrest and mimic the BM microenvironment. Results We found significant decreases of CRIF1 mRNA and protein in the AML group. CRIF1 overexpression increased the proportion of Jurkat cells arrested in G0/G1, while depletion of endogenous CRIF1 decreased cell cycle arrest. Depletion of CRIF1 reversed BMSCs induced cell cycle arrest in leukemia cells. Co-immunoprecipitation showed a specific binding of CDK2 to CRIF1 in Jurkat cells during cell cycle arrest. Co-localization of two proteins in both nucleus and cytoplasm was also observed with immunofluorescent staining. Conclusion CRIF1 may play a regulatory role in the BM microenvironment-induced leukemia cell cycle arrest possibly through interacting with CDK2 and acting as a cyclin-dependent kinase inhibitor. PMID:24520316

  15. Dendritic Cells from Chronic Lymphocytic Leukemia Patients Are Normal Regardless of Ig V Gene Mutation Status

    Microsoft Academic Search

    DAVORKA MESSMER; GLORIA TELUSMA; TARUN WASIL; BRADLEY T MESSMER; STEVEN ALLEN; KANTI R RAI; NICHOLAS CHIORAZZI

    Patients with B-type chronic lymphocytic leukemia (B-CLL) segregate into 2 subgroups based on the mutational status of the immunoglobulin (Ig) V genes and the patients in these subgroups follow very different clinical courses. To examine whether den- dritic cells (DCs) generated from CLL patients can be candidates for immune therapy, we compared the phenotypic and func- tional capacities of DCs

  16. Differential Gene Expression Analysis in K562 Human Leukemia Cell Line Treated with Benzene

    PubMed Central

    Choi, Sulji; Kim, Ji-Young; Moon, Jai-Dong; Baek, Hee Jo; Kook, Hoon

    2011-01-01

    Even though exposure to benzene has been linked to a variety of cancers including leukemia, the detailed molecular mechanisms relevant to benzene-induced carcinogenesis remain to be clearly elucidated. In this study, we evaluated the effects of benzene on differential gene expression in a leukemia cell line. The K562 leukemia cell line used in this study was cultured for 3 h with 10 mM benzene and RNA was extracted. To analyze the gene expression profiles, a 41,000 human whole genome chip was employed for cDNA microarray analysis. We initially identified 6,562 genes whose expression was altered by benzene treatment. Among these, 3,395 genes were upregulated and 3,167 genes were downregulated by more than 2-fold, respectively. The results of functional classification showed that the identified genes were involved in biological pathways including transcription, cell proliferation, the cell cycle, and apoptosis. These gene expression profiles should provide us with further insights into the molecular mechanisms underlying benzene-induced carcinogenesis, including leukemia. PMID:24278550

  17. Cryptococcal osteomyelitis in an adolescent survivor of T-cell acute lymphoblastic leukemia.

    PubMed

    Oh, Djin-Ye; Madhusoodhan, P Pallavi; Springer, Deborah J; Inglima, Kenneth; Chaudhri, Ali A; Heitman, Joseph; Raetz, Elizabeth A; Khaitan, Alka; Rigaud, Mona

    2015-06-01

    Cryptococcosis is infrequent in children, and isolated cryptococcal osteomyelitis is rarely encountered. Here, we describe a 14-year-old patient in remission from T-cell acute lymphoblastic leukemia with osteomyelitis because of Cryptococcus neoformans var. grubii. The patient was effectively treated with antifungal therapy. PMID:25806844

  18. Functional Domain Structure of Human T-Cell Leukemia Virus Type 2 Rex

    Microsoft Academic Search

    Murli Narayan; Ihab Younis; Donna M. D'Agostino; Patrick L. Green

    2003-01-01

    The Rex protein of human T-cell leukemia virus (HTLV) acts posttranscriptionally to induce the cytoplasmic expression of the unspliced and incompletely spliced viral RNAs encoding the viral structural and enzymatic proteins and is therefore essential for efficient viral replication. Rex function requires nuclear import, RNA binding, multimerization, and nuclear export. In addition, it has been demonstrated that the phosphorylation status

  19. 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

  20. Black hairy tongue syndrome.

    PubMed

    Gurvits, Grigoriy E; Tan, Amy

    2014-08-21

    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

  1. Cell cycle regulation and induction of apoptosis by beta-carotene in U937 and HL-60 leukemia cells.

    PubMed

    Upadhyaya, K R; Radha, K S; Madhyastha, H K

    2007-11-30

    In this communication, we report the efficacy of beta-carotene towards differentiation and apoptosis of leukemia cells. Dose (20 microM) and time dependence (12 h) tests of beta- carotene showed a higher magnitude of decrease (significance p < 0.05) in cell numbers and cell viability in HL-60 cells than U937 cells but not normal cell like Peripheral blood mononuclear cell (PBMC). Microscopical observation of beta-carotene treated cells showed a distinct pattern of morphological abnormalities with inclusion of apoptotic bodies in both leukemia cell lines. When cells were treated with 20 microM of beta-carotene, total genomic DNA showed a fragmentation pattern and this pattern was clear in HL-60 than U937 cells. Both the cell lines, on treatment with beta- carotene, showed a clear shift in G(1) phase of the cell cycle. In addition the study also revealed anti-oxidant properties of beta-carotene since there was reduction in relative fluorescent when treated than the control at lower concentration. Collectively this study shows the dual phenomenon of apoptosis and differentiation of leukemia cells on treatment with beta-carotene. PMID:18047798

  2. Angelica sinensis polysaccharide induces erythroid differentiation of human chronic myelogenous leukemia k562 cells.

    PubMed

    Wang, Lu; Jiang, Rong; Song, Shu-Dan; Hua, Zi-Sen; Wang, Jian-Wei; Wang, Ya-Ping

    2015-01-01

    Leukemia is a clonal disorder with blocked normal differentiation and cell death of hematopoietic progenitor cells. Traditional modalities with most used radiation and chemotherapy are nonspecific and toxic which cause adverse effects on normal cells. Differentiation inducing therapy forcing malignant cells to undergo terminal differentiation has been proven to be a promising strategy. However, there is still scarce of potent differentiation inducing agents. We show here that Angelica sinensis polysaccharide (ASP), a major active component in Dong quai (Chinese Angelica sinensis), has potential differentiation inducing activity in human chronic erythro- megakaryoblastic leukemia K562 cells. MTT assays and flow cytometric analysis demonstrated that ASP inhibited K562 cell proliferation and arrested the cell cycle at the G0/G1 phase. ASP also triggered K562 cells to undergo erythroid differentiaton as revealed by morphological changes, intensive benzidine staining and hemoglobin colorimetric reaction, as well as increased expression of glycophorin A (GPA) protein. ASP induced redistribution of STAT5 protein from the cytoplasm to the nucleus. Western blotting analysis further identified that ASP markedly sensitized K562 cells to exogenous erythropoietin (EPO) by activating EPO-induced JAK2/ STAT5 tyrosine phosphorylation, thus augmenting the EPO-mediated JAK2/STAT5 signaling pathway. On the basis of these findings, we propose that ASP might be developed as a potential candidate for chronic myelogenous leukemia inducing differentiation treatment. PMID:25987027

  3. 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.

  4. Inhibition of ERK5 enhances cytarabine-induced apoptosis in acute myeloid leukemia cells

    PubMed Central

    Xu, Yu; Cao, Cuiming; Gong, Xiuchun; Rong, LiJun

    2015-01-01

    Background and aims: Acute myeloid leukemia (AML) is a fatal hematological malignancy which is resistant to a variety of chemotherapy drugs. Phospho-ERK5 (p-ERK5) plays a novel role in chemoresistance in some cancer cells and this pathway is a central mediator of cell survival and apoptotic regulation. The aim of this study was to investigate the effect of a specific ERK5 small interference RNA (siRNA) on proliferation and the sensitivity of HL-60 acute myeloid leukemia (AML) cells to the chemotherapeutic drug cytarabine. Methods: The cells were transfected with siRNAs using Lipofectamine™ 2000 transfection reagent. Relative ERK5 mRNA and protein levels were measured by quantitative real-time PCR, immunocytochemical assay, and Western blotting, respectively. The cytotoxic effects of cytarabine and ERK5 siRNA, alone and in combination, on leukemic cells were determined using colony formation and MTT assay. Apoptosis was assessed by ELISA cell death assay. Results: ERK5 siRNA markedly reduced both mRNA and protein expression levels leading to distinct inhibition of cell proliferation and increased spontaneous apoptosis. Surprisingly, ERK5 siRNA synergistically increased the cell toxic effects of cytarabine. Conclusions: Our study suggests that down-regulation of ERK5 by siRNA can trigger apoptosis and overcome drug resistance of leukemia cells. Therefore, ERK5 siRNA may be an effective adjuvant in AML chemotherapy.

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

    PubMed Central

    Flatt, Terrie; Neville, Kathleen; Lewing, Karen; Dalal, Jignesh

    2012-01-01

    Fanconi anemia is associated with an increased risk of malignancy. Patients are sensitive to the toxic effects of chemotherapy. We report the case of a patient with Fanconi anemia who developed T-cell acute lymphoblastic leukemia. He experienced chemotherapy-related complications including prolonged neutropenia, grade IV vincristine neuropathy, and disseminated aspergillosis. He was successfully treated with modified dosing of cytarabine and intrathecal methotrexate followed by allogeneic bone marrow transplant. The aspergillosis was treated with systemic antifungal treatment and surgical resection. Now 30 months after bone marrow transplant the patient is without evidence of aspergillosis or leukemia. PMID:22937327

  6. T-cell and natural killer cell therapies for hematologic malignancies after hematopoietic stem cell transplantation: enhancing the graft-versus-leukemia effect

    PubMed Central

    Cruz, C. Russell; Bollard, Catherine M.

    2015-01-01

    Hematopoietic stem cell transplantation has revolutionized the treatment of hematologic malignancies, but infection, graft-versus-host disease and relapse are still important problems. Calcineurin inhibitors, T-cell depletion strategies, and immunomodulators have helped to prevent graft-versus-host disease, but have a negative impact on the graft-versus-leukemia effect. T cells and natural killer cells are both thought to be important in the graft-versus-leukemia effect, and both cell types are amenable to ex vivo manipulation and clinical manufacture, making them versatile immunotherapeutics. We provide an overview of these immunotherapeutic strategies following hematopoietic stem cell transplantation, with discussions centered on natural killer and T-cell biology. We discuss the contributions of each cell type to graft-versus-leukemia effects, as well as the current research directions in the field as related to adoptive cell therapy after hematopoietic stem cell transplantation. PMID:26034113

  7. Role of lymphoid cells in age-related change of susceptibility to Friend leukemia virus-induced leukemia.

    PubMed

    Yamaguchi, S; Kitagawa, M; Inoue, M; Tejima, Y; Kimura, M; Aizawa, S; Utsuyama, M; Hirokawa, K

    2001-02-01

    Susceptibility for Friend leukemia virus (FLV)-induced leukemogenesis was examined in the C3H/He (C3H)-->C57BL/6 (B6) radiation bone marrow chimeras of various age groups, and the effect of aging of host mice on the susceptibility was determined. The bone marrow chimera system provided the various age of FLV-resistant host mice (B6) possessing the same age of FLV-susceptible target cells from C3H mice. Using this system, we could determine the aging effect on the host resistancy against FLV without an influence of the aging effect on target cells. First, the young C3H-->young B6 chimeras and young C3H-->old B6 chimeras were compared. The young-->old chimeras were more susceptible to FLV-induced acute disease than the young-->young chimeras. The spleen CD4+ as well as CD8+ T cells were reduced in young-->old chimeras compared with young-->young chimeras. Similarly, the old C3H-->old B6 chimeras were more susceptible than old-->young chimeras and revealed the lower CD4+ T cell ratio in the spleen. Discussion was made on the possible implication of these findings on the role of T cells in age-related change of resistance to FLV-induced leukemogenesis. PMID:11166360

  8. Cancer Stem Cells: Historical Perspectives and Lessons from Leukemia

    Microsoft Academic Search

    Christopher R. Cogle

    \\u000a Cancer has a long history rooted in developmental biology. Early scientists regarded cancer as remnant embryonal tissues waiting\\u000a to be provoked into a malignant state. Whereas this embryonal rest theory fits well with certain childhood cancers like teratocarcinomas,\\u000a acquired cancers in adulthood require more explanation. Because of early advances in hematology and immunology, investigations\\u000a of hematologic malignancies like leukemias have

  9. Oncostatin M and leukemia inhibitory factor regulate the growth of normal human breast epithelial cells.

    PubMed

    Grant, S L; Douglas, A M; Goss, G A; Begley, C G

    2001-01-01

    We have previously reported the inhibitory effects of oncostatin M (OSM) and leukemia inhibitory factor (LIF) on the proliferation of breast cancer cell lines. In this study, we examined the action of OSM and LIF on normal, non-malignant human breast epithelial cells (HBECs). We demonstrated expression of three components of the OSM receptor; gp130, the leukemia inhibitory factor receptor (LIFRbeta) and the OSM specific receptor (OSMRbeta). Treatment of the normal HBECs with OSM and LIF resulted in inhibition of proliferation, even in the presence of the breast mitogen, epidermal growth factor (EGF), which is required for HBEC growth. The inhibition was associated with a reduction of cells in the S-phase of the cell cycle and an accumulation of cells in G0/G1. These results suggest a previously unrecognised physiological role for these growth factors in the regulation of normal breast epithelium. PMID:11811789

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

    ClinicalTrials.gov

    2015-03-25

    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

  11. Coping strategies of adults with leukemia undergoing hematopoietic stem cell transplantation in Iran: a qualitative study.

    PubMed

    Farsi, Zahra; Dehghan Nayeri, Nahid; Negarandeh, Reza

    2010-12-01

    Hematopoietic stem cell transplantation (HSCT) causes significant physical, social, psychological, and emotional stress in patients with leukemia. This qualitative study using semi-structured interviews explored the coping strategies of 10 adults with acute leukemia who were undergoing this form of treatment in transplantation units in a major hospital in Tehran, Iran, from 2009 to 2010. A content analysis identified eight themes and 13 subthemes that described the participants' coping strategies. The major themes were: attribution, denial and avoidance, connection with divine purpose, organizing treatment, seeking social support, modifying, reflection, and patience and resignation. A deeper understanding of the coping strategies that are used by patients with leukemia undergoing HSCT can help healthcare providers to encourage patients to use strategies that are likely to be more effective. Such coping strategies also can help patients to achieve a greater sense of empowerment. PMID:21210928

  12. Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal.

    PubMed

    Valent, P; Sotlar, K; Sperr, W R; Escribano, L; Yavuz, S; Reiter, A; George, T I; Kluin-Nelemans, H C; Hermine, O; Butterfield, J H; Hägglund, H; Ustun, C; Hornick, J L; Triggiani, M; Radia, D; Akin, C; Hartmann, K; Gotlib, J; Schwartz, L B; Verstovsek, S; Orfao, A; Metcalfe, D D; Arock, M; Horny, H-P

    2014-09-01

    Mast cell leukemia (MCL), the leukemic manifestation of systemic mastocytosis (SM), is characterized by leukemic expansion of immature mast cells (MCs) in the bone marrow (BM) and other internal organs; and a poor prognosis. In a subset of patients, circulating MCs are detectable. A major differential diagnosis to MCL is myelomastocytic leukemia (MML). Although criteria for both MCL and MML have been published, several questions remain concerning terminologies and subvariants. To discuss open issues, the EU/US-consensus group and the European Competence Network on Mastocytosis (ECNM) launched a series of meetings and workshops in 2011-2013. Resulting discussions and outcomes are provided in this article. The group recommends that MML be recognized as a distinct condition defined by mastocytic differentiation in advanced myeloid neoplasms without evidence of SM. The group also proposes that MCL be divided into acute MCL and chronic MCL, based on the presence or absence of C-Findings. In addition, a primary (de novo) form of MCL should be separated from secondary MCL that typically develops in the presence of a known antecedent MC neoplasm, usually aggressive SM (ASM) or MC sarcoma. For MCL, an imminent prephase is also proposed. This prephase represents ASM with rapid progression and 5%-19% MCs in BM smears, which is generally accepted to be of prognostic significance. We recommend that this condition be termed ASM in transformation to MCL (ASM-t). The refined classification of MCL fits within and extends the current WHO classification; and should improve prognostication and patient selection in practice as well as in clinical trials. PMID:24675021

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

    Microsoft Academic Search

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

    2011-01-01

    We have previously characterized the effects of 2,6-diisopropylphenyl–docosahexaenoamide (DIP–DHA) conjugates and their analogs on the proliferation and progression of breast cancer cell lines. For this study, we investigated the effects of the DIP–DHA conjugate on 2 representative T cell acute lymphoblastic leukemia (T-ALL) cell lines: CEM and Jurkat. Treatment of both cell lines with DIP–DHA resulted in significantly greater inhibition

  14. Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy.

    PubMed

    Ruela-de-Sousa, R R; Fuhler, G M; Blom, N; Ferreira, C V; Aoyama, H; Peppelenbosch, M P

    2010-01-01

    Natural-food-based compounds show substantial promise for prevention and biotherapy of cancers including leukemia. In general, their mechanism of action remains unclear, hampering rational use of these compounds. Herein we show that the common dietary flavonoid apigenin has anticancer activity, but also may decrease chemotherapy sensitivity, depending on the cell type. We analyzed the molecular consequences of apigenin treatment in two types of leukemia, the myeloid and erythroid subtypes. Apigenin blocked proliferation in both lineages through cell-cycle arrest in G(2)/M phase for myeloid HL60 and G(0)/G(1) phase for erythroid TF1 cells. In both cell lines the JAK/STAT pathway was one of major targets of apigenin. Apigenin inhibited PI3K/PKB pathway in HL60 and induced caspase-dependent apoptosis. In contrast, no apoptosis was detected in TF1 cells, but initiation of autophagy was observed. The block in cell cycle and induction of autophagy observed in this erythroleukemia cell line resulted in a reduced susceptibility toward the commonly used therapeutic agent vincristine. Thus, this study shows that although apigenin is a potential chemopreventive agent due to the induction of leukemia cell-cycle arrest, caution in dietary intake of apigenin should be taken during disease as it potentially interferes with cancer treatment. PMID:21364620

  15. Spleen cell population changes and hemolytic anemia in F344 rats with large granular lymphocyte leukemia.

    PubMed

    Stromberg, P C; Kociba, G J; Grants, I S; Krakowka, G S; Rinehart, J J; Mezza, L E

    1990-11-01

    A spontaneous large granular lymphocyte leukemia from a F344 rat was transplanted to 36 syngeneic recipients to study the interactions among leukemia, T lymphocytes, and the development of immunemediated hemolytic anemia. Six rats were euthanatized at biweekly intervals, and spleen weight, total spleen cellularity, and differential spleen cell counts were correlated with hemograms and osmotic fragility. Sequential changes in splenic architecture were correlated with hematologic parameters. Monoclonal antibodies defining all T lymphocytes (W3/13), T helper-inducer cells (W3/25), and T suppressor cells (OX-8) were used to identify T cells in immunocytochemical techniques on spleen sections, as well as in fluorescence activated cell sorter analysis of spleen cell suspensions. The onset of hemolytic anemic at 7 weeks after transplantation coincided with the first detection of tumor cells in the spleen and peripheral blood. Tumor cells first accumulated in the marginal zones, and then they infiltrated the red pulp sinusoids. Although the leukemia caused dispersion of the splenic lymphoid tissue, there was no significant lymphopenia, and the relative number of helper (W3/25+) and suppressor (OX-8+) lymphocytes did not change. Because the induction of anemia was a relatively early event in splenic involvement, we concluded that anemia was unrelated to disruption of lymphoid architecture; furthermore, it does not appear to be caused by changes in the numbers of regulatory T lymphocytes. PMID:2148994

  16. [Leukemia SH-1 cells purged by ZnPcH(1)-based photodynamic therapy].

    PubMed

    Lin, Xiao-Lan; Huang, Hui-Fang; Chen, Wan-Zi

    2012-08-01

    The objective of this study was to investigate the effect of a novel Zinc phthalocyanine (ZnPcH(1)) based photodynamic therapy (PDT) on acute monocytic leukemia cell lines SHI-1 and its mechanism, so as to provide theory basis for bone marrow purging in vitro for patients with leukemia. The killing effect of ZnPcH(1)-PDT on SHI-1 cells were assessed by MTT method; the SHI-1 cell death patterns were analyzed by AO/EB fluorescence staining, TdT-mediated dUTP nick end labeling (TUNEL), DNA ploidy analysis, and Annexin V-FITC/PI double staining.Cell mixture was established by integrating SHI-1 cells with normal bone marrow MNC (by 1:100-1:10 000). Purging effect of ZnPcH(1)-PDT against SHI-1 mixed into normal MNC was assessed by analyzing the expression of fusion gene MLL/AF6 mRNA using nested RT-PCR. The results showed that ZnPcH(1)-PDT could effectively inhibit SHI-1 cell proliferation in dose-dependent manner, and ZnPcH(1)-PDT could induce cell apoptosis in time-dependent manner. 0.5 µmol/L ZnPcH(1)-PDT could completely photoinactivated kill SHI-1 cells in the simulated remission bone marrow. It concluded that ZnPcH(1)-PDT may be a effective and convenient promising purging technique for leukemia. PMID:22931639

  17. 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 ...

  18. 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-?B transactivation complex. Furthermore, secreted SPARC activated the integrin-linked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent ?-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-?B 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

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

    PubMed

    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

    2014-04-01

    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-?B transactivation complex. Furthermore, secreted SPARC activated the integrin-linked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent ?-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-?B 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

  20. Up-regulation of VEGF and its receptor in refractory leukemia cells

    PubMed Central

    Wang, Lei; Zhang, Wenjun; Ding, Yi; Xiu, Bing; Li, Ping; Dong, Yan; Zhu, Qi; Liang, Aibin

    2015-01-01

    Objective: To analyze the causative mechanisms in refractory leukemia cells. Methods: Vascular endothelial growth factor (VEGF) blood plasma concentrations in 35 de novo, 6 relapse, 20 remission leukemia patients and 10 healthy kids were determined via ELISA analyses. Transcription levels of the VEGF receptors (VEGFR) Fms-like tyrosine kinase-1 (Flt-1) and kinase-domain insert containing receptor (KDR) were determined in participants’ leucocytes with RT-PCR. Apoptosis rates as well as Cyt-C and Caspase-3 expression was determined in Jurkat, JurkatBcl-2, healthy and recurrent leukemia leukocytes with and without VP-16 applications via flow cytometry. Total Akt (t-Akt) expression and its phosphorylation (p-AKT) status in leukocytes of the participants were analyzed with western blots. Results: Healthy children and the remission group had the lowest blood plasma VEGF concentrations (91.16 ± 41.34 vs. 135.80 ± 111.28 pg/ml), followed by de novo leukemia patients (362.49 ± 195.68 pg/ml-494.19 ± 186.23 pg/ml) and relapse patients (574.37 ± 278.45 pg/ml) (P < 0.01). The same trend was statistically significant visible for Flt-1 and KDR expressions in leukocytes of the participants. Stable Bcl-2 overexpression led to reduced apoptosis rates as well as Cyt-C and Caspase-3 expressions in Jurkat cells after VP-16 application, which was similar in leucocytes of remission patients. In contrast to no phosphorylation in healthy children, Akt was phosphorylated in 10% remission samples, 30% de novo leukemia samples and in 67% of recurrent leukemia leucocytes. Conclusion: High VEGF plus VEGFR expression and AKT phosphorylation are highest in leukocytes of remission patients, suggesting VEGF signaling as a cause of reduced apoptosis susceptibility upon treatments.

  1. Sorafenib-Induced Apoptosis of Chronic Lymphocytic Leukemia Cells Is Associated with Downregulation of RAF and Myeloid Cell Leukemia Sequence 1 (Mcl-1)

    PubMed Central

    Fecteau, Jessie-F; Bharati, Ila S; O’Hayre, Morgan; Handel, Tracy M; Kipps, Thomas J; Messmer, Davorka

    2012-01-01

    We have previously shown that sorafenib, a multikinase inhibitor, exhibits cytotoxic effects on chronic lymphocytic leukemia (CLL) cells. Because the cellular microenvironment can protect CLL cells from drug-induced apoptosis, it is important to evaluate the effect of novel drugs in this context. Here we characterized the in vitro cytotoxic effects of sorafenib on CLL cells and the underlying mechanism in the presence of marrow stromal cells (MSCs) and nurselike cells (NLCs). One single dose of 10 ?mol/L or the repeated addition of 1 ?mol/L sorafenib caused caspase-dependent apoptosis and reduced levels of phosphorylated B-RAF, C-RAF, extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3) and myeloid cell leukemia sequence 1 (Mcl-1) in CLL cells in the presence of the microenvironment. We show that the RAF/mitogen-activated protein kinase kinase (MEK)/ERK pathway can modulate Mcl-1 expression and contribute to CLL cell viability, thereby associating so-rafenib cytotoxicity to its impact on RAF and Mcl-1. To evaluate if the other targets of sorafenib can affect CLL cell viability and contribute to sorafenib-mediated cytotoxicity, we tested the sensitivity of CLL cells to several kinase inhibitors specific for these targets. Our data show that RAF and vascular endothelial growth factor receptor (VEGFR) but not KIT, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinase 3 (FLT3) are critical for CLL cell viability. Taken together, our data suggest that sorafenib exerts its cytotoxic effect likely via inhibition of the VEGFR and RAF/MEK/ERK pathways, both of which can modulate Mcl-1 expression in CLL cells. Furthermore, sorafenib induced apoptosis of CLL cells from fludarabine refractory patients in the presence of NLCs or MSCs. Our results warrant further clinical exploration of sorafenib in CLL. PMID:21979753

  2. Sorafenib-induced apoptosis of chronic lymphocytic leukemia cells is associated with downregulation of RAF and myeloid cell leukemia sequence 1 (Mcl-1).

    PubMed

    Fecteau, Jessie-F; Bharati, Ila S; O'Hayre, Morgan; Handel, Tracy M; Kipps, Thomas J; Messmer, Davorka

    2012-01-01

    We have previously shown that sorafenib, a multikinase inhibitor, exhibits cytotoxic effects on chronic lymphocytic leukemia (CLL) cells. Because the cellular microenvironment can protect CLL cells from drug-induced apoptosis, it is important to evaluate the effect of novel drugs in this context. Here we characterized the in vitro cytotoxic effects of sorafenib on CLL cells and the underlying mechanism in the presence of marrow stromal cells (MSCs) and nurselike cells (NLCs). One single dose of 10 ?mol/L or the repeated addition of 1 ?mol/L sorafenib caused caspase-dependent apoptosis and reduced levels of phosphorylated B-RAF, C-RAF, extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3) and myeloid cell leukemia sequence 1 (Mcl-1) in CLL cells in the presence of the microenvironment. We show that the RAF/mitogen-activated protein kinase kinase (MEK)/ERK pathway can modulate Mcl-1 expression and contribute to CLL cell viability, thereby associating so-rafenib cytotoxicity to its impact on RAF and Mcl-1. To evaluate if the other targets of sorafenib can affect CLL cell viability and contribute to sorafenib-mediated cytotoxicity, we tested the sensitivity of CLL cells to several kinase inhibitors specific for these targets. Our data show that RAF and vascular endothelial growth factor receptor (VEGFR) but not KIT, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinase 3 (FLT3) are critical for CLL cell viability. Taken together, our data suggest that sorafenib exerts its cytotoxic effect likely via inhibition of the VEGFR and RAF/MEK/ERK pathways, both of which can modulate Mcl-1 expression in CLL cells. Furthermore, sorafenib induced apoptosis of CLL cells from fludarabine refractory patients in the presence of NLCs or MSCs. Our results warrant further clinical exploration of sorafenib in CLL. PMID:21979753

  3. Investigations on the mechanisms of methotrexate resistance in a cisplatin-resistant L1210 murine leukemia cell subline

    Microsoft Academic Search

    Diana H. Wroblewski; Alok Bhushan; Yongzhi Xuan; Bradford T. Brinton; Thomas R. Tritton; Miles P. Hacker

    1996-01-01

    We report a murine leukemia cell variant (L1210\\/DDP), selected for cisplatin (DDP) resistance, to be cross-resistant to methotrexate\\u000a (MTX). Cross-resistance of L1210 cells to DDP and MTX has been observed by others, and has also been recorded in P388 murine\\u000a leukemia and SSC-25 human squamous carcinoma cells. We demonstrated that MTX resistance is not due to dihydrofolate reductase\\u000a (DHFR) gene

  4. Functional genomics of tumor suppressor miR196b in T-cell acute lymphoblastic leukemia

    Microsoft Academic Search

    Suman Bhatia; Deepak Kaul; Neelam Varma

    2011-01-01

    Huge data accumulated in last few years have shown that differential expression of candidate miRNAs in normal versus transformed\\u000a cell provides important insights into the pathogenesis of cancer including leukemias. In our previous report, we have revealed\\u000a that miR-196b was significantly down-regulated in both EB-3 cells as well as B-cell ALL (acute lymphoblastic leukemia) patients\\u000a as compared to their respective

  5. [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. PMID:25195248

  6. Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells.

    PubMed

    Eberhard, Yanina; McDermott, Sean P; Wang, Xiaoming; Gronda, Marcela; Venugopal, Amudha; Wood, Tabitha E; Hurren, Rose; Datti, Alessandro; Batey, Robert A; Wrana, Jeffrey; Antholine, William E; Dick, John E; Dick, John; Schimmer, Aaron D

    2009-10-01

    Off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication. To identify such compounds, we conducted 2 independent cell-based chemical screens and identified the antimicrobial ciclopirox olamine (CPX) in both screens. CPX decreased cell growth and viability of malignant leukemia, myeloma, and solid tumor cell lines as well as primary AML patient samples at low-micromolar concentrations that appear pharmacologically achievable. Furthermore, oral CPX decreased tumor weight and volume in 3 mouse models of leukemia by up to 65% compared with control without evidence of weight loss or gross organ toxicity. In addition, oral CPX prevented the engraftment of primary AML cells in nonobese diabetic/severe combined immunodeficiency mouse models, thereby establishing its ability to target leukemia stem cells. Mechanistically, CPX bound intracellular iron, and this intracellular iron chelation was functionally important for its cytotoxicity. By electron paramagnetic resonance, CPX inhibited the iron-dependent enzyme ribonucleotide reductase at concentrations associated with cell death. Thus, in summary, CPX has previously unrecognized anticancer activity at concentrations that are pharmacologically achievable. Therefore, CPX could be rapidly repurposed for the treatment of malignancies, including leukemia and myeloma. PMID:19589922

  7. 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 NF?B 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

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

    PubMed

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

    2015-05-10

    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 NF?B 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

  9. Resveratrol induces apoptosis of leukemia cell line K562 by modulation of sphingosine kinase-1 pathway

    PubMed Central

    Tian, Hongying; Yu, Zhongcui

    2015-01-01

    To explore the effects of resveratrol in a human myelogenous leukemia cell line K562 and its potential molecular mechanisms. The anti-proliferation effect of resveratrol-induced apoptosis on K562 cells were detected using MTT assay. Western blotting was performed for detecting changes of SphK1 expression in total cell protein and membrane/cytosol protein in K562 cells respectively after exposure to resveratrol. A biochemical assay was used to measure the activity of SphK after treatment of resveratrol, and then S1P and ceramide levels were examined using ELISA kits. Hochest 33258 staining and flow cytometry were applied to detect the apoptosis condition of K562 cells treated with resveratrol. Resveratrol inhibited the proliferation and induced apoptosis in K562 cells in a dose and time-dependent manner. Western blotting revealed that resveratrol did not affect total SphK1 expression level in K562 cells, but significantly changed the translocation of SphK1, the membrane SphK1 was decreased while cytosol SphK1 level was elevated. The activity of SphK1 in resveratrol treated groups was decreased compared to control group with a significant decrease of S1P and increase of ceramide level. Furthermore, Hoechst 33258 staining and Annexin V-FITC analysis confirmed the notable apoptotic effect of resveratrol in its anti-leukemia process. Resveratrol-induced proliferation inhibition of K562 cells might be mediated through its modulation activity of SphK1 pathway by regulating S1P and ceramide levels, which then affected the proliferation and apoptosis process of leukemia cells. SphK1/S1P pathway represents a target of resveratrol in human leukemia.

  10. Prevalence and Characterization of Murine Leukemia Virus Contamination in Human Cell Lines

    PubMed Central

    Uphoff, Cord C.; Lange, Sandra; Denkmann, Sabine A.; Garritsen, Henk S. P.; Drexler, Hans G.

    2015-01-01

    Contaminations of cell cultures with microbiological organisms are well documented and can be managed in cell culture laboratories applying reliable detection, elimination and prevention strategies. However, the presence of viral contaminations in cell cultures is still a matter of debate and cannot be determined with general detection methods. In the present study we screened 577 human cell lines for the presence of murine leukemia viruses (MLV). Nineteen cell lines were found to be contaminated with MLV, including 22RV1 which is contaminated with the xenotropic murine leukemia virus-related virus variant of MLV. Of these, 17 cell lines were shown to produce active retroviruses determined by product enhanced reverse transcriptase PCR assay for reverse transcriptase activity. The contaminated cell lines derive from various solid tumor types as well as from leukemia and lymphoma types. A contamination of primary human cells from healthy volunteers could not be substantiated. Sequence analyses of 17 MLV PCR products and five complete MLV genomes of different infected cell lines revealed at least three groups of related MLV genotypes. The viruses harvested from the supernatants of infected cell cultures were infectious to uninfected cell cultures. In the course of the study we found that contamination of human genomic DNA preparations with murine DNA can lead to false-positive results. Presumably, xenotransplantations of the human tumor cells into immune-deficient mice to determine the tumorigenicity of the cells are mainly responsible for the MLV contaminations. Furthermore, the use of murine feeder layer cells during the establishment of human cell lines and a cross-contamination with MLV from infected cultures might be sources of infection. A screening of cell cultures for MLV contamination is recommended given a contamination rate of 3.3%. PMID:25927683

  11. Antitumor effects of a monoclonal antibody to human CCR9 in leukemia cell xenografts

    PubMed Central

    Chamorro, Sonia; Vela, Maria; Franco-Villanueva, Ana; Carramolino, Laura; Gutiérrez, Julio; Gómez, Lucio; Lozano, María; Salvador, Beatriz; García-Gallo, Mónica; Martínez-A, Carlos; Kremer, Leonor

    2014-01-01

    Tumor expression of certain chemokine receptors is associated with resistance to apoptosis, migration, invasiveness and metastasis. Because CCR9 chemokine receptor expression is very restricted in healthy tissue, whereas it is present in tumors of distinct origins including leukemias, melanomas, prostate and ovary carcinomas, it can be considered a suitable candidate for target-directed therapy. Here, we report the generation and characterization of 91R, a mouse anti-human CCR9 IgG2b monoclonal antibody that recognizes an epitope within the CCR9 N-terminal domain. This antibody inhibits the growth of subcutaneous xenografts from human acute T lymphoblastic leukemia MOLT-4 cells in immunodeficient Rag2?/? mice. Tumor size in 91R-treated mice was reduced by 85% compared with isotype-matched antibody-treated controls. Tumor reduction in 91R-treated mice was concomitant with an increase in the apoptotic cell fraction and tumor necrotic areas, as well as a decrease in the fraction of proliferating cells and in tumor vascularization. In the presence of complement or murine natural killer cells, 91R promoted in vitro lysis of MOLT-4 leukemia cells, indicating that this antibody might eliminate tumor cells via complement- and cell-dependent cytotoxicity. The results show the potential of the 91R monoclonal antibody as a therapeutic agent for treatment of CCR9-expressing tumors. PMID:24870448

  12. The presence of mature granulocytes/monocytes derived from leukemic cells in MLL-associated leukemia.

    PubMed

    Kobayashi, Shoichi; Obata, Masato; Hagihara, Maki; Motohashi, Kenji; Ito, Satomi; Ohshima, Rika; Sakai, Rika; Maruta, Atsuo; Kanamori, Heiwa

    2009-12-01

    We observed the mature granulocytes/monocytes derived from leukemic cells in patients with acute myeloid leukemia who present mixed lineage leukemia gene (MLL). Morphologic observation and fluorescence in situ hybridization analysis (FISH) for chromosome 11q23 abnormality were studied, and a multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was done to identify the fusion partners with MLL. The bone marrow cells with FISH signals of MLL showed the cell differentiation of the myeloid and/or monocytic lineages in 4 of 6 AML patients. MLL partner genes were AF6, AF9, ELL, and ENL, respectively. There was no correlation between the fusion partner and the appearance of mature cells derived from MLL clones. RT-PCR showed the fusion between MLL exon 9 or 10 and the partner genes in mature granulocytes/monocytes. These findings suggest that subgroup of leukemia cells with MLL rearrangement has the differentiation potential of leukemic cells and mature granulocytes/monocytes derived from MLL clones may be biologically different from normal mature cells. PMID:19936877

  13. Telomerase-negative Immortalized Human Cells Contain a Novel Type of Promyelocytic Leukemia (PML) Body1

    Microsoft Academic Search

    Thomas R. Yeager; Axel A. Neumann; Anna Englezou; Lily I. Huschtscha; Jane R. Noble; Roger R. Reddel

    Telomerase-negative immortalized human cells maintain their tel- omeres by a mechanism known as alternative lengthening of telomeres (ALT). We report here that ALT cells contain a novel promyelocytic leukemia (PML) body (ALT-associated PML body, APB). APBs are large donut-shaped nuclear structures containing PML protein, telomeric DNA, and the telomere binding proteins human telomere repeat binding factors 1 and 2. Immunostaining

  14. ZAP70 Protein Expression and CD38 Positivity in B-cell Chronic Lymphocytic Leukemia

    Microsoft Academic Search

    Marjan Ertault-Daneshpouy; Maria Elena Noguera; Christian Gisselbrecht; Albert Haddad; Pauline Brice; Jean-Pierre Marolleau; Jean Soulier; Nicolas Mounier

    2008-01-01

    Background: The clinical course, disease progression, and survival of B-cell chronic lymphocytic leukemia (B-CLL) have been corre- lated with immunoglobulin heavy-chain variable region mutation status. The biologic parameters 70-kDa zeta-associated protein (ZAP-70) and CD38 expression are easier and faster surrogate markers for mutational status. Objective: To assess retrospectively ZAP-70 expression in B-CLL cells using flow cytometry and examine its relationship

  15. A fibronectin fragment induces tumor necrosis factor production of rat basophilic leukemia cells

    Microsoft Academic Search

    Sadahiro Kamiya; Tatsuya Kawaguchi; Shinobu Hasebe; Naoko Kamiya; Yohei Saito; Shogo Miura; Seiki Wada; Hirofumi Yajima; Takashi Katayama; Fumio Fukai

    2004-01-01

    Proteolytic digest of fibronectin (FN), but not intact FN, induced TNF-? secretion of rat basophilic leukemia (RBL-2H3) cells. As a result of the identification of FN fragment responsible for TNF-? secretion, a 30-kDa fragment derived from the carboxyl-terminal heparin-binding (Hep 2) domain of FN was isolated from the FN digest. The TNF-? secretion was abrogated by treatment of RBL-2H3 cells

  16. Natural killer (NK) cell immunodeficiency in patients with chronic myelogenous leukemia

    Microsoft Academic Search

    Yoshiaki Fujimiya I; Weng-Cheng Chang; Anthony Bakke; David Horwitz; Paul K. Pattengale

    1987-01-01

    Defective natural killer (NK) cell populations from patients with chronic myelogenous leukemia (CML), that reacted with both HNK-1+ and B73.1+ antibodies, were obtained by a flluorescence-activated cell sorter (FACS). These fractions, along with NK fractions from normal donors which reacted with both antibodies, were expanded as bulk cultures or clones by limiting dilution, for 4 weeks in the presence of

  17. Disseminated Strongyloides stercoralis Infection in HTLV1Associated Adult T-Cell Leukemia\\/Lymphoma

    Microsoft Academic Search

    Donn M. Stewart; Roshan Ramanathan; Siddhartha Mahanty; Daniel P. Fedorko; John E. Janik; John C. Morris

    2011-01-01

    A 55-year-old woman with human T-cell lymphotropic virus type-1 (HTLV-1)-associated adult T-cell leukemia (ATL) and a history of previously treated Strongyloides stercoralis infection received anti-CD52 monoclonal antibody therapy with alemtuzumab on a clinical trial. After an initial response, she developed ocular involvement by ATL. Alemtuzumab was stopped and high-dose corticosteroid therapy was started to palliate her ocular symptoms. Ten days

  18. Binding Kinetics of Ecotropic (Moloney) Murine Leukemia Retrovirus with NIH 3T3 Cells

    Microsoft Academic Search

    HONG YU; FRENCH ANDERSON

    1995-01-01

    A quantitative analysis of the binding kinetics of intact Moloney murine leukemia retrovirus (MoMuLV) particles with NIH 3T3 cells was performed with an immunofluorescenceflow cytometry assay. The virus-cell binding equilibrium dissociation constant (KD), expressed in terms of virus particle concentration, was measured to be 8.5 (66.4) 310 212 Mat4 &C and was three- to sixfold lower at temperatures above 15&C.

  19. Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells

    Microsoft Academic Search

    Min-Liang Kuo; Tze-Sing Huang

    1996-01-01

    Curcumin, widely used as a spice and coloring agent in food, possesses potent antioxidant, anti-inflammatory and anti-tumor promoting activities. In the present study, curcumin was found to induce apoptotic cell death in promyelocytic leukemia HL-60 cells at concentrations as low as 3.5 ?g\\/ml. The apoptosis-inducing activity of curcumin appeared in a dose- and time-dependent manner. Flow cytometric analysis showed that

  20. Electron microscopy localization and characterization of functionalized composite organic-inorganic SERS nanoparticles on leukemia cells

    Microsoft Academic Search

    Ai Leen Koh; Catherine M. Shachaf; Sailaja Elchuri; Garry P. Nolan; Robert Sinclair

    2008-01-01

    We demonstrate the use of electron microscopy as a powerful characterization tool to identify and locate antibody-conjugated composite organic-inorganic nanoparticle (COINs) surface enhanced Raman scattering (SERS) nanoparticles on cells. U937 leukemia cells labeled with antibody CD54-conjugated COINs were characterized in their native, hydrated state using wet scanning electron microscopy (SEM) and in their dehydrated state using high-resolution SEM. In both

  1. 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

    2015-06-19

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

  2. 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

  3. Novel insights into the development of T-cell acute lymphoblastic leukemia

    Microsoft Academic Search

    Frank J. T. Staal; Jacques J. M. van Dongen; Anton W. Langerak

    2007-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) results from malignant transformation of immature cells of the T-cell lineage.\\u000a T-ALL is a heterogeneous disease both clinically and genetically. It is generally accepted that T-ALL cells are the malignant\\u000a counterpart of normally developing T cells in the thymus (thymocytes). Recent data using genome-wide gene expression profiling\\u000a and assessment of the rearrangement status of the

  4. Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells

    SciTech Connect

    Okabe, Seiichi, E-mail: okabe@tokyo-med.ac.jp; Tauchi, Tetsuzo; Tanaka, Yuko; Ohyashiki, Kazuma

    2013-06-07

    Highlights: •Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells okabe et al. •Imatinib or nilotinib resistance was involved Src family kinase. •The BCR-ABL point mutation (E334V) was highly resistant to imatinib or nilotinib. •Ponatinib was a powerful strategy against imatinib or nilotinib resistant Ph-positive cells. -- Abstract: Because a substantial number of patients with chronic myeloid leukemia acquire resistance to ABL tyrosine kinase inhibitors (TKIs), their management remains a challenge. Ponatinib, also known as AP24534, is an oral multi-targeted TKI. Ponatinib is currently being investigated in a pivotal phase 2 clinical trial. In the present study, we analyzed the molecular and functional consequences of ponatinib against imatinib- or nilotinib-resistant (R) K562 and Ba/F3 cells. The proliferation of imatinib- or nilotinib-resistant K562 cells did not decrease after treatment with imatinib or nilotinib. Src family kinase Lyn was activated. Point mutation Ba/F3 cells (E334 V) were also highly resistant to imatinib and nilotinib. Treatment with ponatinib for 72 h inhibited the growth of imatinib- and nilotinib-resistant cells. The phosphorylation of BCR-ABL, Lyn, and Crk-L was reduced. This study demonstrates that ponatinib has an anti-leukemia effect by reducing ABL and Lyn kinase activity and this information may be of therapeutic relevance.

  5. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    SciTech Connect

    Waters, Katrina M. [Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Sontag, Ryan L. [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Weber, Thomas J., E-mail: Thomas.Weber@pnl.gov [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States)

    2013-04-15

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ? Circadian-dependent physiological variation impacts therapeutic efficacy. ? Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ? Hepatic leukemia factor anti-death program is conserved in murine and human cells. ? Transcriptomics indicates the anti-death program results from a systems response.

  6. PCFT/SLC46A1 promoter methylation and restoration of gene expression in human leukemia cells

    SciTech Connect

    Gonen, Nitzan; Bram, Eran E. [Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel); Assaraf, Yehuda G. [Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel)], E-mail: assaraf@tx.technion.ac.il

    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. 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. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 803-815, 2015. PMID:24474168

  8. Bryostatin 5 induces apoptosis in acute monocytic leukemia cells by activating PUMA and caspases.

    PubMed

    Wang, Yiwei; Zhang, Jinbao; Wang, Qixia; Zhang, Tao; Yang, Yang; Yi, Yanghua; Gao, Guangxun; Dong, Hongjuan; Zhu, Huafeng; Li, Yue; Lin, Houwen; Tang, Haifeng; Chen, Xiequn

    2013-10-15

    Acute leukemia is a malignant clonal hematopoietic stem cell disease. In the current study, we examined the effects of bryostatin 5 on acute monocytic leukemia cells in vitro and in vivo. We also explored the mechanisms and pathways underlying the increase in apoptosis induced by bryostatin 5. Bryostatin 5 inhibited the growth of primary acute monocytic leukemia cells and U937 cells in a dose- and time-dependent manners. Bryostatin 5 also induced an increase in apoptosis and a decrease in the mitochondrial membrane potential (MMP) in U937 cells. Transmission electron microscopy (TEM) revealed that bryostatin 5-treated cells displayed typical apoptotic characteristics (chromatin condensation, karyopyknosis and formation of crescents and apoptotic bodies). In addition, bryostatin 5 increased the expression of P53 upregulated modulator of apoptosis (PUMA) and slightly increased P53 expression. Bryostatin 5 also significantly decreased Bcl-XL expression and significantly increased the expression levels of Bak, Bax, cleaved caspase 9 and cleaved caspase 3. The pro-apoptotic activity of bryostatin 5 in U937 cells was inhibited by PUMA siRNA and z-LEHD-fmk (a specific caspase 9 inhibitor). In addition, the PUMA siRNA significantly affected the expression of cleaved caspase 9, whereas z-LEHD-fmk had little effect on the expression of PUMA. The results suggest that PUMA is located upstream of caspase 9 in this apoptotic signaling pathway. These novel findings provide mechanistic insight into the induction of apoptosis by bryostatin 5 and might facilitate the development of clinical strategies to enhance the therapeutic efficacy of treatments for acute monocytic leukemia. PMID:24036350

  9. Human Promyelocytic Leukemia Cells in Culture Differentiate into Macrophage-Like Cells when Treated with a Phorbol Diester

    Microsoft Academic Search

    Giovanni Rovera; Daniela Santoli; Caroline Damsky

    1979-01-01

    When suspension cultures of human promyelocytic leukemia cells (line HL60) were treated with 12-O-tetradecanoylphorbol 13-acetate (TPA; 1.6-160 nM), more than 80% of the cells adhered to the plastic substrate within 24 hr. Within the same time period the immature azurophilic granulations typical of HL60 promyelocytic cells disappeared and the nuclear chromatin became more condensed, but the nucleolus was retained. The

  10. Cell differentiation and altered IMP dehydrogenase expression induced in human T-lymphoblastoid leukemia cells by mycophenolic acid and tiazofurin

    Microsoft Academic Search

    K. Kiguchi; F. R. Collart; C. Henning-Chubb; E. Huberman

    1990-01-01

    The IMP dehydrogenase inhibitors mycophenolic acid (MPA) and tiazofurin (TZ) induce a time- and dose-dependent inhibition of cell growth, as well as differentiation in T-lymphoid CEM-2 leukemia cells. The differentiated cells have acquired a suppressor\\/cytotoxic T-lymphocyte phenotype characterized by reactivity with maturation-specific monoclonal antibodies. Coadministration of guanosine and hypoxanthine reduces the growth inhibition and diminishes the induction of differentiation by

  11. Targeting signaling pathways in T-cell acute lymphoblastic leukemia initiating cells.

    PubMed

    Martelli, Alberto M; Lonetti, Annalisa; Buontempo, Francesca; Ricci, Francesca; Tazzari, Pier Luigi; Evangelisti, Camilla; Bressanin, Daniela; Cappellini, Alessandra; Orsini, Ester; Chiarini, Francesca

    2014-09-01

    Leukemia initiating cells (LICs) represent a reservoir that is believed to drive relapse and resistance to chemotherapy in blood malignant disorders. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder of immature hematopoietic precursors committed to the T-cell lineage. T-ALL comprises about 15% of pediatric and 25% of adult ALL cases and is prone to early relapse. Although the prognosis of T-ALL has improved especially in children due to the use of new intensified treatment protocols, the outcome of relapsed T-ALL cases is still poor. Putative LICs have been identified also in T-ALL. LICs are mostly quiescent and for this reason highly resistant to chemotherapy. Therefore, they evade treatment and give rise to disease relapse. At present great interest surrounds the development of targeted therapies against signaling networks aberrantly activated in LICs and important for their survival and drug-resistance. Both the Notch1 pathway and the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) network are involved in T-ALL LIC survival and drug-resistance and could be targeted by small molecules. Thus, Notch1 and PI3K/Akt/mTOR inhibitors are currently being developed for clinical use either as single agents or in combination with conventional chemotherapy for T-ALL patient treatment. In this review, we summarize the existing knowledge of the relevance of Notch1 and PI3K/Akt/mTOR signaling in T-ALL LICs and we examine the rationale for targeting these key signal transduction networks by means of selective pharmacological inhibitors. PMID:24819383

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

    E-print Network

    Sanda, Takaomi

    The oncogenic transcription factor TAL1/SCL is aberrantly expressed in over 40% of cases of human T cell acute lymphoblastic leukemia (T-ALL), emphasizing its importance in the molecular pathogenesis of T-ALL. Here we ...

  13. Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-01-29

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 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); Recurrent Adult Acute Myeloid Leukemia

  14. Incidence of adult T-cell leukemia/lymphoma in nonendemic areas.

    PubMed

    Yoshida, Noriaki; Chihara, Dai

    2015-02-01

    Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm with extremely poor prognosis caused by human T-cell leukemia virus type 1 (HTLV-1). The distribution of HTLV-1 and the incidence of ATLL in endemic areas have been well described, however, little is known about the incidences and the trends of the disease in nonendemic areas. Recently, studies have shown that the HTLV-1 carriers are increasing in nonendemic areas. Also, the incidence of ATLL seems to be significantly increasing in nonendemic areas suggesting that HTLV-1 carriers have emigrated from endemic areas. These epidemiologic studies indicate the necessity of edification of the disease caused by HTLV-1 and establishing appropriate preventive methods against infection in nonendemic areas. PMID:25762122

  15. Cell cycle-dependent expression of a hairy and Enhancer of split (hes) homolog during cleavage and segmentation in leech embryos

    E-print Network

    Weisblat, David A.

    and segmentation in leech embryos Mi Hye Song,1 Franc¸oise Z. Huang, Foster C. Gonsalves, and David A. Weisblat related to hairy and Enhancer of split (hes) from glossiphoniid leeches, Helobdella robusta and Theromyzon rude. In leech, segments arise sequentially in anteroposterior progression from a posterior growth zone

  16. Human NK Cells: From Surface Receptors to the Therapy of Leukemias and Solid Tumors

    PubMed Central

    Moretta, Lorenzo; Pietra, Gabriella; Montaldo, Elisa; Vacca, Paola; Pende, Daniela; Falco, Michela; Del Zotto, Genny; Locatelli, Franco; Moretta, Alessandro; Mingari, Maria Cristina

    2014-01-01

    Natural Killer (NK) cells are major effector cells of the innate immunity. The discovery, over two decades ago, of major histocompatibility complex-class I-specific inhibitory NK receptors and subsequently of activating receptors, recognizing ligands expressed by tumor or virus-infected cells, paved the way to our understanding of the mechanisms of selective recognition and killing of tumor cells. Although NK cells can efficiently kill tumor cells of different histotypes in vitro, their activity may be limited in vivo by their inefficient trafficking to tumor lesions and by the inhibition of their function induced by tumor cells themselves and by the tumor microenvironment. On the other hand, the important role of NK cells has been clearly demonstrated in the therapy of high risk leukemias in the haploidentical hematopoietic stem cell (HSC) transplantation setting. NK cells derived from donor HSC kill leukemic cells residual after the conditioning regimen, thus preventing leukemia relapses. In addition, they also kill residual dendritic cells and T lymphocytes, thus preventing both GvH disease and graft rejection. PMID:24639677

  17. MicroRNAs and B cell receptor signaling in chronic lymphocytic leukemia.

    PubMed

    Mraz, Marek; Kipps, Thomas J

    2013-08-01

    The relative expression levels of certain microRNAs (miRNAs) correlate with known prognostic markers in chronic lymphocytic leukemia (CLL), such as leukemia-cell expression of zeta-associated protein of 70 kDa (ZAP-70), use of unmutated immunoglobulin heavy-chain variable region genes (IGHV), chromosomal abnormalities or dysfunctional p53. Here we review studies that provide evidence suggesting that certain miRNAs (e.g. miR-155, miR-17-92, miR-181, miR-29) can regulate the activated phenotype of CLL cells and/or fitness of the surface-immunoglobulin (sIg) B cell receptor (BCR) complex expressed by CLL cells, thereby accounting for the differential leukemia-cell expression of these miRNAs in different CLL prognostic subgroups. How these miRNAs influence cellular activation and/or BCR signaling through the post-transcriptional regulation of critical signaling molecules (e.g. Lyn, Syk, BTK, SHIP-1, SHP1) is a topic of current research. PMID:23597135

  18. MicroRNAs and B cell receptor signaling in chronic lymphocytic leukemia

    PubMed Central

    Mraz, Marek; Kipps, Thomas J.

    2014-01-01

    The relative expression levels of certain microRNAs (miRNAs) correlate with known prognostic markers in chronic lymphocytic leukemia (CLL), such as leukemia-cell expression of zeta-associated protein of 70 kDa (ZAP-70), use of unmutated immunoglobulin heavy-chain variable region genes (IGHV), chromosomal abnormalities or dysfunctional p53. Here we review studies that provide evidence suggesting that certain miRNAs (e.g. miR-155, miR-17-92, miR-181, miR-29) can regulate the activated phenotype of CLL cells and/or fitness of the surface-immunoglobulin (sIg) B cell receptor (BCR) complex expressed by CLL cells, thereby accounting for the differential leukemia-cell expression of these miRNAs in different CLL prognostic subgroups. How these miRNAs influence cellular activation and/or BCR signaling through the post-transcriptional regulation of critical signaling molecules (e.g. Lyn, Syk, BTK, SHIP-1, SHP1) is a topic of current research. PMID:23597135

  19. Myeloid cell leukemia-1 promotes epithelial-mesenchymal transition of human gastric cancer cells.

    PubMed

    Lee, Wan-Sik; Kim, Nuri; Park, Young-Ran; Oh, Hyung-Hoon; Myung, Eun; Kim, Seung-Hun; Yu, Hyung-Min; Kim, Mi-Young; Oak, Chan-Young; Chung, Cho-Yun; Park, Hyung-Chul; Myung, Dae-Seong; Cho, Sung-Bum; Joo, Young-Eun

    2015-08-01

    Epithelial-mesenchymal transition (EMT) is a critical process that occurs during cancer progression, and cancer stem cells have been shown to acquire the EMT phenotype. Myeloid cell leukemia-1 (Mcl-1) has been implicated in cancer progression and is overexpressed in a variety of human cancers. However, the interaction between Mcl-1 and EMT in human gastric cancer (GC) is unclear. We investigated the impact of Mcl-1 expression levels on EMT and the underlying signaling pathways in human GC cells. We used the human GC cell lines, AGS and SNU638, and small interfering RNAs (siRNAs) to evaluate the effects of Mcl-1 knockdown on cell adhesion, migration and invasion. Expression of Mcl-1 and other target genes was determined using reverse transcription?polymerase chain reaction assays and western blotting. The results revealed that expression levels of Mcl-1 mRNA and protein in the AGS and SNU638 cells were reduced following transfection with Mcl-1 siRNAs. Knockdown of Mcl-1 led to increased cellular adhesion to fibronectin and collagen. Expression levels of vimentin, MMP-2, MMP-9 and Snail protein were decreased following knockdown of Mcl-1. However, expression of E-cadherin was increased in the AGS cells following knockdown of Mcl-1. The expression of cancer stemness markers, such as CD44 and CD133, was not altered by knockdown of Mcl-1. Knockdown of Mcl-1 suppressed tumor cell migration and invasion in both human GC cell lines. Signaling cascades, including the ?-catenin, MEK1/2, ERK1/2 and p38 pathways, were significantly blocked by knockdown of Mcl-1. Our results indicate that Mcl-1 expression induces EMT via ?-catenin, MEK1/2 and MAPK signaling pathways, which subsequently stimulates the invasive and migratory capacity of human GC cells. PMID:26058661

  20. Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor-resistant acute myeloid leukemia cells

    Microsoft Academic Search

    Warren Fiskus; Rekha Rao; Pravina Fernandez; Bryan Herger; Yonghua Yang; Jianguang Chen; Ravindra Kolhe; Aditya Mandawat; Yongchao Wang; Rajeshree Joshi; Kelly Eaton; Pearl Lee; Peter Atadja; Stephen Peiper; Kapil Bhalla

    2008-01-01

    Hydroxamic acid analog pan-histone deacetylase (HDAC) inhibitors (HA-HDIs) have shown preclinical and clinical activ- ity against human acute leukemia. Here we describe HA-HDI-resistant human acute myeloid leukemia (AML) HL-60 (HL- 60\\/LR) cells that are resistant to LAQ824, vorinostat, LBH589, and sodium butyrate. HL-60\\/LR cells show increased expres- sion of HDACs 1, 2, and 4 but lack HDAC6 expression, with concomitant

  1. Amplified C lambda and c-abl genes are on the same marker chromosome in K562 leukemia cells.

    PubMed Central

    Selden, J R; Emanuel, B S; Wang, E; Cannizzaro, L; Palumbo, A; Erikson, J; Nowell, P C; Rovera, G; Croce, C M

    1983-01-01

    The human leukemia cell line K562, derived from a patient with Philadelphia chromosome-positive chronic myelogenous leukemia, contains amplified c-abl oncogenes and unrearranged C lambda genes. Using in situ hybridization techniques, we have determined that the amplified c-abl and C lambda DNA sequences of K562 cells are both located on the same abnormal acrocentric marker chromosome, which may represent an altered Philadelphia chromosome. Images PMID:6580644

  2. Regulatory T-cells in chronic lymphocytic leukemia: actor or innocent bystander?

    PubMed Central

    D’Arena, Giovanni; Simeon, Vittorio; D’Auria, Fiorella; Statuto, Teodora; Sanzo, Paola Di; Martino, Laura De; Marandino, Aurelio; Sangiorgio, Michele; Musto, Pellegrino; Feo, Vincenzo De

    2013-01-01

    Regulatory T (Treg) cells are now under extensive investigation in chronic lymphocytic leukemia (CLL). This small subset of T-cells has been, in fact, considered to be involved in the pathogenesis and progression of CLL. However, whether Treg dysregulation in CLL plays a key role or it rather represents a simple epiphenomenon is still matter of debate. In the former case, Treg cells could be appealing for targeting therapies. Finally, Treg cells have also been proposed as a prognostic indicator of the disease clinical course. PMID:23358515

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

    PubMed Central

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

    2008-01-01

    Multiple lymphomatous polyposis (MLP) is an unusual form of non-Hodgkin’s lymphoma characterized by polyps throughout the gastrointestinal tract. It has been reported that most MLP are observed in cases with mantle cell lymphoma of B-cell type. We herein present a case of a 66-year-old man with adult T-cell leukemia/lymphoma (ATLL). Colonoscopy revealed MLP throughout the colon and histopathological findings of ATLL cell infiltration. The patient died despite combination of chemotherapy. The literature of manifestations of colonic involvement of ATLL is reviewed and the importance of endoscopic evaluation to differentiate ATLL intestinal lesions from opportunistic infectious enterocolitis is discussed. PMID:19030219

  4. 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. PMID:17882653

  5. Inhibition of the checkpoint kinase Chk1 induces DNA damage and cell death in human Leukemia and Lymphoma cells

    PubMed Central

    2014-01-01

    Background Chk1 forms a core component of the DNA damage response and small molecule inhibitors are currently being investigated in the clinic as cytotoxic chemotherapy potentiators. Recent evidence suggests that Chk1 inhibitors may demonstrate significant single agent activity in tumors with specific DNA repair defects, a constitutively activated DNA damage response or oncogene induced replicative stress. Methods Growth inhibition induced by the small molecule Chk1 inhibitor V158411 was assessed in a panel of human leukemia and lymphoma cell lines and compared to cancer cell lines derived from solid tumors. The effects on cell cycle and DNA damage response markers were further evaluated. Results Leukemia and lymphoma cell lines were identified as particularly sensitive to the Chk1 inhibitor V158411 (mean GI50 0.17 ?M) compared to colon (2.8 ?M) or lung (6.9 ?M) cancer cell lines. Chk1 inhibition by V158411 in the leukemia and lymphoma cell lines induced DNA fragmentation and cell death that was both caspase dependent and independent, and prevented cells undergoing mitosis. An analysis of in vitro pharmacodynamic markers identified a dose dependent decrease in Chk1 and cyclin B1 protein levels and Cdc2 Thr15 phosphorylation along with a concomitant increase in H2AX phosphorylation at Ser139 following V158411 treatment. Conclusions These data support the further evaluation of Chk1 inhibitors in hematopoietic cancers as single agents as well as in combination with standard of care cytotoxic drugs. PMID:24913641

  6. Organ-specific microenvironment modifies diverse functional and phenotypic characteristics of leukemia-associated macrophages in mouse T cell acute lymphoblastic leukemia.

    PubMed

    Chen, Sha-Yan; Yang, Xiao; Feng, Wen-Li; Liao, Jin-Feng; Wang, Li-Na; Feng, Li; Lin, Yong-Min; Ren, Qian; Zheng, Guo-Guang

    2015-03-15

    Tumor-associated macrophages are widely studied in solid tumors. The distribution of macrophages in lymph node samples was found to be associated with the prognosis of lymphoma patients. However, the role of macrophages in leukemia and their functional and phenotypic characteristics in hematopoietic malignancies have not been defined. In this study, we examined the distribution and functional and phenotypic characteristics of macrophages in a Notch1-induced mouse model of T cell acute lymphoblastic leukemia (T-ALL). The distribution of macrophages in bone marrow (BM) and spleen, which are proposed as BM and spleen leukemia-associated macrophages (LAMs), were different during the development of leukemia. LAMs stimulated the proliferation of T-ALL cells and had higher migration activity. RNA-sequencing analysis revealed that gene expression profiles of BM and spleen LAMs showed considerable differences. RT-PCR analysis showed that LAMs expressed both M1- and M2-associated phenotypic genes, but they expressed much lower levels of TGF-?1, VEGF-A, and CSF-1 than did tumor-associated macrophages from B16 melanoma. Furthermore, spleen LAMs more potently stimulated the proliferation of T-ALL cells compared with BM LAMs. Moreover, LAMs could be subdivided into M1-like (CD206(-)) and M2-like (CD206(+)) groups. Both CD206(+) and CD206(-) LAMs stimulated the proliferation of T-ALL cells, although CD206(+) LAMs expressed higher levels of most M1- and M2-associated genes. These results suggested the functional and phenotypic characteristics of LAMs, which were modified by organ specific microenvironments. Our results broaden our knowledge about macrophages in malignant microenvironments from solid tumors to leukemia. PMID:25662994

  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. Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia

    PubMed Central

    Kukreja, Manisha; Wang, Tao; Giralt, Sergio A.; Szer, Jeffrey; Arora, Mukta; Woolfrey, Ann E.; Cervantes, Francisco; Champlin, Richard E.; Gale, Robert Peter; Halter, Joerg; Keating, Armand; Marks, David I.; McCarthy, Philip L.; Olavarria, Eduardo; Stadtmauer, Edward A.; Abecasis, Manuel; Gupta, Vikas; Khoury, H. Jean; George, Biju; Hale, Gregory A.; Liesveld, Jane L.; Rizzieri, David A.; Antin, Joseph H.; Bolwell, Brian J.; Carabasi, Matthew H.; Copelan, Edward; Ilhan, Osman; Litzow, Mark R.; Schouten, Harold C.; Zander, Axel R.; Horowitz, Mary M.; Maziarz, Richard T.

    2008-01-01

    Imatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM+) and 900 subjects who did not receive IM before HCT (IM?) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM+ and IM? groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT. PMID:18664621

  9. Measurement of minimal residual disease before and after myeloablative hematopoietic cell transplantation for acute leukemia.

    PubMed

    Appelbaum, Frederick R

    2013-09-01

    Multiparameter flow cytometry (MFC) can identify leukemia-associated immunophenotypes in more than 90% of cases of acute leukemia with detection limits of 10(-3)-10(-4). In order to better understand the potential utility of MFC to measure minimal residual disease (MRD) in the setting of myeloablative hematopoietic cell transplantation (HCT), we studied cohorts of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in complete remission (CR) both pre- and post-HCT. Among 253 patients with AML, the 3-year estimates of overall survival were 73% (CR1) and 73% (CR2) for those who were MRD(neg) and 32% (CR1) and 44% (CR2) for those who were MRD(pos), with relapse rates being more than doubled in those who were MRD(pos) pre-HCT (21% vs 58% for CR1 patients and 19% vs 68% for CR2 patients). The presence of MRD anytime during the first 100 days post-HCT predicted a 6-fold higher risk of subsequent relapse. In 157 patients with ALL, the 3-year overall survivals were 68% for the MRD(neg) cohort vs 40% for those who were MRD(pos) pre-HCT, with probabilities of relapse of 16% in those who were MRD(neg) vs 33% in the MRD(pos) group. As in AML, the presence of MRD in the post-transplant setting indicated that the risk of subsequent relapse was high, but not inevitable. PMID:24309531

  10. Diversity and Complexity of Ceramide Generation After Exposure of Jurkat Leukemia Cells to Irradiation

    SciTech Connect

    Ardail, Dominique [Laboratoire de Radiobiologie Cellulaire et Moleculaire, Faculte de Medecine Lyon-Sud, Universite Lyon 1, Universite de Lyon, Oullins (France)], E-mail: ardail@sante.univ-lyon1.fr; Maalouf, Mira; Boivin, Anthony [Laboratoire de Radiobiologie Cellulaire et Moleculaire, Faculte de Medecine Lyon-Sud, Universite Lyon 1, Universite de Lyon, Oullins (France); Chapet, Olivier [Service de Radiotherapie, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Benite (France); Bodennec, Jacques; Rousson, Robert [Laboratoire de Radiobiologie Cellulaire et Moleculaire, Faculte de Medecine Lyon-Sud, Universite Lyon 1, Universite de Lyon, Oullins (France); Rodriguez-Lafrasse, Claire [Laboratoire de Radiobiologie Cellulaire et Moleculaire, Faculte de Medecine Lyon-Sud, Universite Lyon 1, Universite de Lyon, Oullins (France); Service de Biologie des Tumeurs, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Benite (France)

    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.

  11. 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. PMID:24262935

  12. An epigenetic mechanism of resistance to targeted therapy in T-cell acute lymphoblastic leukemia

    PubMed Central

    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.

    2014-01-01

    The identification of activating NOTCH1 mutations in T-cell acute lymphoblastic leukemia (T-ALL) led to clinical testing of ?-secretase inhibitors (GSI) that prevent NOTCH1 activation1–3. However, responses have been transient4,5, suggesting that resistance limits clinical efficacy. Here we modeled T-ALL resistance, identifying GSI-tolerant ‘persister’ cells that expand in the absence of NOTCH signaling. Rare persisters are already present in naïve T-ALL populations, and the reversibility of the phenotype suggests an epigenetic mechanism. Relative to GSI-sensitive cells, persisters 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 down-regulates these targets and induces growth arrest and apoptosis in persisters, 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. PMID:24584072

  13. Quantitative Phenotyping-Based In Vivo Chemical Screening in a Zebrafish Model of Leukemia Stem Cell Xenotransplantation

    PubMed Central

    Zhang, Beibei; Shimada, Yasuhito; Kuroyanagi, Junya; Umemoto, Noriko; Nishimura, Yuhei; Tanaka, Toshio

    2014-01-01

    Zebrafish-based chemical screening has recently emerged as a rapid and efficient method to identify important compounds that modulate specific biological processes and to test the therapeutic efficacy in disease models, including cancer. In leukemia, the ablation of leukemia stem cells (LSCs) is necessary to permanently eradicate the leukemia cell population. However, because of the very small number of LSCs in leukemia cell populations, their use in xenotransplantation studies (in vivo) and the difficulties in functionally and pathophysiologically replicating clinical conditions in cell culture experiments (in vitro), the progress of drug discovery for LSC inhibitors has been painfully slow. In this study, we developed a novel phenotype-based in vivo screening method using LSCs xenotransplanted into zebrafish. Aldehyde dehydrogenase-positive (ALDH+) cells were purified from chronic myelogenous leukemia K562 cells tagged with a fluorescent protein (Kusabira-orange) and then implanted in young zebrafish at 48 hours post-fertilization. Twenty-four hours after transplantation, the animals were treated with one of eight different therapeutic agents (imatinib, dasatinib, parthenolide, TDZD-8, arsenic trioxide, niclosamide, salinomycin, and thioridazine). Cancer cell proliferation, and cell migration were determined by high-content imaging. Of the eight compounds that were tested, all except imatinib and dasatinib selectively inhibited ALDH+ cell proliferation in zebrafish. In addition, these anti-LSC agents suppressed tumor cell migration in LSC-xenotransplants. Our approach offers a simple, rapid, and reliable in vivo screening system that facilitates the phenotype-driven discovery of drugs effective in suppressing LSCs. PMID:24454867

  14. Polymeric nanoparticle-mediated silencing of CD44 receptor in CD34+ acute myeloid leukemia cells.

    PubMed

    Gul-Uluda?, Hilal; Valencia-Serna, Juliana; Kucharski, Cezary; Marquez-Curtis, Leah A; Jiang, Xiaoyan; Larratt, Loree; Janowska-Wieczorek, Anna; Uluda?, Hasan

    2014-11-01

    The adhesion receptor CD44 plays an important role in the survival and retention of leukemic stem/progenitor cells (LSPC) within the bone marrow (BM) niche, as well as in the high relapse rates of acute myeloid leukemia (AML). Down-regulating CD44 could be clinically relevant not only for suppression of the deregulated function of LSPC but also in LSPC response to chemotherapeutic agents. Small interfering RNA (siRNA) delivery is a promising approach for AML treatment, and we recently reported effective siRNA delivery into difficult-to-transfect AML cell lines using lipid-substituted polyethylenimine/siRNA complexes (polymeric nanoparticles). In this study, we investigated polymeric nanoparticle-mediated silencing of CD44 in CD34+ LSPC cell models (leukemic KG-1 and KG-1a cell lines) as well as primary AML cells. Polymeric nanoparticle-mediated silencing decreased surface CD44 levels in KG-1, KG-1a and primary AML cells by up to 27%, 30% and 20% at day 3, respectively. Moreover, CD44 silencing resulted in induction of apoptosis in KG-1 cells, reduced adhesion of KG-1 and KG-1a cells to hyaluronic acid-coated cell culture plates and BM-MSC, and decreased adhesion of primary AML cells to BM-MSC. Our results suggest that polymeric nanoparticle-mediated silencing of CD44 might be a useful technique for inhibiting LSPC interactions with their microenvironment, thereby prohibiting leukemia progression or sensitizing LSPC to chemotherapy. PMID:25262448

  15. Tumor Suppressor Inactivation in the Pathogenesis of Adult T-Cell Leukemia

    PubMed Central

    Nicot, Christophe

    2015-01-01

    Tumor suppressor functions are essential to control cellular proliferation, to activate the apoptosis or senescence pathway to eliminate unwanted cells, to link DNA damage signals to cell cycle arrest checkpoints, to activate appropriate DNA repair pathways, and to prevent the loss of adhesion to inhibit initiation of metastases. Therefore, tumor suppressor genes are indispensable to maintaining genetic and genomic integrity. Consequently, inactivation of tumor suppressors by somatic mutations or epigenetic mechanisms is frequently associated with tumor initiation and development. In contrast, reactivation of tumor suppressor functions can effectively reverse the transformed phenotype and lead to cell cycle arrest or death of cancerous cells and be used as a therapeutic strategy. Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disease associated with infection of CD4 T cells by the Human T-cell Leukemia Virus Type 1 (HTLV-I). HTLV-I-associated T-cell transformation is the result of a multistep oncogenic process in which the virus initially induces chronic T-cell proliferation and alters cellular pathways resulting in the accumulation of genetic defects and the deregulated growth of virally infected cells. This review will focus on the current knowledge of the genetic and epigenetic mechanisms regulating the inactivation of tumor suppressors in the pathogenesis of HTLV-I. PMID:26170835

  16. A comparison of dihydrofolate reductase activity in intact leukemia cells and squamous cell carcinoma.

    PubMed

    FitzGerald, G B; Wick, M M

    1989-06-01

    This report examines the intracellular activity of dihydrofolate reductase using an in situ assay designed to measure enzymatic activity in intact cells. The rate of uptake of folic acid exceeded the rate of in situ dihydrofolate reductase activity suggesting that the reduction of folate to dihydrofolate, rather than transport, was the rate limiting step. In situ dihydrofolate reductase activity varied linearly with cell number. A comparison of the in situ activity revealed that a squamous cell carcinoma selected for methotrexate (MTX) resistant (SCC-15R) had 100 times greater dihydrofolate reductase (DHFR) activity than L1210 leukemia. In agreement with this finding, the in situ DHFR activity in SCC-15R cells was 50-fold less sensitive to the inhibitory effects of MTX than the L1210 in situ DHFR activity (IC50 = 1.1 x 10(-5) M and 2.4 x 10.7(-7) M respectively). The inhibition of in situ dihydrofolate reductase activity by MTX was found to correlate with the inhibition of growth, DNA synthesis (CdR incorporation) and in situ thymidylate synthase activity. PMID:2757754

  17. [Cauda equina relapse after autologous stem cell transplantation in a patient with primary plasma cell leukemia].

    PubMed

    Okudaira, Taeko; Nagasaki, Akitoshi; Miyagi, Takashi; Yoshida, Maki; Tamaki, Kazumitsu; Takasu, Nobuyuki

    2010-04-01

    We report a rare case showing involvement with the cauda equina after autologous peripheral blood stem cell transplantation for primary plasma cell leukemia (PCL). A 55-year-old man was diagnosed with PCL(IgA-k type, stage III)in November of 2006. He was treated with VAD chemotherapy consisting of vincristine, doxorubicin, and dexamethasone. After achieving hematological remission, he received tandem high-dose melphalan supported by autologous peripheral blood stem cell transplantation. Five months after his second transplant, he complained of lumbago and bilateral leg pain. M-protein and Bence-Jones protein were not detected in serum or urine. An axial magnetic resonance imaging study revealed enlargement of the cauda equina nerve roots on T-1 weighted image. A sagittal T-1 weighted gadolinium-enhanced imaging study showed hyperintensities along the cauda equina. Leptomeningeal enhancement was also seen below the level of Th6. A cytological examination of the cerebrospinal fluid (CSF) with May-Giemsa stain showed atypical plasma cells. Immunoelectrophoresis of the CSF revealed monoclonal IgA-k type protein. A diagnosis of central nervous system (CNS)relapse was made. The patient died of pneumonia two months after relapse. It should be kept in mind that CNS relapse can occur during hematological remission in patients with multiple myeloma including PCL. PMID:20414040

  18. Germline-Competent Mouse-Induced Pluripotent Stem Cell Lines Generated on Human Fibroblasts without Exogenous Leukemia Inhibitory Factor

    Microsoft Academic Search

    Chunliang Li; Hongyao Yu; Yu Ma; Guilai Shi; Jing Jiang; Junjie Gu; Ying Yang; Shibo Jin; Zhe Wei; Hua Jiang; Jinsong Li; Ying Jin; Catherine M. Verfaillie

    2009-01-01

    Induced pluripotent stem (iPS) cells have attracted enormous attention due to their vast potential in regenerative medicine, pharmaceutical screening and basic research. Most prior established iPS cell lines were derived and maintained on mouse embryonic fibroblast (MEF) cells supplemented with exogenous leukemia inhibitory factor (LIF). Drawbacks of MEF cells impede optimization as well as dissection of reprogramming events and limit

  19. Crystal structures of inhibitor complexes of human T-cell leukemia virus (HTLV-1) protease.

    PubMed

    Satoh, Tadashi; Li, Mi; Nguyen, Jeffrey-Tri; Kiso, Yoshiaki; Gustchina, Alla; Wlodawer, Alexander

    2010-08-27

    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. PMID:20600105

  20. 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 (NCI); (Kyoto)

    2010-09-28

    Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with several serious diseases, such as adult T-cell leukemia and tropical spastic paraparesis/myelopathy. For a number of years, the protease (PR) encoded by HTLV-1 has been a target for designing antiviral drugs, but that effort was hampered by limited available structural information. We report a high-resolution crystal structure of HTLV-1 PR complexed with a statine-containing inhibitor, a significant improvement over the previously available moderate-resolution structure. We also report crystal structures of the complexes of HTLV-1 PR with five different inhibitors that are more compact and more potent. A detailed study of structure-activity relationships was performed to interpret in detail the influence of the polar and hydrophobic interactions between the inhibitors and the protease.

  1. 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 (NCI); (Kyoto)

    2010-09-17

    Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with several serious diseases, such as adult T-cell leukemia and tropical spastic paraparesis/myelopathy. For a number of years, the protease (PR) encoded by HTLV-1 has been a target for designing antiviral drugs, but that effort was hampered by limited available structural information. We report a high-resolution crystal structure of HTLV-1 PR complexed with a statine-containing inhibitor, a significant improvement over the previously available moderate-resolution structure. We also report crystal structures of the complexes of HTLV-1 PR with five different inhibitors that are more compact and more potent. A detailed study of structure-activity relationships was performed to interpret in detail the influence of the polar and hydrophobic interactions between the inhibitors and the protease.

  2. Prophylaxis and treatment of acute lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Chen, Runzhe; Campbell, Jos L; Chen, Baoan

    2015-01-01

    Relapse of acute lymphoblastic leukemia remains a major cause of death in patients following allogeneic hematopoietic stem cell transplantation. Several factors may affect the concurrence and outcome of relapse, which include graft-versus-host disease, minimal residual disease or intrinsic factors of the disease, and transplantation characteristics. The mainstay of relapse prevention and treatment is donor leukocyte infusions, targeted therapies, second transplantation, and other novel therapies. In this review, we mainly focus on addressing the impact of graft-versus-host disease on relapse and the prophylaxis and treatment of acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation. We also make recommendations for critical strategies to prevent relapse after transplantation and challenges that must be addressed to ensure success. PMID:25709473

  3. ?12-prostaglandin J3, an omega-3 fatty acid–derived metabolite, selectively ablates leukemia stem cells in mice

    PubMed Central

    Hegde, Shailaja; Kaushal, Naveen; Ravindra, Kodihalli C.; Chiaro, Christopher; Hafer, Kelsey T.; Gandhi, Ujjawal H.; Thompson, Jerry T.; van den Heuvel, John P.; Kennett, Mary J.; Hankey, Pamela

    2011-01-01

    Targeting cancer stem cells is of paramount importance in successfully preventing cancer relapse. Recently, in silico screening of public gene-expression datasets identified cyclooxygenase-derived cyclopentenone prostaglandins (CyPGs) as likely agents to target malignant stem cells. We show here that ?12-PGJ3, a novel and naturally produced CyPG from the dietary fish-oil ?-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA; 20:5) alleviates the development of leukemia in 2 well-studied murine models of leukemia. IP administration of ?12-PGJ3 to mice infected with Friend erythroleukemia virus or those expressing the chronic myelogenous leukemia oncoprotein BCR-ABL in the hematopoietic stem cell pool completely restored normal hematologic parameters, splenic histology, and enhanced survival. More importantly, ?12-PGJ3 selectively targeted leukemia stem cells (LSCs) for apoptosis in the spleen and BM. This treatment completely eradicated LSCs in vivo, as demonstrated by the inability of donor cells from treated mice to cause leukemia in secondary transplantations. Given the potency of ?-3 polyunsaturated fatty acid–derived CyPGs and the well-known refractoriness of LSCs to currently used clinical agents, ?12-PGJ3 may represent a new chemotherapeutic for leukemia that targets LSCs. PMID:21967980

  4. MLL-ENL leukemia burden initiated in femoral diaphysis and preceded by mature B-cell depletion

    PubMed Central

    Jaracz-Ros, Agnieszka; Lewandowski, Daniel; Barroca, Vilma; Lavau, Catherine; Roméo, Paul-Henri

    2011-01-01

    Background Molecular and cellular events that resulted in leukemia development are well characterized but initial engraftment and proliferation of leukemic cells in bone marrow and early modifications of the bone marrow microenvironment induced by engrafted leukemic cells remain to be clarified. Design and Methods After retro-orbital injection of 1,000 leukemic cells expressing Mixed Lineage Leukemia-Eleven Nineteen Leukemia fusion protein in non-conditioned syngenic mice, kinetics of leukemic burden and alterations of femoral hematopoietic populations were followed using an in vivo confocal imaging sytem and flow cytometry. Results Three days after injection, 5% of leukemic cells were found in femurs. Little proliferation of engrafted leukemic cells could then be detected for more than two weeks while the number of femoral leukemic cells remained stable. Twenty days after injection, leukemic cells preferentially proliferated in femoral diaphysis where they formed clusters on the surface of blood vessels and bone. B220+ lymphoid cells were found near these leukemic cell clusters and this association is correlated with a decreased number of femoral B220+IgM+ cells. Increasing the number of injected leukemic cells or conditioning recipient mice with ?-irradiation resulted in leukemic cell development in diaphysis and knee. Competition experiments indicate that proliferation but not engraftment is a rate-limiting factor of leukemic cells spreading in diaphysis. Finally, 30 days after injection leukemia developed. Conclusions After retro-orbital injection of 1,000 leukemic cells expressing Mixed Lineage Leukemia-Eleven Nineteen Leukemia into syngenic mice, leukemic cell burden preferentially initiates in femoral diaphysis and is preceded by changes of femoral B-lymphoid populations. PMID:21933859

  5. CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells

    Microsoft Academic Search

    T Vaisitti; S Aydin; D Rossi; F Cottino; L Bergui; G D'Arena; L Bonello; A L Horenstein; P Brennan; C Pepper; G Gaidano; F Malavasi; S Deaglio

    2010-01-01

    Homing of chronic lymphocytic leukemia (CLL) cells to sites favoring growth, a critical step in disease progression, is principally coordinated by the CXCL12\\/CXCR4 axis. A cohort of 62 CLL patients was divided into migrating and nonmigrating subsets according to chemotaxis toward CXCL12. Migrating patients phosphorylated extracellular signal-regulated kinase 1\\/2 (ERK1\\/2) proteins more than nonmigrating patients (P<0.0002). CD38 expression was the

  6. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia

    Microsoft Academic Search

    Anders Castor; Lars Nilsson; Ingbritt Åstrand-Grundström; Miranda Buitenhuis; Carole Ramirez; Kristina Anderson; Bodil Strömbeck; Stanislaw Garwicz; Albert N Békássy; Kjeld Schmiegelow; Birgitte Lausen; Peter Hokland; Sören Lehmann; Gunnar Juliusson; Bertil Johansson; Sten Eirik W Jacobsen

    2005-01-01

    The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210

  7. Cytotoxic efficacy of bendamustine in human leukemia and breast cancer cell lines

    Microsoft Academic Search

    S. Konstantinov; A. Kostovski; M. Topashka-Ancheva; M. Genova; M. Berger

    2002-01-01

    . Purpose: The purpose of this study was to characterise bendamustine's cytotoxic and apoptotic activity in a panel of leukemia and breast cancer cell lines in comparison to its clastogenicity in murine bone marrow. Methods: The cytotoxic effect of bendamustine was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT)-dye reduction assay. Induction of apoptosis was evidenced by DNA gel electrophoresis, nuclear

  8. Cytotoxic effect of conjugated trienoic fatty acids on mouse tumor and human monocytic leukemia cells

    Microsoft Academic Search

    Rikako Suzuki; Ryoko Noguchi; Tomoki Ota; Masayuki Abe; Kazuo Miyashita; Teruo Kawada

    2001-01-01

    The cytotoxicity of fatty acids from seed oils containing conjugated linolenic acids (CLN) was studied. Fatty acids from pomegranate,\\u000a tung, and catalpa were cytotoxic to human monocytic leukemia cells at concentrations exceeding 5 ?M for pomegranate and tung\\u000a and 10 ?M for catalpa, but fatty acids from pot marigold oil had no effect at concentrations ranging up to 163 ?M.

  9. Autologous hematopoietic stem cell transplantation in adult acute lymphoblastic leukemia: still not out of fashion

    Microsoft Academic Search

    Michael Doubek; Frantisek Folber; Zdenek Koristek; Yvona Brychtova; Marta Krejci; Miroslav Tomiska; Milan Navratil; Petra Mikulasova; Jiri Mayer

    2009-01-01

    The role of autologous hematopoietic stem cell transplantation (autoHSCT) in adult acute lymphoblastic leukemia (ALL) is still\\u000a unclear. We retrospectively analyzed the results of the autoHSCT and maintenance therapy, with oral 6-mercaptopurine and methotrexate,\\u000a in comparison to conventional-dose chemotherapy in the consolidation treatment of adult ALL and lymphoblastic lymphoma (LBL).\\u000a The patients, with HLA identical sibling donor, underwent allogeneic transplantation,

  10. Inhibitory effects of seaweeds on histamine release from rat basophile leukemia cells (RBL-2H3)

    Microsoft Academic Search

    Yoshimasa Sugiura; Yoshirou Takeuchi; Makoto Kakinuma; Hideomi Amano

    2006-01-01

    The effects of 80% methanol extracts from frozen samples of 41 macroalgae and one sea grass collected in the Ise-Shima region\\u000a of Japan were investigated on histamine release from rat basophile leukemia cells (RBL-2H3) sensitized with antidinitrophenyl\\u000a (DNP) IgE and stimulated with DNP-BSA. Of the 21 brown algae, five green and 15 red algae, and one sea grass tested, only

  11. Modification of the fatty acid composition of L1210 murine leukemia cells

    Microsoft Academic Search

    C. Patrick Burns; DIANA G. LUTTENEGGERo; Shiao-Ping L. Wei; Arthur A. Spector

    1977-01-01

    We have compared the effect of diets containing 16% sunflower seed oil (polyunsaturated fat-rich) or 16% coconut oil (saturated\\u000a fat-rich) fed for 3–7 weeks on the composition of L1210 murine leukemia cells which were transplanted into the peritoneal\\u000a cavity during the final week of feeding. The L1210 phospholipids of mice fed the sunflower oil diet contained 43% polyenoic\\u000a fatty acids

  12. Cancer Cachexia Syndrome Developed in Nude Mice Bearing Melanoma Cells Producing Leukemia-inhibitory Factor1

    Microsoft Academic Search

    Mitsuo Mori; Ken Yamaguchi; Satoshi Honda; Koichi Nagasaki; Masakazu Ueda; Osahiko Abe; Kaoru Abe

    Melanoma-derived lipoprotein lipase inhibitor (MLPLI) is a factor purified from the conditioned medium of a human melanoma cell line, SEKI, which induced severe cachexia in tumor-bearing nude mice. Amino acid sequencing revealed that the amino-terminal portion was identical to that of leukemia-inhibitory factor (LIF). To determine whether MLPLI is actually LIF, the expression of LIF mRNA was examined in the

  13. Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells

    Microsoft Academic Search

    Ulf Klein; Yuhai Tu; Gustavo A. Stolovitzky; Michela Mattioli; Giorgio Cattoretti; Hervé Husson; Arnold Freedman; Giorgio Inghirami; Lilla Cro; Luca Baldini; Antonino Neri; Andrea Califano; Riccardo Dalla-Favera

    B cell-derived chronic lymphocytic leukemia (B-CLL) represents a common malignancy whose cell derivation and pathogenesis are unknown. Recent studies have shown that ? 50% of CLLs display hypermutated immunoglobulin variable region (IgV) sequences and a more fa- vorable prognosis, suggesting that they may represent a distinct subset of CLLs which have transited through germinal centers (GCs), the physiologic site of

  14. Synergistic effect of HMGB1 knockdown and cordycepin in the K562 human chronic myeloid leukemia cell line.

    PubMed

    Chen, Xi; Wang, Ying; Liu, Juan; Xu, Ping; Zhang, Xiao-Min; Tian, Yao-Yao; Xue, Yan-Ming; Gao, Xin-Yu; Liu, Yao; Wang, Jing-Hua

    2015-09-01

    The high-mobility group box 1 (HMGB1) protein is a DNA-binding nuclear protein, which is overexpressed in leukemia cells. Cordycepin is characterized by strong antileukemic properties and is regarded as an effective natural compound for leukemia therapy. The aim of the present study was to investigate the impact of HMGB1 knockdown and cordycepin treatment on proliferation, apoptosis, reactive oxygen species (ROS) levels and adhesion of K562 human chronic myeloid leukemia cells. The Cell Counting kit?8 assay was used to determine the proliferation of K562 cells. The cell cycle and apoptosis of K562 cells was determined using flow cytometric analysis. In addition, a cell adhesion assay was performed. Western blotting was used to determine the protein expression of cyclooxygenase 2, Bax, receptor for advanced glycation end-products and Bcl?2. The data collected demonstrated that HMGB1 knockdown combined with cordycepin treatment had significant anti?proliferative and pro?apoptotic effects. In addition, it increased the ROS levels and reduced the adhesion of K562 cells. It was also identified that HMGB1 knockdown had synergistic effects with cordycepin, which aided in accelerating apoptosis, and inhibiting proliferation and adhesion in chronic myeloid leukemia cells. These results indicated that HMGB1 may be used as a potential therapeutic target, with cordycepin having potential as an auxiliary drug. Therefore, it is suggested that HMGB1 knockdown and corycepin treatement may present a promising therapeutic strategy for leukemia. PMID:26081986

  15. Interleukin-34 induces monocytic-like differentiation in leukemia cell lines

    PubMed Central

    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-?). 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-1? and -1? 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.

  16. Fludarabine Nucleoside Modulates Nuclear “Survival and Death” Proteins in Resistant Chronic Lymphocytic Leukemia Cells

    Microsoft Academic Search

    Silke Henrich; Swetlana Mactier; Giles Best; Stephen P. Mulligan; Ben Crossett; Richard Ian Christopherson

    2011-01-01

    The nuclear mechanisms by which fludarabine nucleoside (F-ara-A) induces apoptosis have been investigated in human MEC1 cells derived from B-cell chronic lymphocytic leukemia. Upon treatment of cells with F-ara-A (100 ?M, 72 hours), 15 nuclear proteins changed in abundance by more than 2-fold. Nuclear proteins up-regulated included calmodulin (4.3-fold), prohibitin (3.9-fold), ?-actin variant (3.7-fold), and structure-specific recognition protein 1 (3.7-fold);

  17. Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells

    Microsoft Academic Search

    Shumin Zhang; Haiyen E Zhau; Adeboye O Osunkoya; Shareen Iqbal; Xiaojian Yang; Songqing Fan; Zhengjia Chen; Ruoxiang Wang; Fray F Marshall; Leland WK Chung; Daqing Wu

    2010-01-01

    BACKGROUND: Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family, which inhibits cell apoptosis by sequestering pro-apoptotic proteins Bim and Bid. Mcl-1 overexpression has been associated with progression in leukemia and some solid tumors including prostate cancer (PCa). However, the regulatory mechanism for Mcl-1 expression in PCa cells remains elusive. RESULTS: Immunohistochemical analyses revealed that Mcl-1 expression was

  18. Maritoclax induces apoptosis in acute myeloid leukemia cells with elevated Mcl-1 expression.

    PubMed

    Doi, Kenichiro; Liu, Qiang; Gowda, Krishne; Barth, Brian M; Claxton, David; Amin, Shantu; Loughran, Thomas P; Wang, Hong-Gang

    2014-08-01

    Acute myeloid leukemia (AML) is one of the deadliest leukemias for which there is an urgent and unmet need for the development of novel treatment strategies. Multiple drug resistance mechanisms mediate poor drug response and relapse in patients, and a selective Mcl-1 inhibitor has been speculated to be a promising agent in the treatment of AML. Here, we describe that maritoclax, a small molecule Mcl-1 inhibitor, induces Mcl-1 proteasomal degradation without transcriptional downregulation. Maritoclax killed AML cell lines and primary cells with elevated Mcl-1 levels through selective Mcl-1 downregulation, and synergized with ABT-737 to overcome Mcl-1-mediated ABT-737 resistance. Maritoclax was more effective than daunorubicin at inducing leukemic cell death when co-cultured with HS-5 bone marrow stroma cells, while being less toxic than daunorubicin against HS-5 stroma cells, primary mouse bone marrow cells, and hematopoietic progenitor cells. Moreover, maritoclax administration at 20 mg/kg/d intraperitoneally caused significant U937 tumor shrinkage, as well as 36% tumors remission rate in athymic nude mice, without apparent toxicity to healthy tissue or circulating blood cells. In summary, our studies suggest that maritoclax belongs to a novel class of Mcl-1 inhibitors that has the potential to be developed for the treatment of AML. PMID:24842334

  19. Viscous flow on hairy surfaces

    NASA Astrophysics Data System (ADS)

    Bartenwerfer, M.; Bechert, D. W.

    1991-02-01

    Viscous flow on a hairy surface is investigated analytically. This flow can be the viscous sublayer of a turbulent boundary layer. The hairy surface is modeled with strings stretched in the streamwise direction above a plate. Velocity and shear stress distributions are calculated. As a by-product, the theory provides orthogonal grids which may be utilized in future numerical flow computations. The distance of the apparent origin of the velocity profile from the surface is determined. This distance characterizes how deep the strings protrude into the flow. It is found that thin strings protrude much deeper into the flow than normal riblets do. For the latter, drag reduction has been shown experimentally.

  20. Clinical course of juvenile myelomonocytic leukemia in the blast crisis phase treated by acute myeloid leukemia-oriented chemotherapy and allogeneic hematopoietic stem cell transplantation.

    PubMed

    Ueda, Satoshi; Sakata, Naoki; Muramatsu, Hideki; Sakaguchi, Hirotoshi; Wang, Xinan; Xu, Yinyan; Kojima, Seiji; Yamaguchi, Toshihiro; Higa, Takeshi; Takemura, Tsukasa

    2014-11-01

    Juvenile myelomonocytic leukemia (JMML) is a mixed myeloproliferative and myelodysplastic disorder that occurs in early childhood. The clinical course of JMML is highly variable. A third of patients follow a relatively indolent course, although approximately 15% cases are thought to develop acute myeloid leukemia, referred to as blast crisis. The etiology and clinical characteristics of blast crisis remain unclear. We document the case of a 27-month-old boy who presented with hepatosplenomegaly, skin rash, and lymphadenopathy. An initial diagnosis of acute erythroid leukemia was made according to the French-American-British classification. Following estimation of hypersensitivity to GM-CSF and genetic analysis of PTPN11, he was diagnosed with JMML in the blast crisis phase. Although he had several poor prognostic factors, including monosomy 7 and high HbF percentage, he achieved partial remission after treatment with acute myeloid leukemia-oriented chemotherapy followed by allogeneic hematopoietic stem cell transplantation. He has been in complete remission for over 6 years. PMID:25047104

  1. Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

    PubMed Central

    Li, Zhaoyang; Younger, Kenisha; Gartenhaus, Ronald; Joseph, Ann Mary; Hu, Fang; Baer, Maria R.; Brown, Patrick; Davila, Eduardo

    2015-01-01

    Signaling via the MyD88/IRAK pathway in T cells is indispensable for cell survival; however, it is not known whether this pathway functions in the progression of T acute lymphoblastic leukemia (T-ALL). Here, we determined that compared with thymic and peripheral T cells, T-ALL cells from patients have elevated levels of IRAK1 and IRAK4 mRNA as well as increased total and phosphorylated protein. Targeted inhibition of IRAK1 and IRAK4, either with shRNA or with a pharmacological IRAK1/4 inhibitor, dramatically impeded proliferation of T-ALL cells isolated from patients and T-ALL cells in a murine leukemia model; however, IRAK1/4 inhibition had little effect on cell death. We screened several hundred FDA-approved compounds and identified a set of drugs that had enhanced cytotoxic activity when combined with IRAK inhibition. Administration of an IRAK1/4 inhibitor or IRAK knockdown in combination with either ABT-737 or vincristine markedly reduced leukemia burden in mice and prolonged survival. IRAK1/4 signaling activated the E3 ubiquitin ligase TRAF6, increasing K63-linked ubiquitination and enhancing stability of the antiapoptotic protein MCL1; therefore, IRAK inhibition reduced MCL1 stability and sensitized T-ALL to combination therapy. These studies demonstrate that IRAK1/4 signaling promotes T-ALL progression through stabilization of MCL1 and suggest that impeding this pathway has potential as a therapeutic strategy to enhance chemotherapeutic efficacy. PMID:25642772

  2. In situ real-time monitoring of apoptosis on leukemia cells by surface infrared spectroscopy

    NASA Astrophysics Data System (ADS)

    Yamaguchi, Ryo-taro; Hirano-Iwata, Ayumi; Kimura, Yasuo; Niwano, Michio; Miyamoto, Ko-ichiro; Isoda, Hiroko; Miyazaki, Hitoshi

    2009-01-01

    We have investigated in situ real-time monitoring of apoptosis on human promyelocytic leukemia (HL-60) cells using infrared absorption spectroscopy with the multiple internal reflection (MIR-IRAS) geometry. Actinomycin D (Act D)-induced apoptosis on HL-60 cells was monitored for 24 h. Apoptotic cells showed two strong peaks around the protein amide I and amide II bands probably due to the leakage of cytoplasmic proteins, while growing viable cells showed a peak corresponding to the secretion of metabolites and two downward peaks corresponding to uptake of nutrients from culture media. In addition, IR absorption peak intensity of the amide I and amide II bands was proportional to the extracellular concentration of lactate dehydrogenase, a marker protein for cell damage. These results demonstrate that our MIR-IRAS method is useful for discrimination of apoptotic cells from viable ones and cell apoptotic processes can be monitored in situ by analyzing the amide I and amide II peak intensity.

  3. Establishment and characterization of a human T-cell leukemia line (LALW-2) in nude mice.

    PubMed

    White, L; Meyer, P R; Benedict, W F

    1984-05-01

    Lymphoblasts from the peripheral blood of a 10-year-old boy who was treated for T-cell acute lymphoblastic leukemia were heterotransplanted intraocularly into nude mice. The resultant tumors and their metastases were serially passaged both intraocularly and subcutaneously in the mice. The mouse tumors closely resembled morphologically and cytochemically a human T-cell lymphoma. The primary cells, as well as cells from subsequent in vivo passages, were predominantly of a suppressor T-cell phenotype (OKT8-positive). No viral products were identified. Chromosome analysis revealed a near-diploid karyotype with a translocation between chromosomes 11 and 14. The tumorigenicity, morphology, cytochemistry, immunologic phenotype, and karyotypic pattern of the cells remained constant through six serial in vivo passages over a period of 10 months. This is the first report of direct heterotransplantation and long-term in vivo maintenance of primary human T-cells in immunologically unmanipulated nude mice. PMID:6609263

  4. Allogeneic stem cell transplantation for chronic lymphocytic leukemia: Lessons to be learned from minimal residual disease studies

    Microsoft Academic Search

    Sebastian Böttcher; Matthias Ritgen; Peter Dreger

    2011-01-01

    Allogeneic stem cell transplantation (alloSCT) is a potentially curative treatment strategy for poor-risk chronic lymphocytic leukemia (CLL). The crucial anti-leukemic principle of alloSCT in CLL appears to be the graft-versus-leukemia effect (GVL). Evidence for GVL in CLL is particularly provided by studies analysing the kinetics of minimal residual disease (MRD). The purpose of this review is to summarize the methodologies

  5. BIOLOGICAL MECHANISMS AND CLINICAL IMPLICATIONS OF BCR-ABL-INDUCED MITOCHONDRIAL OXIDATIVE STRESS AND CELL SURVIVAL IN CHRONIC MYELOID LEUKEMIA

    Microsoft Academic Search

    Hui Zhang

    2012-01-01

    Chronic myeloid leukemia (CML), a myeloproliferative disorder, represents approximately 15-20% of all adult leukemia. The development of CML is clearly linked to the constitutively active protein-tyrosine kinase BCR-ABL, which is encoded by BCR-ABL fusion gene as the result of chromosome 9\\/22 translocation (Philadelphia chromosome). Previous studies have demonstrated that oxidative stress-associated genetic, metabolic and biological alterations contribute to CML cell

  6. Myelodysplasia and acute leukemia following high-dose chemotherapy and autologous bone marrow or peripheral blood stem cell transplantation

    Microsoft Academic Search

    RM Sobecks; MM Le Beau; J Anastasi; SF Williams

    1999-01-01

    Therapy-related myelodysplastic syndrome (t-MDS)\\/ acute myeloid leukemia (t-AML) has been reported after autologous bone marrow or peripheral blood stem cell transplantation (ABMT\\/PBSCT) for various malignancies. We retrospectively reviewed all adult ABMT\\/PBSCT cases performed at the University of Chicago Medical Center from 1985 to 1997 in order to determine the incidence of therapy-related leukemia. Among 649 patients, seven (1.1%) developed therapy-related

  7. Acute myeloid leukemia impairs natural killer cells through the formation of a deficient cytotoxic immunological synapse.

    PubMed

    Khaznadar, Zena; Henry, Guylaine; Setterblad, Niclas; Agaugue, Sophie; Raffoux, Emmanuel; Boissel, Nicolas; Dombret, Hervé; Toubert, Antoine; Dulphy, Nicolas

    2014-10-01

    Acute myeloid leukemia (AML) cells are killed by allogeneic NK cells. However, autologous NK cells from AML patients express decreased levels of activating receptors, and show reduced cytotoxicity. Here, we investigated how interactions between NK and AML cells might cause loss of NK-cell activity in patients. Our results show that AML cell lines and primary blasts alter the NK-cell phenotype, reducing their cytotoxic potential upon prolonged contact. Downregulation of NK-cell-activating receptors was contact-dependent and correlated with conjugate formation. Time-lapse imaging of HL60 AML cell line and NK-cell interactions showed a high proportion of noncytolytic contacts. Studies of NK-cell immunological synapses revealed a defect in lytic synapse formation. Namely, despite correct F-actin and LFA-1 recruitment, polarization of lytic granules toward primary blasts or AML cell lines was reduced. The NK-AML cell line synapses showed impairment of CD3? recruitment. Attempts to correct these synapse defects by cytokine stimulation of NK cells improved conjugate formation, but not granule polarization. Pretreatment of AML cell lines with the immunomodulating molecule lenalidomide significantly enhanced granule polarization. We speculate that combining immunomodulatory drugs and cytokines could increase AML cell sensitivity to autologous NK cells and reinforce the activity of allogeneic NK cells in adoptive immunotherapy. PMID:25041786

  8. Azacitidine in Treating Patients With Relapsed Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia Who Have Undergone Stem Cell Transplant

    ClinicalTrials.gov

    2013-12-10

    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); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  9. Dendritic cells and regulation of graft-versus-host disease and graft-versus-leukemia activity

    PubMed Central

    Stenger, Elizabeth O.; Turnquist, H?th R.; Mapara, Markus Y.

    2012-01-01

    Hematopoietic stem cell transplantation is the only curative treatment for many malignant hematologic diseases, with an often critical graft-versus-leukemia effect. Despite peritransplant prophylaxis, GVHD remains a significant cause of posthematopoietic stem cell transplantation morbidity and mortality. Traditional therapies have targeted T cells, yet immunostimulatory dendritic cells (DCs) are critical in the pathogenesis of GVHD. Furthermore, DCs also have tolerogenic properties. Monitoring of DC characteristics may be predictive of outcome, and therapies that target DCs are innovative and promising. DCs may be targeted in vivo or tolerogenic (tol) DCs may be generated in vitro and given in the peritransplant period. Other cellular therapies, notably regulatory T cells (Treg) and mesenchymal stem cells, mediate important effects through DCs and show promise for the prevention and treatment of GVHD in early human studies. Therapies are likely to be more effective if they have synergistic effects or target both DCs and T cells in vivo, such as tolDCs or Treg. Given the effectiveness of tolDCs in experimental models of GVHD and their safety in early human studies for type 1 diabetes, it is crucial that tolDCs be investigated in the prevention and treatment of human GVHD while ensuring conservation of graft-versus-leukemia effects. PMID:22403259

  10. 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. PMID:24060312

  11. Occurrence and modulation of therapeutic targets of Aurora kinase inhibition in pediatric acute leukemia cells.

    PubMed

    Jayanthan, Aarthi; Cooper, Todd M; Hoeksema, Kimberley A; Lotfi, Shamim; Woldum, Evan; Lewis, Victor A; Narendran, Aru

    2013-07-01

    Acute lymphoblastic leukemia (ALL) is one of the most prevelant pediatric malignancies. Although cure rates have improved in recent decades, approximately one in five children relapse, and survival rates post-relapse remain low. Therefore, more effective and innovative therapeutic strategies are needed in order to improve the outcome in these children. Aurora kinases, a family of serine/threonine kinases essential for regulated mitosis, are overexpressed in many forms of cancer, and have been identified as potential targets for cancer therapeutics. Based on this premise, we evaluated the activity of the Aurora-A/B inhibitor AT9283 against pediatric leukemia cells. It was found that AT9283 significantly inhibited the growth and survival of cell lines derived from patients with pediatric leukemia. Specifically, AT9283 promoted Flt-3 dephosphorylation, inhibiting the activity of downstream effectors such as Erk and Mek. In addition, apoptotic markers were also identified, providing a panel of markers for biological correlative analysis for drug activity. Lastly, drug combination studies demonstrated the potential of several novel and conventional agents to synergize with AT9283, including apicidin, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and doxorubicin. These data provide a rationale for further studies and the formulation of a clinical trial of AT9283 for the treatment of refractory pediatric ALL. PMID:23176524

  12. Fenretinide Targets Chronic Myeloid Leukemia Stem/Progenitor Cells by Regulation of Redox Signaling

    PubMed Central

    Du, Yanzhi; Xia, Yuan; Pan, Xiaoling; Chen, Zi; Wang, Aihua; Wang, Kankan; Li, Junmin

    2014-01-01

    Abstract Aims: We have recently shown that fenretinide preferentially targets CD34+ cells of acute myeloid leukemia (AML), and here, we test whether this agent exerts the effect on CD34+ cells of chronic myeloid leukemia (CML), which are refractory to imatinib. Results: As tested by colony-forming cell assays using clinical specimens, both number and size of total colonies derived from CD34+ CML cells were significantly reduced by fenretinide, and by combining fenretinide with imatinib. In particular, colonies derived from erythroid progenitors and more primitive pluripotent/multipotent progenitors were highly sensitive to fenretinide/fenretinide plus imatinib. Accordantly, fenretinide appeared to induce apoptosis in CD34+ CML cells, particularly with regard to the cells in the subpopulation of CD34+CD38?. Through cell quiescent assays, including Ki-67 negativity test, we added evidence that nonproliferative CD34+ CML cells were largely eliminated by fenretinide. Transcriptome and molecular data further showed that mechanisms underlying the apoptosis in CD34+ CML cells were highly complex, involving multiple events of oxidative stress responses. Innovation and Conclusion: As compared with CD34+ AML cells, the apoptotic effects of fenretinide on CD34+ CML cells were more prominent whereas less varied among the samples of different patients, and also various stress-responsive events appeared to be more robust in fenretinide-treated CD34+ CML cells. Thus, the combination of fenretinide with imatinib may represent a more sophisticated strategy for CML treatment, in which imatinib mainly targets leukemic blast cells through the intrinsic pathway of apopotosis, whereas fenretinide primarily targets CML stem/progenitor cells through the oxidative/endoplasmic reticulum stress-mediated pathway. Antioxid. Redox Signal. 20, 1866–1880. PMID:24021153

  13. Regulation of bcl-2 family in hydrogen peroxide-induced apoptosis in human leukemia HL60 cells

    Microsoft Academic Search

    Jung Eun Lee; Jeongwon Sohn; Jung Hwa Lee; Kwang Chul Lee; Chang Sung Son; Young Chang Tockgo

    2000-01-01

    Numerous types of cells have been shown to undergo apoptosis when exposed to oxidant agent such as hydrogen peroxide. In order to understand the func- tional relationship between the anti- and pro-apop- totic regulatory proteins in the cells under oxidant stress, we have studied the level of expression of apoptosis regulatory proteins, bcl-2 and bax, in human leukemia HL-60 cells.

  14. Cytotoxicity, DNA Cross-Linking, and Single Strand Breaks Induced by Activated Cyclophosphamide and Acrolein in Human Leukemia Cells

    Microsoft Academic Search

    Tim R. Crook; Robert L. Souhami; E. M. McLean

    1986-01-01

    The in vitro cytotoxicity and mechanism of action of Cyclophosphamide (CP) were studied in a dual cell culture system, using rat hepatocytes and K562 human chronic myeloid leukemia cells. Cytotoxicity and DNA damage were measurable in KS62 cells using CP concentrations that are clinically attainable. Alkaline elution analysis of cellular DNA demon strated the presence of concentration- and time-dependent DNA

  15. All three receptors for vascular endothelial growth factor (VEGF) are expressed on B-chronic lymphocytic leukemia (CLL) cells

    Microsoft Academic Search

    O Bairey; O Boycov; E Kaganovsky; Y Zimra; M Shaklai; E Rabizadeh

    2004-01-01

    B-chronic lymphocytic leukemia (B-CLL) cells have a long survival owing to an alteration in the normal pathways of apoptosis. CLL cells have been found to produce and secrete vascular endothelial growth factor (VEGF). In addition to its major role in angiogenesis, VEGF affects cell survival by interfering with apoptosis. The aim of the present study was to investigate the expression

  16. mTOR Inhibition by Everolimus in Childhood Acute Lymphoblastic Leukemia Induces Caspase-Independent Cell Death

    PubMed Central

    Baraz, Rana; Cisterne, Adam; Saunders, Philip O.; Hewson, John; Thien, Marilyn; Weiss, Jocelyn; Basnett, Jordan; Bradstock, Kenneth F.; Bendall, Linda J.

    2014-01-01

    Increasingly, anti-cancer medications are being reported to induce cell death mechanisms other than apoptosis. Activating alternate death mechanisms introduces the potential to kill cells that have defects in their apoptotic machinery, as is commonly observed in cancer cells, including in hematological malignancies. We, and others, have previously reported that the mTOR inhibitor everolimus has pre-clinical efficacy and induces caspase-independent cell death in acute lymphoblastic leukemia cells. Furthermore, everolimus is currently in clinical trial for acute lymphoblastic leukemia. Here we characterize the death mechanism activated by everolimus in acute lymphoblastic leukemia cells. We find that cell death is caspase-independent and lacks the morphology associated with apoptosis. Although mitochondrial depolarization is an early event, permeabilization of the outer mitochondrial membrane only occurs after cell death has occurred. While morphological and biochemical evidence shows that autophagy is clearly present it is not responsible for the observed cell death. There are a number of features consistent with paraptosis including morphology, caspase-independence, and the requirement for new protein synthesis. However in contrast to some reports of paraptosis, the activation of JNK signaling was not required for everolimus-induced cell death. Overall in acute lymphoblastic leukemia cells everolimus induces a cell death that resembles paraptosis. PMID:25014496

  17. The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplantation for Patients with Acute Leukemia.

    PubMed

    Holter-Chakrabarty, Jennifer L; Pierson, Namali; Zhang, Mei-Jie; Zhu, Xiaochun; Akpek, Görgün; Aljurf, Mahmoud D; Artz, Andrew S; Baron, Frédéric; Bredeson, Christopher N; Dvorak, Christopher C; Epstein, Robert B; Lazarus, Hillard M; Olsson, Richard F; Selby, George B; Williams, Kirsten M; Cooke, Kenneth R; Pasquini, Marcelo C; McCarthy, Philip L

    2015-07-01

    Limited clinical data are available to assess whether the sequencing of cyclophosphamide (Cy) and total body irradiation (TBI) changes outcomes. We evaluated the sequence in 1769 (CyTBI, n = 948; TBICy, n = 821) recipients of related or unrelated hematopoietic cell transplantation who received TBI (1200 to 1500 cGY) for acute leukemia from 2003 to 2010. The 2 cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Philadelphia chromosome-positive acute lymphoblastic leukemia, HLA-matched siblings, stem cell source, antithymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect transplantation-related mortality (24% versus 23% at 3 years, P = .67; relative risk, 1.01; P = .91), leukemia relapse (27% versus 29% at 3 years, P = .34; relative risk, .89, P = .18), leukemia-free survival (49% versus 48% at 3 years, P = .27; relative risk, .93; P = .29), chronic GVHD (45% versus 47% at 1 year, P = .39; relative risk, .9; P = .11), or overall survival (53% versus 52% at 3 years, P = .62; relative risk, .96; P = .57) for CyTBI and TBICy, respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (P = .08), respectively. This study demonstrates that the sequence of Cy and TBI does not impact transplantation outcomes and complications in patients with acute leukemia undergoing hematopoietic cell transplantation with myeloablative conditioning. PMID:25840335

  18. ERK5 pathway regulates transcription factors important for monocytic differentiation of human myeloid leukemia cells.

    PubMed

    Wang, Xuening; Pesakhov, Stella; Harrison, Jonathan S; Danilenko, Michael; Studzinski, George P

    2014-07-01

    Mitogen-activated protein kinases (MAPKs) are important transducers of external signals for cell growth, survival, and other cellular responses including cell differentiation. Several MAPK cascades are known with the MEK1/2-ERK1/2, JNK, and p38MAPKs receiving most attention, but the role of MEK5-ERK5 in intracellular signaling deserves more scrutiny, as this pathway transmits signals that can complement ERK/2 signaling. We hypothesized that the ERK5 pathway plays a role in the control of monocytic differentiation, which is disturbed in myeloid leukemia. We therefore examined the cellular phenotype and key molecular events which occur when human myeloid leukemia cells, acute (AML) or chronic (CML), are forced to differentiate by vitamin D derivatives (VDDs). This study was performed using established cell lines HL60 and U937, and primary cultures of blasts from 10 patients with ML. We found that ERK5 and its direct downstream target transcription factor MEF2C are upregulated by 1,25D in parallel with monocytic differentiation. Further, inhibition of ERK5 activity by specific pharmacological agents BIX02189 and XMD8-92 alters the phenotype of these cells by reducing the abundance of the VDD-induced surface monocytic marker CD14, and concomitantly increasing surface expression of the general myeloid marker CD11b. Similar results were obtained when the expression of ERK5 was reduced by siRNA or short hairpin (sh) RNA. ERK5 inhibition resulted in an expected decrease in MEF2C activation. We also found that in AML cells the transcription factor C/EBP? is positively regulated, while C/EBP? is negatively regulated by ERK5. These findings provide new understanding of dysregulated differentiation in human myeloid leukemia. PMID:24264602

  19. Increased seroreactivity to human T cell lymphoma/leukemia virus-related endogenous sequence-1 Gag peptides in patients with human T cell lymphoma/leukemia virus myelopathy.

    PubMed

    Perzova, Raisa; Graziano, Elliot; Sanghi, Swathi; Welch, Caitlin; Benz, Patricia; Abbott, Lynn; Lalone, Danielle; Glaser, Jordan; Loughran, Thomas; Sheremata, William; Poiesz, Bernard J

    2015-02-01

    Previously, we had shown that although only 8% of patients with large granular lymphocytic leukemia (LGLL) were infected with human T cell lymphoma/leukemia virus (HTLV)-2, almost half had antibodies to HTLV Gag and Env peptides. Herein, we investigated whether this could be due to cross-reactive antibodies to two homologous peptides in the Gag protein of the endogenous retrovirus HTLV-related endogenous sequence-1 (HRES-1). In addition, we had previously shown that patients with HTLV neurodegenerative diseases had increased seroreactivity to homologous HERV-K10 endogenous retrovirus peptides. Hence, in this study we also examined whether these patients had increased seroreactivity to the aforementioned HRES-1 Gag peptides. Sera from 100 volunteer blood donors (VBD), 53 patients with LGLL, 74 subjects with HTLV-1 or 2 infection (58 nonmyelopathy and 16 myelopathy), and 83 patients with multiple sclerosis (MS) were evaluated. The HTLV-positive myelopathy (HAM) patients had a statistically increased prevalence of antibodies to both HRES-1 Gag peptides (81%) vs. the VBD (0%), LGLL patients (13%), and MS patients (1%), and the HTLV-positive nonmyelopathy subjects (21%). The data suggest that cross-reactivity to HRES-1 peptides could be involved in the pathogenesis of HAM. The difference between the VBD and LGLL patients was also statistically significant, also suggesting a possible association in a minority of patients. PMID:25295378

  20. Alpha 2-macroglobulin restricts plasminogen activation to the surface of RC2A leukemia cells.

    PubMed Central

    Stephens, R W; Tapiovaara, H; Reisberg, T; Bizik, J; Vaheri, A

    1991-01-01

    Human RC2A myelomonocytic leukemia cells are able to activate the prourokinase (pro-u-PA) they secrete so that active u-PA is present both in serum-free conditioned medium from these cells, as well as on the cell surface. When the cells are grown in serum-containing medium, no u-PA activity can be found in the medium but active u-PA is found bound to the cell surface where it can generate bound plasmin. This distribution of u-PA activity was shown to be, first, the net result of slow inactivation of free active u-PA by serum inhibitor(s) and simultaneous rapid uptake of u-PA onto the cell surface. Binding to cells was at least six times faster than inactivation by 10% serum. The principal serum inhibitor of u-PA was identified as alpha 2-macroglobulin (alpha 2M), and prior inactivation of u-PA by purified human alpha 2M was also shown to prevent uptake of u-PA activity onto cells. Second, although endogenous u-PA could form covalent complexes with purified alpha 2M in the culture medium of RC2A cells, covalent alpha 2M complexes were not formed by u-PA on the cell surface; the u-PA taken up in this compartment was protected against alpha 2M inhibition. u-PA anchored to plastic surfaces via monoclonal antibodies to the amino-terminal region of u-PA was also protected against alpha 2M, suggesting that the protection of cell surface u-PA results from a steric effect. These results provide evidence as to how the active u-PA produced by leukemia cells can contribute to proteolytic activity on their cell surface in the presence of serum inhibitors. Images PMID:1724917

  1. Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias.

    PubMed

    So, Alex Yick-Lun; Sookram, Reeshelle; Chaudhuri, Aadel A; Minisandram, Aarathi; Cheng, David; Xie, Catherine; Lim, Ee Lyn; Flores, Yvette Garcia; Jiang, Shuai; Kim, Jocelyn Tammy; Keown, Christopher; Ramakrishnan, Parameswaran; Baltimore, David

    2014-08-28

    The oncomir microRNA-125b (miR-125b) is upregulated in a variety of human neoplastic blood disorders and constitutive upregulation of miR-125b in mice can promote myeloid and B-cell leukemia. We found that miR-125b promotes myeloid and B-cell neoplasm by inducing tumorigenesis in hematopoietic progenitor cells. Our study demonstrates that miR-125b induces myeloid leukemia by enhancing myeloid progenitor output from stem cells as well as inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors. Through functional and genetic analyses, we demonstrated that miR-125b induces myeloid and B-cell leukemia by inhibiting interferon regulatory factor 4 (IRF4) but through distinct mechanisms; it induces myeloid leukemia through repressing IRF4 at the messenger RNA (mRNA) level without altering the genomic DNA and induces B-cell leukemia via genetic deletion of the gene encoding IRF4. PMID:25006123

  2. Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival

    PubMed Central

    Chen, Yaoyu; Peng, Cong; Abraham, Sheela A.; Shan, Yi; Guo, Zhiru; Desouza, Ngoc; Cheloni, Giulia; Li, Dongguang; Holyoake, Tessa L.; Li, Shaoguang

    2014-01-01

    Cancer stem cells (CSCs) are responsible for the initiation and maintenance of some types of cancer, suggesting that inhibition of these cells may limit disease progression and relapse. Unfortunately, few CSC-specific genes have been identified. Here, we determined that the gene encoding arachidonate 15-lipoxygenase (Alox15/15-LO) is essential for the survival of leukemia stem cells (LSCs) in a murine model of BCR-ABL–induced chronic myeloid leukemia (CML). In the absence of Alox15, BCR-ABL was unable to induce CML in mice. Furthermore, Alox15 deletion impaired LSC function by affecting cell division and apoptosis, leading to an eventual depletion of LSCs. Moreover, chemical inhibition of 15-LO function impaired LSC function and attenuated CML in mice. The defective CML phenotype in Alox15-deficient animals was rescued by depleting the gene encoding P-selectin, which is upregulated in Alox15-deficient animals. Both deletion and overexpression of P-selectin affected the survival of LSCs. In human CML cell lines and CD34+ cells, knockdown of Alox15 or inhibition of 15-LO dramatically reduced survival. Loss of Alox15 altered expression of PTEN, PI3K/AKT, and the transcription factor ICSBP, which are known mediators of cancer pathogenesis. These results suggest that ALOX15 has potential as a therapeutic target for eradicating LSCs in CML. PMID:25105362

  3. Cytotoxic and apoptotic effects of boron compounds on leukemia cell line.

    PubMed

    Canturk, Zerrin; Tunali, Ya?mur; Korkmaz, Seval; Gulba?, Zafer

    2014-08-27

    In this study we investigated the effects of boric acid and sodium tetraborate on an acute leukemia cell line and healthy human lymphocytes. We evaluated the effects of boric acid and sodium tetraborate on the HL-60 cell line and healthy human lymphocytes by using the methods of MTT, Neutral Red, AO (flow cytometry) and transmission electron microscope. We found that there were dead cells at a concentration of 500 µM boric acid and sodium tetraborate (50 % and 40 %, respectively). An apoptotic effect was found at a concentration of 1,000 µM concentration in normal lymphocytes and HL-60 (acute leukemia cells) cells (2.5 % and 8.8 % respectively). We observed that boric acid at a concentration of 500 µM caused double nucleus and micronucleus formation in both HL-60 cells and lymphocytes. An expansion in mitochondrial dimension and deformation in cristas also appeared. Our findings suggest that boric acid is more effective than sodium tetraborate on the HL-60, and boric acid in particular showed a cytotoxic effect on HL-60 in comparison to healthy lymphocytes and it also affected the mitochondrial pathway. PMID:25159521

  4. BCL-2 inhibitors sensitize therapy-resistant chronic lymphocytic leukemia cells to VSV oncolysis.

    PubMed

    Samuel, Sara; Beljanski, Vladimir; Van Grevenynghe, Julien; Richards, Stephanie; Ben Yebdri, Fethia; He, Zhong; Nichols, Carmen; Belgnaoui, S Mehdi; Steel, Courtney; Goulet, Marie-Line; Shamy, April; Brown, Dawn; Abesada, Guillermo; Haddad, Elias K; Hiscott, John

    2013-07-01

    Many primary cancers including chronic lymphocytic leukemia (CLL) are resistant to vesicular stomatitis virus (VSV)-induced oncolysis due to overexpression of the antiapoptotic and antiautophagic members of the B-cell lymphoma-2 (BCL-2) family. In the present study, we investigated the mechanisms of CLL cell death induced as a consequence of VSV infection in the presence of BCL-2 inhibitors, obatoclax, and ABT-737 in primary ex vivo CLL patient samples. Microarray analysis of primary CD19? CD5? CLL cells treated with obatoclax and VSV revealed changes in expression of genes regulating apoptosis, the mechanistic target of rapamycin (mTOR) pathway, and cellular metabolism. A combined therapeutic effect was observed for VSV and BCL-2 inhibitors in cells from untreated patients and from patients unresponsive to standard of care therapy. In addition, combination treatment induced several markers of autophagy--LC3-II accumulation, p62 degradation, and staining of autophagic vacuoles. Inhibition of early stage autophagy using 3-methyladenine (3-MA) led to increased apoptosis in CLL samples. Mechanistically, a combination of BCL-2 inhibitors and VSV disrupted inhibitory interactions of Beclin-1 with BCL-2 and myeloid cell leukemia-1 (MCL-1), thus biasing cells toward autophagy. We propose a mechanism in which changes in cellular metabolism, coupled with pharmacologic disruption of the BCL-2-Beclin-1 interactions, facilitate induction of apoptosis and autophagy to mediate the cytolytic effect of VSV. PMID:23689597

  5. PKC? Regulates T-Cell Leukemia-Initiating Activity via Reactive Oxygen Species

    PubMed Central

    Giambra, Vincenzo; Jenkins, Christopher R.; Wang, Hongfang; Lam, Sonya H.; Shevchuk, Olena O.; Nemirovsky, Oksana; Wai, Carol; Gusscott, Sam; Chiang, Mark Y.; Aster, Jon C.; Humphries, R. Keith; Eaves, Connie; Weng, Andrew P.

    2013-01-01

    Reactive oxygen species (ROS), a by-product of cellular metabolism, damage intracellular macromolecules and, in excess, can promote normal hematopoietic stem cell differentiation and exhaustion1–3. However, mechanisms that regulate ROS levels in leukemia-initiating cells (LICs) and the biological role of ROS in these cells remain largely unknown. We show here the ROSlow subset of CD44+ cells in T-cell acute lymphoblastic leukemia (T-ALL), a malignancy of immature T-cell progenitors, to be highly enriched in the most aggressive LICs, and that ROS are maintained at low levels by downregulation of protein kinase C theta (PKC?). Strikingly, primary mouse T-ALLs lacking PKC? show improved LIC activity whereas enforced PKC? expression in both mouse and human primary T-ALLs compromised LIC activity. We also demonstrate that PKC? is positively regulated by RUNX1, and that NOTCH1, which is frequently activated by mutation in T-ALL4–6 and required for LIC activity in both mouse and human models7,8, downregulates PKC? and ROS via a novel pathway involving induction of RUNX3 and subsequent repression of RUNX1. These results reveal key functional roles for PKC? and ROS in T-ALL and suggest that aggressive biological behavior in vivo could be limited by therapeutic strategies that promote PKC? expression/activity or ROS accumulation. PMID:23086478

  6. Dunaliella salina exhibits an antileukemic immunity in a mouse model of WEHI-3 leukemia cells.

    PubMed

    Chuang, Wen-Chen; Ho, Yung-Chyuan; Liao, Jiunn-Wang; Lu, Fung-Jou

    2014-11-26

    Dunaliella salina has been shown to have antioxidant property and induce apoptotic cell death of human cancer cells in vitro. However, there is no information available on D. salina showing an antileukemia effect or immunomodulatory activity in vivo. This study applied D. salina to syngeneic leukemia-implanted mice (BALB/c and WEHI-3) to investigate its immunological and antileukemia properties. Oral administration of D. salina (184.5, 369, and 922.5 mg/kg) inhibited spleen metastasis and prolonged the survival in BALB/c mice that had received an intravenous injection of WEHI-3 cells. The results revealed that D. salina had reduced spleen enlargement in murine leukemia. It had also increased the population and proliferation of T-cells (CD3) and B-cells (CD19) following Con A/LPS treatment on flow cytometry and MTT assay, respectively. Furthermore, D. salina increased the phagocytosis of macrophages and enhanced the cytotoxicity of natural killer cells on flow cytometry and LDH assay. Moreover, D. salina enhanced the levels of interferon-? and interleukin 2 (IL-2) but reduced the levels of IL-4 and IL-10 in leukemic mice. In conclusion, these results demonstrated that the application of D. salina had beneficial effects on WEHI-3 leukemic mice by prolonging survival via modulating the immune responses. PMID:25380534

  7. Homoharringtonine acts synergistically with SG235TRAIL, a conditionally replicating adenovirus, in human leukemia cell lines

    Microsoft Academic Search

    Hai-tao Meng; Lu Li; Hui Liu; Ying Wang; Gong-chu Li; Wen-bin Qian

    2009-01-01

    Aim:To investigate the synergistic effects of SG235-TRAIL, a novel oncolytic adenovirus expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and homoharringtonine (HHT) in human leukemia cell lines.Methods:The combined effect of SG235-TRAIL and HHT was assessed using a crystal violet assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, followed by combination index analysis. Cell apoptosis was measured using flow cytometry combined with fluorescein-isothiocyanate-Annexin V

  8. 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. PMID:21705331

  9. Exosomal shuttling of miR-126 in endothelial cells modulates adhesive and migratory abilities of chronic myelogenous leukemia cells

    PubMed Central

    2014-01-01

    Background Recent findings indicate that exosomes released from cancer cells contain microRNAs (miRNAs) that may be delivered to cells of tumor microenvironment. Results To elucidate whether miRNAs secreted from chronic myelogenous leukemia cells (CML) are shuttled into endothelial cells thus affecting their phenotype, we first analysed miRNAs content in LAMA84 exosomes. Among the 124 miRNAs identified in LAMA84 exosomes, we focused our attention on miR-126 which was found to be over-overexpressed in exosomes compared with producing parental cells. Transfection of LAMA84 with Cy3-labelled miR-126 and co-culture of leukemia cells with endothelial cells (EC) confirmed that miR-126 is shuttled into HUVECs. The treatment of HUVECs with LAMA84 exosomes for 24 hours reduced CXCL12 and VCAM1 expression, both at the mRNA and protein level, and negatively modulated LAMA84 motility and cells adhesion. Transfection in HUVECs of miR-126 inhibitor reversed the decrease of CXCL12 and restored the motility and adhesion of LAMA84 cells while the over-expression of miR-126, showed opposite effects. Conclusion Our results show that the miR-126 shuttled by exosomes is biologically active in the target cells, and support the hypothesis that exosomal miRNAs have an important role in tumor-endothelial crosstalk occurring in the bone marrow microenvironment, potentially affecting disease progression. PMID:25015105

  10. Rituximab, Romidepsin, and Lenalidomide in Treating Patients With Recurrent or Refractory B-cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2014-10-30

    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

  11. Ginsenoside Rh2 induces cell cycle arrest and differentiation in human leukemia cells by upregulating TGF-? expression.

    PubMed

    Chung, Kyung-Sook; Cho, Sung-Hee; Shin, Ji-Sun; Kim, Dong-Hyun; Choi, Jung-Hye; Choi, Sang Y; Rhee, Young K; Hong, Hee-Do; Lee, Kyung-Tae

    2013-02-01

    The triterpene saponin ginsenoside Rh2 has been shown to have antiproliferative effects on various cancer cells. However, the effect of Rh2 on the cell cycle and its underlying molecular mechanism in human leukemia cells are not fully understood. In this study, we found that Rh2 inhibited the proliferation of human leukemia cells concentration- and time-dependently with an IC(50) of ~38 µM. DNA flow cytometric analysis indicated that Rh2 blocked cell cycle progression at the G(1) phase in HL-60 and U937 cells, and this was found to be accompanied by the downregulations of cyclin-dependent kinase (CDK) 4, CDK6, cyclin D1, cyclin D2, cyclin D3 and cyclin E at the protein level. However, CDK inhibitors (CDKIs), such as p21(CIP1/WAF1) and p27(KIP1), were gradually upregulated after Rh2 treatment at the protein and messenger RNA (mRNA) levels. In addition, Rh2 markedly enhanced the bindings of p21(CIP1/WAF1) and p27(KIP1) to CDK2, CDK4 and CDK6, and these bindings reduced CDK2, CDK4 and CDK6 activities. Furthermore, Rh2 induced the differentiation of HL-60 cells as demonstrated by biochemical assays and the expression levels of cell surface antigens. In addition, treatment of HL-60 cells with Rh2 significantly increased transforming growth factor-? (TGF-?) production, and cotreatment with TGF-? neutralizing antibody prevented the Rh2-induced downregulations of CDK4 and CDK6, upregulations of p21(CIP1/WAF1) and p27(KIP1) levels and the induction of differentiation. These results demonstrate that the Rh2-mediated G(1) arrest and the differentiation are closely linked to the regulation of TGF-? production in human leukemia cells. PMID:23125221

  12. Adult B-cell acute lymphoblastic leukemia cells display decreased PTEN activity and constitutive hyperactivation of PI3K/Akt pathway despite high PTEN protein levels.

    PubMed

    Gomes, A Margarida; Soares, Maria V D; Ribeiro, Patrícia; Caldas, Joana; Póvoa, Vanda; Martins, Leila R; Melão, Alice; Serra-Caetano, Ana; de Sousa, Aida B; Lacerda, João F; Barata, João T

    2014-06-01

    Adult B-cell acute lymphoblastic leukemia remains a major therapeutic challenge, requiring a better characterization of the molecular determinants underlying disease progression and resistance to treatment. Here, using a phospho-flow cytometry approach we show that adult diagnostic B-cell acute lymphoblastic leukemia specimens display PI3K/Akt pathway hyperactivation, irrespective of their BCR-ABL status and despite paradoxically high basal expression of PTEN, the major negative regulator of the pathway. Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation. In agreement, we found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls. Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells. Our studies indicate that CK2-mediated PTEN posttranslational inactivation, associated with PI3K/Akt pathway hyperactivation, are a common event in adult B-cell acute lymphoblastic leukemia and suggest that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy. PMID:24561792

  13. Self-renewal related signaling in myeloid leukemia stem cells

    Microsoft Academic Search

    Florian H. Heidel; Brenton G. Mar; Scott A. Armstrong

    A key characteristic of hematopoietic stem cells (HSC) is the ability to self-renew. Several genes and signaling pathways\\u000a control the fine balance between self-renewal and differentiation in HSC and potentially also in leukemic stem cells. Besides\\u000a pathways such as Wnt signaling, Hedgehog signaling and Notch signaling, transcription factors (FoxOs) and cell fate determinants\\u000a may also play a role in stem

  14. ERK5 Pathway Regulates Transcription Factors Important for Monocytic Differentiation of Human Myeloid Leukemia Cells

    PubMed Central

    Wang, Xuening; Pesakhov, Stella; Harrison, Jonathan S; Danilenko, Michael; Studzinski, George P

    2014-01-01

    Mitogen-activated protein kinases (MAPKs) are important transducers of external signals for cell growth, survival and other cellular responses including cell differentiation. Several MAPK cascades are known with the MEK1/2-ERK1/2, JNK, and p38MAPKs receiving most attention, but the role of MEK5-ERK5 in intracellular signaling deserves more scrutiny, as this pathway transmits signals that can complement ERK/2 signaling. We hypothesized that the ERK5 pathway plays a role in the control of monocytic differentiation, which is disturbed in myeloid leukemia. We therefore examined the cellular phenotype and key molecular events which occur when human myeloid leukemia cells, acute (AML) or chronic (CML), are forced to differentiate by vitamin D derivatives (VDDs). This study was performed using established cell lines HL60 and U937, and primary cultures of blasts from 10 patients with ML. We found that ERK5 and its direct downstream target transcription factor MEF2C are upregulated by 1,25D in parallel with monocytic differentiation. Further, inhibition of ERK5 activity by specific pharmacological agents BIX02189 and XMD8-92 alters the phenotype of these cells by reducing the abundance of the VDD-induced surface monocytic marker CD14, and concomitantly increasing surface expression of the general myeloid marker CD11b. Similar results were obtained when the expression of ERK5 was reduced by siRNA or short hairpin (sh) RNA. ERK5 inhibition resulted in an expected decrease in MEF2C activation. We also found that in AML the transcription factor C/EBP? is positively regulated, while C/EBP? is negatively regulated by ERK5. These findings provide new understanding of dysregulated differentiation in human myeloid leukemia. PMID:24264602

  15. Ganoderma lucidum extracts inhibited leukemia WEHI-3 cells in BALB/c mice and promoted an immune response in vivo.

    PubMed

    Chang, Yung-Hsien; Yang, Jai-Sing; Yang, Jiun-Long; Wu, Chang-Lin; Chang, Shu-Jen; Lu, Kung-Wen; Lin, Jen-Jyh; Hsia, Te-Chun; Lin, Yi-Ting; Ho, Chin-Chih; Wood, W Gibson; Chung, Jing-Gung

    2009-12-01

    Ganoderma lucidum (G. lucidum) is a medicinal mushroom having biological effects such as immunomodulation and anti-tumor actions. In China and many other Asian countries, G. lucidum is used as a folk remedy to promote health and longevity. Although many studies have shown that G. lucidum modulates the immune system, including, for example, antigen-presenting cells, natural killer (NK) cells, and the T and B lymphocytes, the effects of G. lucidum on the WEHI-3 leukemic BALB/c mice are unclear. We attempted to determine whether G. lucidum would promote immune responses in BALB/c mice injected with WEHI-3 leukemia cells. The effects of G. lucidum on the survival rate of WEHI-3 leukemia cells injected into BALB/c mice were examined. It increased the percentages of CD3 and CD19, but decreased the percentages of Mac-3 and CD11b markers, suggesting that differentiation of the precursor of T and B cells was promoted but macrophages were inhibited. It decreased the weight of spleens as compared with control mice. It also promoted phagocytosis by macrophage from peripheral blood mononuclear cell (PBMC) and it also promoted natural killer cell activity. It decreased the percentage of leukemia cells in the spleens of mice before they were injected with WEHI-3 cells. Apparently, G. lucidum affects murine leukemia WEHI-3 cells in vivo. PMID:19966494

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

    PubMed

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

    2011-07-29

    We have previously characterized the effects of 2,6-diisopropylphenyl-docosahexaenoamide (DIP-DHA) conjugates and their analogs on the proliferation and progression of breast cancer cell lines. For this study, we investigated the effects of the DIP-DHA conjugate on 2 representative T cell acute lymphoblastic leukemia (T-ALL) cell lines: CEM and Jurkat. Treatment of both cell lines with DIP-DHA resulted in significantly greater inhibition of proliferation and induction of apoptosis than that of parent compounds, 2,6-diisopropylphenol (DIP) or docosahexaenoate (DHA). Treatment of the cells with DIP-DHA resulted in increased activation of caspase-3, and caspase-7. Furthermore, induction of apoptosis in both cell lines was reversed in the presence of a caspase family inhibitor. Treatment with DIP-DHA reduced mitochondrial membrane potential. These observations suggest that the effects are driven by intrinsic apoptotic pathways. DIP-DHA treatment also downregulated surface CXCR4 expression, an important chemokine receptor involved in cancer metastasis that is highly expressed in both CEM and Jurkat cells. In conclusion, our data suggest that the DIP-DHA conjugate exhibits significantly more potent effects on CEM and Jurkat cells than that of DIP or DHA alone. These conjugates have potential use for treatment of patients with T cell acute lymphoblastic leukemia. PMID:21749860

  17. T-cell depleted allogeneic hematopoietic cell transplants as a platform for adoptive therapy with leukemia selective or virus-specific T-cells.

    PubMed

    O'Reilly, R J; Koehne, G; Hasan, A N; Doubrovina, E; Prockop, S

    2015-06-01

    Allogeneic hematopoietic cell transplants adequately depleted of T-cells can reduce or prevent acute and chronic GVHD in both HLA-matched and haplotype-disparate hosts, without post-transplant prophylaxis with immunosuppressive drugs. Recent trials indicate that high doses of CD34+ progenitors from G-CSF mobilized peripheral blood leukocytes isolated and T-cell depleted by immunoadsorption to paramagnetic beads, when administered after myeloablative conditioning with TBI and chemotherapy or chemotherapy alone can secure consistent engraftment and abrogate GVHD in patients with acute leukemia without incurring an increased risk of a recurrent leukemia. Early clinical trials also indicate that high doses of in vitro generated leukemia-reactive donor T-cells can be adoptively transferred and can induce remissions of leukemia relapse without GVHD. Similarly, virus-specific T-cells generated from the transplant donor or an HLA partially matched third party, have induced remissions of Rituxan-refractory EBV lymphomas and can clear CMV disease or viremia persisting despite antiviral therapy in a high proportion of cases. Analyses of treatment responses and failures illustrate both the advantages and limitations of donor or banked, third party-derived T-cells, but underscore the potential of adoptive T-cell therapy in the absence of ongoing immunosuppression. PMID:26039207

  18. 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. PMID:24002693

  19. Tcl1 protein functions as an inhibitor of de novo DNA methylation in B-cell chronic lymphocytic leukemia (CLL)

    PubMed Central

    Palamarchuk, Alexey; Yan, Pearlly S.; Zanesi, Nicola; Wang, Linan; Rodrigues, Benjamin; Murphy, Mark; Balatti, Veronica; Bottoni, Arianna; Nazaryan, Natalya; Alder, Hansjuerg; Rassenti, Laura; Kipps, Thomas J.; Freitas, Michael; Croce, Carlo M.; Pekarsky, Yuri

    2012-01-01

    B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia. Deregulation of the T-cell leukemia/lymphoma 1 oncogene (TCL1) in mouse B cells causes a CD5+ leukemia similar to aggressive human CLL. To examine the mechanisms by which Tcl1 protein exerts its oncogenic activity in B cells, we performed proteomics experiments to identify its interacting partners. We found that Tcl1 physically interacts with de novo DNA methylthansferases Dnmt3A and Dnmt3B. We further investigated the effects of Tcl1 up-regulation on the enzymatic activity of Dnmt3A and found that Tcl1 overexpression drastically inhibits Dnmt3A function. In addition, B cells from TCL1 transgenic mice showed a significant decrease in DNA methylation compared with WT controls. Similarly, CLL samples with high Tcl1 expression showed a decrease in DNA methylation compared with CLL samples with low Tcl1 expression. Given the previous reports of inactivating mutations of DNMT3A in acute myelogenous leukemia and myelodysplastic syndrome, our results suggest that inhibition of de novo DNA methylation may be a common oncogenic mechanism in leukemogenesis. PMID:22308499

  20. Tcl1 protein functions as an inhibitor of de novo DNA methylation in B-cell chronic lymphocytic leukemia (CLL).

    PubMed

    Palamarchuk, Alexey; Yan, Pearlly S; Zanesi, Nicola; Wang, Linan; Rodrigues, Benjamin; Murphy, Mark; Balatti, Veronica; Bottoni, Arianna; Nazaryan, Natalya; Alder, Hansjuerg; Rassenti, Laura; Kipps, Thomas J; Freitas, Michael; Croce, Carlo M; Pekarsky, Yuri

    2012-02-14

    B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia. Deregulation of the T-cell leukemia/lymphoma 1 oncogene (TCL1) in mouse B cells causes a CD5(+) leukemia similar to aggressive human CLL. To examine the mechanisms by which Tcl1 protein exerts its oncogenic activity in B cells, we performed proteomics experiments to identify its interacting partners. We found that Tcl1 physically interacts with de novo DNA methylthansferases Dnmt3A and Dnmt3B. We further investigated the effects of Tcl1 up-regulation on the enzymatic activity of Dnmt3A and found that Tcl1 overexpression drastically inhibits Dnmt3A function. In addition, B cells from TCL1 transgenic mice showed a significant decrease in DNA methylation compared with WT controls. Similarly, CLL samples with high Tcl1 expression showed a decrease in DNA methylation compared with CLL samples with low Tcl1 expression. Given the previous reports of inactivating mutations of DNMT3A in acute myelogenous leukemia and myelodysplastic syndrome, our results suggest that inhibition of de novo DNA methylation may be a common oncogenic mechanism in leukemogenesis. PMID:22308499

  1. Understanding Leukemia

    MedlinePLUS

    ... I 800.955.4572 I www.LLS.org Tracking Your Leukemia Tests These tips may help you ... Tyrosine kinase inhibitor (TKI). A drug that blocks cell growth. Gleevec®, Sprycel® and Tasigna® are TKIs that ... team consists of master’s level oncology professionals who are available by phone Monday through Friday, 9 am to 6 pm ( ...

  2. Impact of bone marrow stromal cells on Bcl-2 family members in chronic lymphocytic leukemia

    PubMed Central

    Patel, Viralkumar; Balakrishnan, Kumudha; Wierda, William G.; Gandhi, Varsha

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the western world. High levels of Bcl-2 family anti-apoptotic proteins are responsible for apoptotic-resistance. Besides anti-apoptotic proteins, microenvironment provides substantial surviving signals to CLL leukemic cells. However, the in-depth-knowledge on the role of individual Bcl-2 family members in the context of microenvironment is still limited. We performed a comprehensive analysis of transcripts and proteins of 18 Bcl-2 family members using “apoptosis array micro fluidic card” in primary cells before and after stromal co-cultures. Our data showed that, 5 of 6 anti-apoptotic members (excluding Bcl-b), 2 of 3 pro-apoptotic members (excluding Bok) and 6 of 9 BH3-only members were present at detectable mRNA levels in CLL cells. Importantly, stromal mediated extended survival of CLL cells was in strong association with elevated global transcription. Upon co-culturing with stromal cells, there was early response of increase in anti- (2/5) and pro-apoptotic protein (3/8) transcripts on day 1, while increase in anti-apoptotic proteins were observed on day 3, with no significant change in pro-apoptotic proteins. Our study revealed a differential pattern of expression of both transcripts and proteins following stromal co-cultures, proposing significance of Bcl-2 family members in stromal microenvironment. PMID:23837491

  3. Mechanism of Hericium erinaceus (Yamabushitake) mushroom-induced apoptosis of U937 human monocytic leukemia cells.

    PubMed

    Kim, Sung Phil; Kang, Mi Young; Choi, Yong Hee; Kim, Jae Ho; Nam, Seok Hyun; Friedman, Mendel

    2011-06-01

    Phytochemicals in some foods are a potential source of bioactive safe compounds for cancer chemoprevention and suppression of tumor initiation, promotion, and metastasis. In the present study, we evaluated hot water (HWE), microwaved 50% ethanol (MWE), acidic (ACE), and alkaline (AKE) extracts of the fruitbody (sporocarp) of Hericium erinaceus (Yamabushitake, Lion's Mane) mushrooms for their ability to induce apoptosis (programmed cell death) in U937 human monocytic leukemia cells. Cell culture, cell viability, cytotoxicity, flow cytometry, chromosomal DNA integrity, mitochondrial membrane potential, expression of pro- and anti-apoptotic proteins, and activation and inhibition of caspase assays were carried out to help define the mechanism of observed apoptosis. The aqueous and aqueous/ethanolic extracts were active in all assays, whereas the acidic and alkaline extracts with the similar proximate compositions were both inactive. The results of the bioassays with the active extracts are consistent with an apoptosis mechanism governing suppression of the cell proliferation pathway that involves activation of mitochondria-mediated caspase-3 and caspase-9 but not caspase-8. Proximate analysis of the freeze-dried mushroom powder showed that it contains high amounts of proteins, carbohydrates, and minerals. The results indicate that H. erinaceus mushrooms may have therapeutic potential against human leukemia. PMID:21779573

  4. Factors that contribute to long-term survival in patients with leukemia not in remission at allogeneic hematopoietic cell transplantation

    PubMed Central

    2011-01-01

    Background There has been insufficient examination of the factors affecting long-term survival of more than 5 years in patients with leukemia that is not in remission at transplantation. Method We retrospectively analyzed leukemia not in remission at allogeneic hematopoietic cell transplantation (allo-HCT) performed at our institution between January 1999 and July 2009. Forty-two patients with a median age of 39 years received intensified conditioning (n = 9), standard (n = 12) or reduced-intensity conditioning (n = 21) for allo-HCT. Fourteen patients received individual chemotherapy for cytoreduction during the three weeks prior to reduced-intensity conditioning. Diagnoses comprised acute leukemia (n = 29), chronic myeloid leukemia-accelerated phase (n = 2), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) (n = 10) and plasma cell leukemia (n = 1). In those with acute leukemia, cytogenetic abnormalities were intermediate (44%) or poor (56%). The median number of blast cells in bone marrow (BM) was 26.0% (range; 0.2-100) before the start of chemotherapy for allo-HCT. Six patients had leukemic involvement of the central nervous system. Stem cell sources were related BM (7%), related peripheral blood (31%), unrelated BM (48%) and unrelated cord blood (CB) (14%). Results Engraftment was achieved in 33 (79%) of 42 patients. Median time to engraftment was 17 days (range: 9-32). At five years, the cumulative probabilities of acute graft-versus-host disease (GVHD) and chronic GVHD were 63% and 37%, respectively. With a median follow-up of 85 months for surviving patients, the five-year Kaplan-Meier estimates of leukemia-free survival rate and overall survival (OS) were 17% and 19%, respectively. At five years, the cumulative probability of non-relapse mortality was 38%. In the univariable analyses of the influence of pre-transplant variables on OS, poor-risk cytogenetics, number of BM blasts (>26%), MDS overt AML and CB as stem cell source were significantly associated with worse prognosis (p = .03, p = .01, p = .02 and p < .001, respectively). In addition, based on a landmark analysis at 6 months post-transplant, the five-year Kaplan-Meier estimates of OS in patients with and without prior history of chronic GVHD were 64% and 17% (p = .022), respectively. Conclusion Graft-versus-leukemia effects possibly mediated by chronic GVHD may have played a crucial role in long-term survival in, or cure of active leukemia. PMID:21477348

  5. 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. PMID:25828744

  6. Bone Marrow Cells in Acute Lymphoblastic Leukemia Create a Proinflammatory Microenvironment Influencing Normal Hematopoietic Differentiation Fates

    PubMed Central

    Vilchis-Ordoñez, Armando; Contreras-Quiroz, Adriana; Dorantes-Acosta, Elisa; Reyes-López, Alfonso; Quintela-Nuñez del Prado, Henry Martin; Venegas-Vázquez, Jorge; Mayani, Hector; Ortiz-Navarrete, Vianney; López-Martínez, Briceida; Pelayo, Rosana

    2015-01-01

    B-cell acute lymphoblastic leukemia (B-ALL) is a serious public health problem in the pediatric population worldwide, contributing to 85% of deaths from childhood cancers. Understanding the biology of the disease is crucial for its clinical management and the development of therapeutic strategies. In line with that observed in other malignancies, chronic inflammation may contribute to a tumor microenvironment resulting in the damage of normal processes, concomitant to development and maintenance of neoplastic cells. We report here that hematopoietic cells from bone marrow B-ALL have the ability to produce proinflammatory and growth factors, including TNF?, IL-1?, IL-12, and GM-CSF that stimulate proliferation and differentiation of normal stem and progenitor cells. Our findings suggest an apparently distinct CD13+CD33+ population of leukemic cells contributing to a proinflammatory microenvironment that may be detrimental to long-term normal hematopoiesis within B-ALL bone marrow. PMID:26090405

  7. Bone Marrow Cells in Acute Lymphoblastic Leukemia Create a Proinflammatory Microenvironment Influencing Normal Hematopoietic Differentiation Fates.

    PubMed

    Vilchis-Ordoñez, Armando; Contreras-Quiroz, Adriana; Vadillo, Eduardo; Dorantes-Acosta, Elisa; Reyes-López, Alfonso; Quintela-Nuñez Del Prado, Henry Martin; Venegas-Vázquez, Jorge; Mayani, Hector; Ortiz-Navarrete, Vianney; López-Martínez, Briceida; Pelayo, Rosana

    2015-01-01

    B-cell acute lymphoblastic leukemia (B-ALL) is a serious public health problem in the pediatric population worldwide, contributing to 85% of deaths from childhood cancers. Understanding the biology of the disease is crucial for its clinical management and the development of therapeutic strategies. In line with that observed in other malignancies, chronic inflammation may contribute to a tumor microenvironment resulting in the damage of normal processes, concomitant to development and maintenance of neoplastic cells. We report here that hematopoietic cells from bone marrow B-ALL have the ability to produce proinflammatory and growth factors, including TNF?, IL-1?, IL-12, and GM-CSF that stimulate proliferation and differentiation of normal stem and progenitor cells. Our findings suggest an apparently distinct CD13(+)CD33(+) population of leukemic cells contributing to a proinflammatory microenvironment that may be detrimental to long-term normal hematopoiesis within B-ALL bone marrow. PMID:26090405

  8. Horizontal transmission of clonal cancer cells causes leukemia in soft-shell clams.

    PubMed

    Metzger, Michael J; Reinisch, Carol; Sherry, James; Goff, Stephen P

    2015-04-01

    Outbreaks of fatal leukemia-like cancers of marine bivalves throughout the world have led to massive population loss. The cause of the disease is unknown. We recently identified a retrotransposon, Steamer, that is highly expressed and amplified to high copy number in neoplastic cells of soft-shell clams (Mya arenaria). Through analysis of Steamer integration sites, mitochondrial DNA single-nucleotide polymorphisms (SNPs), and polymorphic microsatellite alleles, we show that the genotypes of neoplastic cells do not match those of the host animal. Instead, neoplastic cells from dispersed locations in New York, Maine, and Prince Edward Island (PEI), Canada, all have nearly identical genotypes that differ from those of the host. These results indicate that the cancer is spreading between animals in the marine environment as a clonal transmissible cell derived from a single original clam. Our findings suggest that horizontal transmission of cancer cells is more widespread in nature than previously supposed. PMID:25860608

  9. Rimonabant-induced apoptosis in leukemia cell lines: activation of caspase-dependent and -independent pathways.

    PubMed

    Gallotta, Dario; Nigro, Patrizia; Cotugno, Roberta; Gazzerro, Patrizia; Bifulco, Maurizio; Belisario, Maria Antonietta

    2010-08-01

    Rimonabant (SR141716), a cannabinoid CB1 receptor antagonist known for anti-obesity activity, has more recently been shown to inhibit tumor cell growth. Here we demonstrated the antitumor potential of SR141716 in leukemia-derived cell lines and its low toxicity in normal cells (PBMC). SR141716 (1-20microM range of doses) reduced Jurkat and U937 cell number by activating death signals as well as affecting cell cycle progression. The most prominent response in U937 to SR141716 was a G(0)/G(1) block, while in Jurkat cells there was activation of cell death processes. SR141716-treated cells exhibited the morphological and biochemical features of apoptosis and to some extent necrosis. Apoptotic mode of cell death was confirmed in both cell lines by analysis of cell morphology, phosphatidylserine exposure and DNA fragmentation. Moreover, the drug was found to induce an early and robust mitochondrial membrane depolarization. In Jurkat cells the apoptotic process was typically caspase-dependent, while in U937 caspase-independent pathways were also activated. The contribution of PARP activation to SR141716-induced apoptosis in U937 was suggested by protein PARylation, AIF release and apoptosis reversal by PARP inhibitors. Moreover, SR141716 negatively modulated, especially in U937, the PI3K/AKT pathways. In conclusion, our data indicate that SR141716 elicits alternative response and/or cell death pathways depending on the cell type affected. PMID:20417624

  10. Significance of cytogenetic and fluorescence in situ hybridization analysis in evaluating antichronic myeloid leukemia efficacy of different immune effector cells

    Microsoft Academic Search

    Chun-Rong Tong; Bo Hong; Jing-Ying Qiu; Zhong Chen; Dao-Pei Lu

    2002-01-01

    We report on the antileukemia effect of interleukin 2 (IL2) on different immune cells from 22 patients with chronic myeloid leukemia (CML). Bone marrow cells from these patients were first cultured in modified long-term bone marrow culture medium for several days, then separately cultured with lymphokine activated killer cells (LAK), cytokine-induced killer cells (CIK), and dendritic cell cocultured CIK (DC-CIK)

  11. CAR therapy for hematological cancers: can success seen in the treatment of B-cell acute lymphoblastic leukemia be applied to other hematological malignancies?

    PubMed

    Pegram, Hollie J; Smith, Eric L; Rafiq, Sarwish; Brentjens, Renier J

    2015-06-01

    Chimeric antigen receptor (CAR) T-cell therapy has recently come into the spotlight due to impressive results in patients with B-cell acute lymphoblastic leukemia. By targeting CD19, a marker expressed most B-cell tumors, as well as normal B cells, CAR T-cell therapy has been investigated as a treatment strategy for B-cell leukemia and lymphoma. This review will discuss the successes of this therapy for the treatment of B-cell acute lymphoblastic leukemia and the challenges to this therapeutic strategy. We will also discuss application of CAR T-cell therapy to chronic lymphocytic leukemia and other B-cell malignancies including a follicular lymphoma, diffuse large B-cell lymphoma, as well as acute and plasma cell malignancies. PMID:26065479

  12. Dequalinium induces apoptosis in peripheral blood mononuclear cells isolated from human chronic lymphocytic leukemia.

    PubMed

    Pajuelo, Lucia; Calviño, Eva; Diez, Jose Carlos; Boyano-Adánez, Maria Del Carmen; Gil, Juana; Sancho, Pilar

    2011-12-01

    B-cell chronic lymphocytic leukemia (B-CLL) is an abnormal neoplasic proliferation of B cells, which accumulate mainly in the bone marrow and blood preventing both B cells development in the lymph nodes and the ability to fight against infection. The antitumor agents used in chemotherapy are aimed at inducing malignant cell death, thus limiting the growth and spreading of these cells. However, the lack of specificity for tumor cells exhibited by these agents causes undesirable side effects that have led to the investigation of new therapeutic strategies designed to specifically target malignant cells and thus trigger selective cell destruction. Dequalinium (DQA) is an antitumoral agent that selectively accumulates in the mitochondria and has been shown to display anticancer activity in cells from different malignancies. In the present study, the DQA-induced cytotoxicity in B-CLL cells was analyzed by measuring cell viability and cell death, either by necrosis or apoptosis. Our results support the importance of DQA as a selective and potential antileukemic drug with a higher cytotoxic effect on peripheral blood mononuclear cells from B-CLL patients than in those from healthy donors and encourage the performance of further studies in combination with other agents. PMID:20524037

  13. Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation.

    PubMed

    Andersson, E I; Rajala, H L M; Eldfors, S; Ellonen, P; Olson, T; Jerez, A; Clemente, M J; Kallioniemi, O; Porkka, K; Heckman, C; Loughran, T P; Maciejewski, J P; Mustjoki, S

    2013-01-01

    T-cell large granular lymphocytic (T-LGL) leukemia is a clonal disease characterized by the expansion of mature CD3+CD8+ cytotoxic T cells. It is often associated with autoimmune disorders and immune-mediated cytopenias. Our recent findings suggest that up to 40% of T-LGL patients harbor mutations in the STAT3 gene, whereas STAT5 mutations are present in 2% of patients. In order to identify putative disease-causing genetic alterations in the remaining T-LGL patients, we performed exome sequencing from three STAT mutation-negative patients and validated the findings in 113 large granular lymphocytic (LGL) leukemia patients. On average, 11 CD8+ LGL leukemia cell-specific high-confidence nonsynonymous somatic mutations were discovered in each patient. Interestingly, all patients had at least one mutation that affects either directly the STAT3-pathway (such as PTPRT) or T-cell activation (BCL11B, SLIT2 and NRP1). In all three patients, the STAT3 pathway was activated when studied by RNA expression or pSTAT3 analysis. Screening of the remaining 113 LGL leukemia patients did not reveal additional patients with same mutations. These novel mutations are potentially biologically relevant and represent rare genetic triggers for T-LGL leukemia, and are associated with similar disease phenotype as observed in patients with mutations in the STAT3 gene. PMID:24317090

  14. Bovine lactoferricin causes apoptosis in Jurkat T-leukemia cells by sequential permeabilization of the cell membrane and targeting of mitochondria

    SciTech Connect

    Mader, Jamie S. [Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 1X5 (Canada); Richardson, Angela [Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 1X5 (Canada); Salsman, Jayme [Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 1X5 (Canada); Top, Deniz [Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 1X5 (Canada); Antueno, Roberto de [Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 1X5 (Canada); Duncan, Roy [Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 1X5 (Canada); Hoskin, David W. [Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 1X5 (Canada) and Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 1X5 (Canada)]. E-mail: d.w.hoskin@dal.ca

    2007-07-15

    Bovine lactoferricin (LfcinB) is a cationic antimicrobial peptide that kills Jurkat T-leukemia cells by the mitochondrial pathway of apoptosis. However, the process by which LfcinB triggers mitochondria-dependent apoptosis is not well understood. Here, we show that LfcinB-induced apoptosis in Jurkat T-leukemia cells was preceded by LfcinB binding to, and progressive permeabilization of the cell membrane. Colloidal gold electron microscopy revealed that LfcinB entered the cytoplasm of Jurkat T-leukemia cells prior to the onset of mitochondrial depolarization. LfcinB was not internalized by endocytosis because endocytosis inhibitors did not prevent LfcinB-induced cytotoxicity. Furthermore, intracellular delivery of LfcinB via fusogenic liposomes caused the death of Jurkat T-leukemia cells, as well as normal human fibroblasts. Collectively, these findings suggest that LfcinB caused damage to the cell membrane that allowed LfcinB to enter the cytoplasm of Jurkat T-leukemia cells and mediate cytotoxicity. In addition, confocal microscopy showed that intracellular LfcinB co-localized with mitochondria in Jurkat T-leukemia cells, while flow cytometry and colloidal gold electron microscopy showed that LfcinB rapidly associated with purified mitochondria. Furthermore, purified mitochondria treated with LfcinB rapidly lost transmembrane potential and released cytochrome c. We conclude that LfcinB-induced apoptosis in Jurkat T-leukemia cells resulted from cell membrane damage and the subsequent disruption of mitochondrial membranes by internalized LfcinB.

  15. Synergistic property of cordycepin in cultivated Cordyceps militaris-mediated apoptosis in human leukemia cells.

    PubMed

    Chou, Shang-Min; Lai, Wan-Jung; Hong, Tzu-Wen; Lai, Jui-Ya; Tsai, Sheng-Hong; Chen, Yen-Hsun; Yu, Sz-Hsien; Kao, Cheng-Hsiang; Chu, Richard; Ding, Shih-Torng; Li, Tsai-Kun; Shen, Tang-Long

    2014-10-15

    Cordyceps militaris is a well-known Chinese traditional medicinal mushroom frequently used for tonics and recently of a potential interest for cancer intervention. Here, we explored the cancer cell killing activity of the hot water extracts of C. militaris cultured mycelia (CM(MY)) and cultivated fruiting bodies (CM(FB)). We found that CM(FB) exhibited a greater cytotoxic effect against various cancer cells over CM(MY). Apoptotic phenotypes including apoptotic body formation, DNA laddering, caspase 3 activation and cleavage of PARP proteins were induced by CM(FB) treatment but only slightly induced by same concentration of CM(MY) treatment in human HL-60 leukemia cells. Cordycepin in CM(FB) (10.47 mg/g) is significantly higher (? 15.2 times) than that of CM(MY) (0.69 mg/g). Using isobolographic analysis, the synergy of cytotoxicity was observed across different combined concentrations of CM(MY) and cordycepin. By complementing cordycepin into CM(MY) to the level comparable with CM(FB), we observed that CM(MY) (500 ?g/ml) with cordycepin (4.8 ?g/ml) induced apoptosis to a level similar to that induced by CM(FB) (500 ?g/ml). Together, our results suggest that cordycepin possesses a synergistic cytotoxic effect with Cordyceps militaris-mediated apoptosis in human leukemia cells and therefore explaining a better anti-proliferating activity of CM(FB) over CM(MY). PMID:25442260

  16. Regulation of leukemia-initiating cell activity by the ubiquitin ligase FBXW7

    PubMed Central

    King, Bryan; Trimarchi, Thomas; Reavie, Linsey; Xu, Luyao; Mullenders, Jasper; Ntziachristos, Panagiotis; Aranda-Orgilles, Beatriz; Perez-Garcia, Arianne; Shi, Junwei; Vakoc, Christopher; Sandy, Peter; Shen, Steven S.; Ferrando, Adolfo; Aifantis, Iannis

    2013-01-01

    SUMMARY Sequencing efforts led to the identification of somatic mutations that could affect self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase FBXW7. Missense FBXW7 mutations are prevalent in various tumors, including T-cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. We show here that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes, but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting a novel effective therapeutic strategy. PMID:23791182

  17. Levofloxacin in Preventing Infection in Young Patients With Acute Leukemia Receiving Chemotherapy or Undergoing Stem Cell Transplantation | Division of Cancer Prevention

    Cancer.gov

    This randomized phase III trial studies how well levofloxacin works in preventing infection in young patients with acute leukemia receiving chemotherapy or undergoing stem cell transplant. Giving antibiotics may be effective in preventing or controlling early infection in patients receiving chemotherapy or undergoing stem cell transplant for acute leukemia. It is not yet known whether levofloxacin is effective in preventing infection.

  18. T cells raised against allogeneic HLA-A2/CD20 kill primary follicular lymphoma and acute lymphoblastic leukemia cells.

    PubMed

    Abrahamsen, Ingerid Weum; Kjellevoll, Synneva; Greve-Isdahl, Margrethe; Mensali, Nadia; Wälchli, Sébastien; Kumari, Shraddha; Loland, Beate Fossum; Egeland, Torstein; Kolstad, Arne; Olweus, Johanna

    2012-04-15

    T cells mediating a graft-versus-leukemia/lymphoma effects without causing graft-versus-host disease would greatly improve the safety and applicability of hematopoietic stem cell transplantation. We recently demonstrated that highly peptide- and HLA-specific T cells can readily be generated against allogeneic HLA-A*02:01 in complex with a peptide from the B cell-restricted protein CD20. Here, we show that such CD20-specific T cells can easily be induced from naïve precursors in cord blood, demonstrating that they do not represent cross-reactive memory cells. The cells displayed high avidity and mediated potent cytotoxic effects on cells from patients with the CD20(pos) B cell malignancies follicular lymphoma (FL) and acute lymphoblastic leukemia (ALL). However, the cytotoxicity was consistently lower for cells from two of the ALL patients. The ALL cells that were less efficiently killed did not display lower surface expression of CD20 or HLA-A*02:01, or mutations in the CD20 sequence. Peptide pulsing fully restored the levels of cytotoxicity, indicating that they are indeed susceptible to T cell-mediated killing. Adoptive transfer of CD20-specific T cells to an HLA-A*02:01(pos) patient requires an HLA-A*02:01(neg) , but otherwise HLA identical, donor. A search clarified that donors meeting these criteria can be readily identified even for patients with rare haplotypes. The results bear further promise for the clinical utility of CD20-specific T cells in B cell malignancies. PMID:21630262

  19. Abnormal centrosome amplification in cells through the targeting of Ran-binding protein-1 by the human T cell leukemia virus type-1 Tax oncoprotein

    PubMed Central

    Peloponese, Jean-Marie; Haller, Kerstin; Miyazato, Akiko; Jeang, Kuan-Teh

    2005-01-01

    Human T cell leukemia virus type-1 (HTLV-1) is an oncogenic retrovirus etiologically causal of adult T cell leukemia. The virus encodes a Tax oncoprotein that functions in transcriptional regulation, cell cycle control, and transformation. Because adult T cell leukemia like many other human cancers is a disease of genomic instability with frequent gains and losses of chromosomes, to understand this disease it is important to comprehend how HTLV-1 engenders aneuploidy in host cells. In this regard, loss of cell cycle checkpoints permits tolerance of aneuploidy but does not explain how aneuploidy is created. We show here that HTLV-1 Tax causes abnormal centrosome fragmentation in the mitotic phase of the cell cycle. We report that Tax directly binds Ran and Ran-binding protein-1, locates to centrosomes/spindle poles, and causes supernumerary centrosomes. PMID:16365316

  20. Effects of the hedgehog inhibitor GDC-0449, alone or in combination with dasatinib, on BCR-ABL-positive leukemia cells.

    PubMed

    Okabe, Seiichi; Tauchi, Tetsuzo; Tanaka, Yuko; Katagiri, Seiichiro; Ohyashiki, Kazuma

    2012-11-01

    Hedgehog (Hh)-glioma-associated oncogene homolog (Gli) signaling is implicated in a large number of human cancers such as leukemia. In this study, we investigated the effects of the potent Hh antagonist GDC-0449 on the BCR-ABL-positive cell line OM9;22 and primary samples when leukemia cells were protected by a feeder cell line (S9 cells). The numbers of OM9;22 cells significantly increased with S9 cells. Treatment of OM9;22 cells with GDC-0449 caused cell growth inhibition and induced apoptosis. Moreover, GDC-0449 inhibited the colony growth of Philadelphia chromosome (Ph)-positive primary samples. We next investigated the effects of a combination of GDC-0449 and dasatinib on these cell lines. The growth inhibition typically promoted by dasatinib was significantly reduced in the presence of S9 cells. Treatment of Ph-positive leukemia cells with GDC-0449 and dasatinib in the presence of S9 caused significantly more cytotoxicity than that caused by each drug alone. Inhibition of Gli1 or Gli2 by siRNA transfection reduced the growth of the Ph-positive cell line K562 and increased cytotoxicity of dasatinib. Moreover, colony formations of Gli1 or Gli2 knockdown cells were also reduced. Data from this study suggest that administration of the Hh inhibitor GDC-0449 inhibits BCR-ABL-positive cell growth and enhances the cytotoxic effects of dasatinib in the presence of feeder cells. PMID:22642671

  1. Transgenic analysis of the stem cell leukemia +19 stem cell enhancer in adult and embryonic hematopoietic and endothelial cells.

    PubMed

    Silberstein, Lev; Sánchez, María-José; Socolovsky, Merav; Liu, Ying; Hoffman, Gary; Kinston, Sarah; Piltz, Sandie; Bowen, Mark; Gambardella, Laure; Green, Anthony R; Göttgens, Berthold

    2005-10-01

    Appropriate transcriptional regulation is critical for the biological functions of many key regulatory genes, including the stem cell leukemia (SCL) gene. As part of a systematic dissection of SCL transcriptional regulation, we have previously identified a 5,245-bp SCL +18/19 enhancer that targeted embryonic endothelium together with embryonic and adult hematopoietic progenitors and stem cells (HSCs). This enhancer is proving to be a powerful tool for manipulating hematopoietic progenitors and stem cells, but the design and interpretation of such transgenic studies require a detailed understanding of enhancer activity in vivo. In this study, we demonstrate that the +18/19 enhancer is active in mast cells, megakaryocytes, and adult endothelium. A 644-bp +19 core enhancer exhibited similar temporal and spatial activity to the 5,245-bp +18/19 fragment both during development and in adult mice. Unlike the +18/19 enhancer, the +19 core enhancer was only active in adult mice when linked to the eukaryotic reporter gene human placental alkaline phosphatase. Activity of a single core enhancer in HSCs, endothelium, mast cells, and megakaryocytes suggests possible overlaps in their respective transcriptional programs. Moreover, activity in a proportion of thymocytes and other SCL-negative cell types suggests the existence of a silencer elsewhere in the SCL locus. PMID:16051983

  2. Loss of T cell progenitor checkpoint control underlies leukemia initiation in Rag1-deficient NOD mice

    PubMed Central

    Yui, Mary A.; Feng, Ni; Zhang, Jingli A.; Liaw, Chen Yee; Rothenberg, Ellen V.; Longmate, Jeffrey A.

    2013-01-01

    NOD mice exhibit major defects in the earliest stages of T cell development in the thymus. Genome-wide genetic and transcriptome analyses were used to investigate the origins and consequences of an early T cell developmental checkpoint breakthrough in Rag1-deficient NOD mice. QTL analysis mapped the presence of checkpoint breakthrough cells to several known NOD diabetes susceptibility regions, particularly Idd9/11 on chromosome 4, suggesting common genetic origins for T cell defects affecting this trait and autoimmunity. Genome-wide RNA deep-sequencing of NOD and B6 Rag1-deficient thymocytes revealed the effects of genetic background prior to breakthrough, as well as the cellular consequences of the breakthrough. Transcriptome comparison between the two strains showed enrichment in differentially expressed signal transduction genes, prominently tyrosine kinase and actin-binding genes, in accord with their divergent sensitivities to activating signals. Emerging NOD breakthrough cells aberrantly expressed both stem cell-associated proto-oncogenes, such as Lmo2, Hhex, Lyl1, and Kit which are normally repressed at the commitment checkpoint, and post-?-selection checkpoint genes including Cd2 and Cd5. Co-expression of genes characteristic of multi-potent progenitors and more mature T cells persists in the expanding population of thymocytes, and in the thymic leukemias that emerge with age in these mice. These results show that Rag1-deficient NOD thymocytes have T cell defects that can collapse regulatory boundaries at two early T cell checkpoints, which may predispose them to both leukemia and autoimmunity. PMID:23440410

  3. Induction of apoptosis in human myeloid leukemia cells by remote exposure of resistive barrier cold plasma.

    PubMed

    Thiyagarajan, Magesh; Anderson, Heather; Gonzales, Xavier F

    2014-03-01

    Cold atmospheric plasma (CAP), an ambient temperature ionized gas, is gaining extensive interest as a promising addition to anti-tumor therapy primarily due to the ability to generate and control delivery of electrons, ions, excited molecules, UV photons, and reactive species such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) to a specific site. The heterogeneous composition of CAP offers the opportunity to mediate several signaling pathways that regulate tumor cells. Consequently, the array of CAP generated products has limited the identification of the mechanisms of action on tumor cells. The aim of this work is to assess the cell death response of human myeloid leukemia cells by remote exposure to CAP generated RNS by utilizing a novel resistive barrier discharge system that primarily produces RNS. The effect of variable treatments of CAP generated RNS was tested in THP-1 cell (human monocytic leukemia cell line), a model for hematological malignancy. The number of viable cells was evaluated with erythrosine-B staining, while apoptosis and necrosis was assessed by endonuclease cleavage observed by agarose gel electrophoresis and detection of cells with the exclusionary dye propidium iodide and fluorescently labeled annexin-V by flow cytometry and fluorescent microscopy. Our observations indicate that treatment dosage levels of 45 s of exposure to CAP emitted RNS-induced apoptotic cell death and for higher dosage conditions of ?50 s of exposure to CAP induced necrosis. Overall the results suggest that CAP emitted RNS play a significant role in the anti-tumor potential of CAP. PMID:24022746

  4. Cell differentiation and altered IMP dehydrogenase expression induced in human T-lymphoblastoid leukemia cells by mycophenolic acid and tiazofurin

    SciTech Connect

    Kiguchi, K.; Collart, F.R.; Henning-Chubb, C.; Huberman, E. (Argonne National Lab., IL (United States))

    1990-03-01

    The IMP dehydrogenase inhibitors mycophenolic acid (MPA) and tiazofurin (TZ) induce a time- and dose-dependent inhibition of cell growth, as well as differentiation in T-lymphoid CEM-2 leukemia cells. The differentiated cells have acquired a suppressor/cytotoxic T-lymphocyte phenotype characterized by reactivity with maturation-specific monoclonal antibodies. Coadministration of guanosine and hypoxanthine reduces the growth inhibition and diminishes the induction of differentiation by either MPA or TZ. No such reduction was observed for differentiation induced by phorbol 12-myristate 13-acetate (PMA). The lack of a consistent pattern of IMPDH expression in CEM-2 cells treated with IMPDH inhibitors or PMA indicates that no general association exists between the induction of cell differentiation and the expression of IMPDH. Nevertheless, the results indicating the IMPDH inhibitors can induce differentiation in CEM-2 cells suggest that this treatment may provide a useful approach to circumvent the differentiation block in some tumor cells.

  5. Treatment Option Overview (Adult Acute Myeloid Leukemia)

    MedlinePLUS

    ... abnormal myeloblasts (a type of white blood cell), red blood cells, or platelets. Adult acute myeloid leukemia ( ... is made mostly of fat. Leukemia may affect red blood cells, white blood cells, and platelets. Normally, ...

  6. FIP1L1-PDGFRA in chronic eosinophilic leukemia and BCR-ABL1 in chronic myeloid leukemia affect different leukemic cells.

    PubMed

    Crescenzi, B; Chase, A; Starza, R La; Beacci, D; Rosti, V; Gallì, A; Specchia, G; Martelli, M F; Vandenberghe, P; Cools, J; Jones, A V; Cross, N C P; Marynen, P; Mecucci, C

    2007-03-01

    We investigated genetically affected leukemic cells in FIP1L1-PDGFRA+ chronic eosinophilic leukemia (CEL) and in BCR-ABL1+ chronic myeloid leukemia (CML), two myeloproliferative disorders responsive to imatinib. Fluorescence in situ hybridization specific for BCR-ABL1 and for FIP1L1-PDGFRA was combined with cytomorphology or with lineage-restricted monoclonal antibodies and applied in CML and CEL, respectively. In CEL the amount of FIP1L1-PDGFRA+ cells among CD34+ and CD133+ cells, B and T lymphocytes, and megakaryocytes were within normal ranges. Positivity was found in eosinophils, granulo-monocytes and varying percentages of erythrocytes. In vitro assays with imatinib showed reduced survival of peripheral blood mononuclear cells but no reduction in colony-forming unit growth medium (CFU-GM) growth. In CML the BCR-ABL1 fusion gene was detected in CD34+/CD133+ cells, granulo-monocytes, eosinophils, erythrocytes, megakaryocytes and B-lymphocytes. Growth of both peripheral blood mononuclear cells and CFU-GM was inhibited by imatinib. This study provided evidence for marked differences in the leukemic masses which are targeted by imatinib in CEL or CML, as harboring FIP1L1-PDGFRA or BCR-ABL1. PMID:17215855

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

    SciTech Connect

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

    2009-05-29

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

  8. 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.

  9. Clerodane diterpenes isolated from Polyalthia longifolia induce apoptosis in human leukemia HL-60 cells.

    PubMed

    Sari, Dina Permata; Ninomiya, Masayuki; Efdi, Mai; Santoni, Adlis; Ibrahim, Sanusi; Tanaka, Kaori; Koketsu, Mamoru

    2013-01-01

    Polyalthia is a versatile genus of shrubs and trees found in tropic and sub-tropic regions. In this study, three clerodane diterpenes, kolavenic acid (1), polyalthialdoic acid (2), and 16?-hydroxy-cleroda-3,13(14)Z-dien-15,16-olide (3) isolated from Polyalthia longifolia leaves were evaluated for their apoptotic potential against human leukemia HL-60 cells. Compounds 2 and 3 inhibited cell proliferation with IC?? values of 21.8 and 13.7 ?M, respectively. Morphological changes and DNA fragmentation analysis indicated that these diterpenes induce apoptotic cell death in the HL-60 cells. Our results revealed the importance of P. longifolia as a chemopreventive medicinal plant. PMID:24088522

  10. The small molecule calactin induces DNA damage and apoptosis in human leukemia cells.

    PubMed

    Lee, Chien-Chih; Lin, Yi-Hsiung; Chang, Wen-Hsin; Wu, Yang-Chang; Chang, Jan-Gowth

    2012-09-01

    We purified calactin from the roots of the Chinese herb Asclepias curassavica L. and analyzed its biologic effects in human leukemia cells. Our results showed that calactin treatment caused DNA damage and resulted in apoptosis. Increased phosphorylation levels of Chk2 and H2AX were observed and were reversed by the DNA damage inhibitor caffeine in calactin-treated cells. In addition, calactin treatment showed that a decrease in the expression of cell cycle regulatory proteins Cyclin B1, Cdk1, and Cdc25C was consistent with a G2/M phase arrest. Furthermore, calactin induced extracellular signal-regulated kinase (ERK) phosphorylation, activation of caspase-3, caspase-8, and caspase-9, and PARP cleavage. Pretreatment with the ERK inhibitor PD98059 significantly blocked the loss of viability in calactin-treated cells. It is indicated that calactin-induced apoptosis may occur through an ERK signaling pathway. Our data suggest that calactin is a potential anticancer compound. PMID:22828439

  11. Peripheral T-lymphocytes express WNT7A and its restoration in leukemia-derived lymphoblasts inhibits cell proliferation

    PubMed Central

    2012-01-01

    Background WNT7a, a member of the Wnt ligand family implicated in several developmental processes, has also been reported to be dysregulated in some types of tumors; however, its function and implication in oncogenesis is poorly understood. Moreover, the expression of this gene and the role that it plays in the biology of blood cells remains unclear. In addition to determining the expression of the WNT7A gene in blood cells, in leukemia-derived cell lines, and in samples of patients with leukemia, the aim of this study was to seek the effect of this gene in proliferation. Methods We analyzed peripheral blood mononuclear cells, sorted CD3 and CD19 cells, four leukemia-derived cell lines, and blood samples from 14 patients with Acute lymphoblastic leukemia (ALL), and 19 clinically healthy subjects. Reverse transcription followed by quantitative Real-time Polymerase chain reaction (qRT-PCR) analysis were performed to determine relative WNT7A expression. Restoration of WNT7a was done employing a lentiviral system and by using a recombinant human protein. Cell proliferation was measured by addition of WST-1 to cell cultures. Results WNT7a is mainly produced by CD3 T-lymphocytes, its expression decreases upon activation, and it is severely reduced in leukemia-derived cell lines, as well as in the blood samples of patients with ALL when compared with healthy controls (p ?0.001). By restoring WNT7A expression in leukemia-derived cells, we were able to demonstrate that WNT7a inhibits cell growth. A similar effect was observed when a recombinant human WNT7a protein was used. Interestingly, restoration of WNT7A expression in Jurkat cells did not activate the canonical Wnt/?-catenin pathway. Conclusions To our knowledge, this is the first report evidencing quantitatively decreased WNT7A levels in leukemia-derived cells and that WNT7A restoration in T-lymphocytes inhibits cell proliferation. In addition, our results also support the possible function of WNT7A as a tumor suppressor gene as well as a therapeutic tool. PMID:22313908

  12. A feedback model for leukemia including cell competition and the action of the immune system

    NASA Astrophysics Data System (ADS)

    Balea, S.; Halanay, A.; Neamtu, M.

    2014-12-01

    A mathematical model, coupling the dynamics of short-term stem-like cells and mature leukocytes in leukemia with that of the immune system, is investigated. The model is described by a system of nine delay differential equations with nine delays. Three equilibrium points E0, E1, E2 are highlighted. The stability and the existence of the Hopf bifurcation for the equilibrium points are investigated. In the analysis of the model, the rate of asymmetric division and the rate of symmetric division are very important.

  13. Granulocytic differentiation of HL-60 promyelocytic leukemia cells is associated with increased expression of Cul5.

    PubMed

    Baxter, Shaneen S; Carlson, Lauren A; Mayer, Alejandro M S; Hall, Mary L; Fay, Michael J

    2009-01-01

    The human HL-60 promyelocytic leukemia cell line has been widely used as a model for studying granulocytic differentiation. All-trans retinoic acid (ATRA) treatment of HL-60 cells promotes granulocytic differentiation and is effective as differentiation therapy for patients with acute promyelocytic leukemia. The identification of genes that are transcriptionally regulated by ATRA has provided insight into granulocytic differentiation and differentiation therapy. The Asb-2 (ankyrin repeat SOCS box 2) gene has previously been identified as a transcriptional target in ATRA-treated HL-60 cells. The ASB-2 protein forms an E3 ubiquitin ligase complex with the proteins, Cul5, regulator of cullin 2 (ROC2), and elongin B and C. The purpose of this study was to determine if there is increased expression of Cul5 during granulocytic differentiation of HL-60 cells. To induce granulocytic differentiation, HL-60 cells were treated for 5 d with ATRA and differentiation was confirmed by examining superoxide anion production, nuclear morphology, and changes in the expression of CD11b, CD13, and CD15. Quantitative real-time RT-PCR was used to measure Cul5 mRNA expression and also the expression of other components of the E3 ubiquitin ligase (ASB-2, ROC2, elongin B and C). Granulocytic differentiation of HL-60 cells was associated with a 1.6-, 1.7-, and 23-fold statistically significant (P cells. Increased expression of multiple components of the Cul5-containing E3 ubiquitin ligase complex with ATRA treatment of HL-60 cells indicates that this complex may play an important role in granulocytic differentiation. PMID:19118439

  14. CITED2-mediated human hematopoietic stem cell maintenance is critical for acute myeloid leukemia.

    PubMed

    Korthuis, P M; Berger, G; Bakker, B; Rozenveld-Geugien, M; Jaques, J; de Haan, G; Schuringa, J J; Vellenga, E; Schepers, H

    2015-03-01

    As the transcriptional coactivator CITED2 (CBP/p300-interacting-transactivator-with-an ED-rich-tail 2) can be overexpressed in acute myeloid leukemia (AML) cells, we analyzed the consequences of high CITED2 expression in normal and AML cells. CITED2 overexpression in normal CD34(+) cells resulted in enhanced hematopoietic stem and progenitor cell (HSPC) output in vitro, as well as in better hematopoietic stem cell (HSC) engraftability in NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice. This was because of an enhanced quiescence and maintenance of CD34(+)CD38(-) HSCs, due in part to an increased expression of the cyclin-dependent kinase inhibitor CDKN1A. We demonstrated that PU.1 is a critical regulator of CITED2, as PU.1 repressed CITED2 expression in a DNA methyltransferase 3A/B (DNMT3A/B)-dependent manner in normal CD34(+) cells. CD34(+) cells from a subset of AML patients displayed higher expression levels of CITED2 as compared with normal CD34(+) HSPCs, and knockdown of CITED2 in AML CD34(+) cells led to a loss of long-term expansion, both in vitro and in vivo. The higher CITED2 expression resulted from reduced PU.1 activity and/or dysfunction of mutated DNMT3A/B. Collectively, our data demonstrate that increased CITED2 expression results in better HSC maintenance. In concert with low PU.1 levels, this could result in a perturbed myeloid differentiation program that contributes to leukemia maintenance. PMID:25184385

  15. Docosahexaenoic acid induces dose dependent cell death in an early undifferentiated subtype of acute myeloid leukemia cell line.

    PubMed

    Yamagami, Takashi; Porada, Christopher D; Pardini, Ronald S; Zanjani, Esmail D; Almeida-Porada, Graça

    2009-02-01

    Acute myeloid leukemia (AML) is the most frequently diagnosed adulthood leukemia, yet current therapies offer a cure rate of less than 30%. This may be due in part to the fact that the leukemia-initiating cells in AML reside within the rare and highly primitive CD34(+)CD38(-) hematopoietic stem/progenitor cell (HSC) population that are often resistant to chemotherapy. Docosahexanoic acid (DHA), a major component of fish oil, has previously been shown to inhibit the induction and progression of breast, prostate and colon cancer, and increase the therapeutic effects of numerous chemotherapeutics, often by enhancing apoptosis. In the present studies, we investigated DHA's effect on the primitive and undifferentiated AML cell line KG1a, to explore the potential of this fatty acid to serve as adjuvant therapy for AML. Treatment of KG1a cells with DHA for 96 hours did not lead to maturation or cell cycle modification when compared to an untreated KG1a control (n = 4). However, DHA treatment of KG1a cells resulted in a progressive loss of viability, DNA fragmentation, and an increase in Annexin V expression, demonstrating DHA-induced apoptosis (n = 4). Moreover, expression of the pro-apoptotic protein Bax was increased, with resultant skewing in the Bax/bcl-2 ratio, providing a mechanistic explanation for the observed DHA-induced increase in apoptosis. Since we also show that DHA does not have a detrimental effect on normal hematopoiesis our results suggest that DHA could potentially serve as an well-tolerated adjuvant in the treatment of AML patients. PMID:19197149

  16. Anti-leukemia activity of a bacterial toxin with natural specificity for LFA-1 on white blood cells

    PubMed Central

    Kachlany, Scott C.; Schwartz, Amy B.; Balashova, Nataliya V.; Hioe, Catarina E.; Tuen, Michael; Le, Amy; Kaur, Manpreet; Mei, Yongyi; Rao, Jia

    2009-01-01

    The oral bacterium, Aggregatibacter actinomycetemcomitans, produces a leukotoxin (LtxA) that is specific for white blood cells (WBCs) from humans and Old World primates by interacting with lymphocyte function antigen-1 (LFA-1) on susceptible cells. To determine if LtxA could be used as a therapeutic agent for the treatment of WBC diseases, we tested the in vitro and in vivo anti-leukemia activity of the toxin. LtxA kills human malignant WBC lines and primary leukemia cells from acute myeloid leukemia patients, but healthy peripheral blood mononuclear cells (PBMCs) are relatively resistant to LtxA-mediated cytotoxicity. Levels of LFA-1 on cell lines correlated with killing by LtxA and the toxin preferentially killed cells expressing the activated form of LFA-1. In a SCID mouse model for human leukemia, LtxA had potent therapeutic value resulting in long-term survival in LtxA-treated mice. Intravenous infusion of LtxA into a rhesus macaque resulted in a drop in WBC counts at early times post-infusion; however, red blood cells, platelets, hemoglobin and blood chemistry values remained unaffected. Thus, LtxA may be an effective and safe novel therapeutic agent for the treatment of hematologic malignancies. PMID:19747730

  17. Kuromoji (Lindera umbellata) essential oil-induced apoptosis and differentiation in human leukemia HL-60 cells

    PubMed Central

    MAEDA, HAYATO; YAMAZAKI, MAO; KATAGATA, YOHTARO

    2012-01-01

    Essential oils diluted from certain plants have been shown to have antitumor activity against several human tumor cell lines. Kuromoji (Lindera umbellata) essential oil (KEO) has long been used in Japan as a traditional medicine. KEO and its major chemical constituent, linalool, were investigated in this study for their ability to induce apoptosis and differentiation in human leukemia HL-60 cells. HL-60 cells were treated with 5 or 50 ?g/ml KEO or linalool for 24 or 48 h. Then, cell proliferation and apoptosis induction were estimated. In addition, HL-60 cells are known to differentiate into granulocyte or monocytes by a variety of compounds. Therefore, the effect of KEO or linalool on differentiation of HL-60 cells was assessed by Giemsa stain and a nitroblue tetrazolium reduction assay. Cells treated with KEO or linalool for 48 h showed significantly suppressed cell proliferation, with induced apoptosis. Moreover, KEO and linalool promoted cell differentiation. Treatment with KEO cells at the same dose as linalool showed an almost identical effect on HL-60 cells. These results suggest that KEO and linalool have efficacy as anticancer therapeutic products. PMID:22969843

  18. Chaetoglobosin A preferentially induces apoptosis in chronic lymphocytic leukemia cells by targeting the cytoskeleton.

    PubMed

    Knudsen, P B; Hanna, B; Ohl, S; Sellner, L; Zenz, T; Döhner, H; Stilgenbauer, S; Larsen, T O; Lichter, P; Seiffert, M

    2014-06-01

    Chronic lymphocytic leukemia (CLL) is an incurable malignancy of mature B cells. One of the major challenges in treatment of CLL is the achievement of a complete remission to prevent relapse of disease originating from cells within lymphoid tissues and subsequent chemoresistance. In search for novel drugs that target CLL cells in protective microenvironments, we performed a fungal extract screen using cocultures of primary CLL cells with bone marrow-derived stromal cells. A secondary metabolite produced by Penicillium aquamarinium was identified as Chaetoglobosin A (ChA), a member of the cytochalasan family that showed preferential induction of apoptosis in CLL cells, even under culture conditions that mimic lymphoid tissues. In vitro testing of 89 CLL cases revealed effective targeting of CLL cells by ChA, independent of bad prognosis characteristics, like 17p deletion or TP53 mutation. To provide insight into its mechanism of action, we showed that ChA targets filamentous actin in CLL cells and thereby induces cell-cycle arrest and inhibits membrane ruffling and cell migration. Our data further revealed that ChA prevents CLL cell activation and sensitizes them for treatment with PI3K and BTK inhibitors, suggesting this compound as a novel potential drug for CLL. PMID:24280868

  19. New drugs in the treatment of acute and chronic leukemia with some emphasis on m-AMSA.

    PubMed

    Jehn, U; Heinemann, V

    1991-01-01

    Several new cytostatic drugs have entered clinical phase I-II studies for the treatment of leukemia: the most promising are pyrimidine analogs such as 5-aza-cytidine, 5-aza-2'-deoxycytidine, 5-aza-cytosine arabinoside, and 2',2'-difluorodeoxycytidine. Fludarabine, a fluorinated purine analog, appears to be active in CLL and multiple myeloma. Deoxycoformycin, an adenosine analog, showed good activity in the treatment of hairy cell leukemia and T-cell neoplasias. 2-chloro-deoxyadenosine has recently been introduced into the treatment of CLL and hairy-cell leukemia refractory to deoxycoformicin. Tiazofurin, an antimetabolite which interferes with nicotine-adenine-dinucleotide (NAD) metabolism, has been applied in CML blast crisis. Other agents include 13-cis retinoic acid and 1, 25-dihydroxy vitamin D3 as differentiation inducers, and homoharringtonine, an alkylating agent which is widely used for ANLL treatment in China. Among new anthracyclines, aclarubicin, idarubicin, THP-adriamycin and fluoro-adriamycin should be mentioned. Mitoxantrone, a substituted anthraquinone, has successfully been applied in the treatment of relapsed and refractory ANLL. Amsacrine (m-AMSA), finally, is a synthetic aminoacridine which intercalates into DNA and inhibits DNA topoisomerase II. m-AMSA is not cross-resistant to anthracyclines and has been particularly active in ANLL treatment. Studies using m-AMSA alone or in combination revealed comparable results to anthracycline--containing regimens. Cardiotoxicity of the anthracycline congestive type has not been observed with m-AMSA. The EORTC Leukemia Cooperative Group has successfully used m-AMSA in several trials prepositioning this drug stepwise: from relapsed and refractory ANLL, into intensive maintenance treatment during first remission in ANLL, and, still on-going, into intensive consolidation. PMID:2064323

  20. Induction of apoptosis by cordycepin via reactive oxygen species generation in human leukemia cells.

    PubMed

    Jeong, Jin-Woo; Jin, Cheng-Yun; Park, Cheol; Hong, Su Hyun; Kim, Gi-Young; Jeong, Yong Kee; Lee, Jae-Dong; Yoo, Young Hyun; Choi, Yung Hyun

    2011-06-01

    Cordycepin (3'-deoxyadenosin), a specific polyadenylation inhibitor, is the main functional component in Cordyceps militaris, one of the top three renowned traditional Chinese medicines. Cordycepin has been shown to possess many pharmacological activities including immunological stimulation, and anti-bacterial, anti-viral, and anti-tumor effects. However, the mechanisms underlying its anti-cancer mechanisms are not yet understood. In this study, the apoptotic effects of cordycepin were investigated in human leukemia cells. Treatment with cordycepin significantly inhibited cell growth in a concentration-dependent manner by inducing apoptosis but not necrosis. This induction was associated with generation of reactive oxygen species (ROS), mitochondrial dysfunction, activation of caspases, and cleavage of poly(ADP-ribose) polymerase protein. However, apoptosis induced by cordycepin was attenuated by caspase inhibitors, indicating an important role for caspases in cordycepin responses. Administration of N-acetyl-l-cysteine, a scavenger of ROS, also significantly inhibited cordycepin-induced apoptosis and activation of caspases. These results support a mechanism whereby cordycepin induces apoptosis of human leukemia cells through a signaling cascade involving a ROS-mediated caspase pathway. PMID:21310227

  1. Glutaminase activity determines cytotoxicity of l-asparaginases on most leukemia cell lines.

    PubMed

    Parmentier, Jean Hugues; Maggi, Maristella; Tarasco, Erika; Scotti, Claudia; Avramis, Vassilios I; Mittelman, Steven D

    2015-07-01

    l-Asparaginase (ASNase) is a front-line chemotherapy for acute lymphoblastic leukemia (ALL), which acts by deaminating asparagine and glutamine. To evaluate the importance of glutaminase activity, we exploited a recently developed mutant of Helicobacter pylori ASNase (dm HpA), with amino acid substitutions M121C/T169M. The mutant form has the same asparaginase activity as wild-type but lacks glutaminase activity. Wild-type and dm HpA were compared with the clinically used ASNases from Escherichia coli (l-ASP) and Erwinia chrysanthemi (ERWase). Asparaginase activity was similar for all isoforms, while glutaminase activity followed the rank order: ERWase>l-ASP>wild-type HpA>dm HpA. Cytotoxic efficacy of ASNases was tested on 11 human leukemia cell lines and two patient-derived ALL samples. Two cell lines which we had previously shown to be asparagine-dependent were equally sensitive to the asparaginase isoforms. The other nine lines and the two patient-derived samples were more sensitive to isoforms with higher glutaminase activities. ERWase was overall the most effective ASNase on all cell lines tested whereas dm HpA, having the lowest glutaminase activity, was the least effective. These data demonstrate that asparaginase activity alone may not be sufficient for ASNase cytotoxicity, and that glutaminase activity may be required for full anti-leukemic efficacy. PMID:25941002

  2. In vitro anticancer activity of loquat tea by inducing apoptosis in human leukemia cells.

    PubMed

    Zar, Phyu Phyu Khine; Yano, Satoshi; Sakao, Kozue; Hashimoto, Fumio; Nakano, Takayuki; Fujii, Makoto; Hou, De-Xing

    2014-01-01

    Fresh loquat leaves have been used as folk health herb in Asian countries for long time, although the evidence supporting their functions is still minimal. This study aimed to clarify the chemopreventive effect of loquat tea extract (LTE) by investigating the inhibition on proliferation, and underlying mechanisms in human promyelocytic leukemia cells (HL-60). LTE inhibited proliferation of HL-60 in a dose-dependent manner. Molecular data showed that the isolated fraction of LTE induced apoptosis of HL-60 as characterized by DNA fragmentation; activation of caspase-3, -8, and -9; and inactivation of poly(ADP)ribose polymerase. Moreover, LTE fraction increased the ratio of pro-apoptotic Bcl-2-associated X protein (Bax)/anti-apoptotic myeloid cell leukemia 1 (Mcl-1) that caused mitochondrial membrane potential loss and cytochrome c released to cytosol. Thus, our data indicate that LTE might induce apoptosis in HL-60 cells through a mitochondrial dysfunction pathway. These findings enhance our understanding for chemopreventive function of loquat tea. PMID:25118018

  3. Activity of ladanein on leukemia cell lines and its occurrence in Marrubium vulgare.

    PubMed

    Alkhatib, Racha; Joha, Sami; Cheok, Meyling; Roumy, Vincent; Idziorek, Thierry; Preudhomme, Claude; Quesnel, Bruno; Sahpaz, Sevser; Bailleul, François; Hennebelle, Thierry

    2010-01-01

    Three methoxylated flavones isolated from Marrubium peregrinum - ladanein, scutellarein-5,7,4'-trimethyl ether, and scutellarein-5,6,7,4'-tetramethyl ether - were assayed for their cytotoxicity towards a recently developed dasatinib-resistant murine leukemia cell line (DA1-3b/M2 (BCR-ABL)), together with the structurally related non-methylated flavone scutellarein. The most active compound, ladanein, was looked for in 20 common Lamiaceae species by a quick HPLC screening. Among the possible positive results, the most interesting source was found to be Marrubium vulgare, which led to the isolation and identification of ladanein for the first time in this species. Ladanein also displayed moderate (20-40 microM) activities against K562, K562R (imatinib-resistant), and 697 human leukemia cell lines but was toxic neither to MOLM13 nor to human peripheral blood mononuclear cells. This work provides a common natural source for the hemi-synthesis of future ladanein-derived flavones and the study of their antileukemic activity. PMID:19644796

  4. Tuning surface wettability by designing hairy structures

    NASA Astrophysics Data System (ADS)

    Pei, Han-Wen; Liu, Hong; Lu, Zhong-Yuan; Zhu, You-Liang

    2015-02-01

    We present a molecular dynamics simulation study on the controlling factors that influence the wettability of a hairy surface. By adopting the hairs with appropriate grafting density, hair length, and hair rigidity, the hairy surface shows good performance on droplet repellency. When the droplet sits on the hairy surface, the flexible hairs can spontaneously bundle with the appropriate amount of neighboring hairs to enhance the surface hydrophobicity, thus providing a new possibility to control the surface wettability. The hairy surface with tunable grafting density and hair rigidity, bridges the gap between surfaces with soft polymer brushes and surfaces that are completely hard but porous.

  5. Adult T-Cell Leukemia: Antigen in an ATL Cell Line and Detection of Antibodies to the Antigen in Human Sera

    Microsoft Academic Search

    Yorio Hinuma; Kinya Nagata; Masao Hanaoka; Masuyo Nakai; Tadashi Matsumoto; Ken-Ichiro Kinoshita; Shigeru Shirakawa; Isao Miyoshi

    1981-01-01

    Indirect immunofluorescence of certain human sera demonstrated an antigen(s) in the cytoplasm of 1-5% of the cells of a T-cell line, MT-1, from a patient with adult T-cell leukemia (ATL), which is endemic in southwestern Japan. The antigen was not detected in other human lymphoid cell lines, including six T-cell lines, seven B-cell lines, and four non-T non-B cell lines.

  6. [Experimental study on aging effect of Angelica sinensis polysaccharides combined with cytarabine on human leukemia KG1alpha cell lines].

    PubMed

    Xu, Chun-Yan; Geng, Shan; Liu, Jun; Zhu, Jia-Hong; Zhang, Xian-Ping; Jiang, Rong; Wang, Ya-Ping

    2014-04-01

    The latest findings of our laboratory showed that Angelica sinensis polysaccharide (ASP) showed a definite effect in regulating the aging of hematopoietic stem cells. Leukemia is a type of malignant hematopoietic tumor in hematopoietic stem cells. There have been no relevant reports about ASP's effect in regulating the aging of leukemia cells. In this study, human acute myeloid leukemia (AML) KG1alpha cell lines in logarithmic growth phase were taken as the study object, and were divided into the ASP group, the cytarabine (Ara-C) group, the ASP + Ara-C group and the control group. The groups were respectively treated with different concentration of ASP, Ara-C and ASP + Ara-C for different periods, with the aim to study the effect of ASP combined with Ara-C in regulating the aging of human acute myeloid leukemia KG1alpha cell lines and its relevant mechanism. The results showed that ASP, Ara-C and ASP + Ara-C could obviously inhibit KG1alpha cell proliferation in vitro, block the cells in G0/G1 phase. The cells showed the aging morphological feature. The percentage of positive stained aging cells was dramatically increased, and could significantly up-regulate the expression of aging-related proteins P16 and RB, which were more obvious in the ASP + Ara-C group. In conclusion, the aging mechanism of KG1alpha cell induced by ASP and Ara-C may be related to the regulation of the expression of aging-related proteins, suggesting that the combined administration of ASP and anticancer drugs plays a better role in the treatment of leukemia . PMID:25011265

  7. Molecular phylogeny of human T-cell leukemia virus type I and II of amerindians in Colombia and Chile

    Microsoft Academic Search

    Tomoyuki Miura; Masahiro Yamashita; Vladimir Zaninovic; Luis Cartier; Jun Takehisa; Tatsuhiko Igarashi; Eiji Ido; Toshinobu Fujiyoshi; Shunro Sonoda; Kazuo Tajima; Masanori Hayami I

    1997-01-01

    Six human T-cell leukemia virus type I (HTLV-I) and eight human T-cell leukemia virus type II (HTLV-II) cases newly isolated\\u000a from the South American countries of Colombia and Chile were analyzed together with the two Amerindian HTLV-I isolates previously\\u000a reported. All of the HTLV-I isolates belonged to the transcontinental subgroup of the “cosmopolitan” group, and Colombian\\u000a isolates, including those from

  8. The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells

    SciTech Connect

    Trinks, Cecilia, E-mail: Cecilia.trinks@liu.se [Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden)] [Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Severinsson, Emelie A., E-mail: Emelie.severinsson@liu.se [Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Holmlund, Birgitta, E-mail: Birgitta.holmlund@lio.se [Department of Oncology, County Council of Ostergoetland, Linkoeping (Sweden)] [Department of Oncology, County Council of Ostergoetland, Linkoeping (Sweden); Green, Anna, E-mail: Anna.green@liu.se [Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden)] [Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Green, Henrik, E-mail: Henrik.green@liu.se [Clinical Pharmacology, Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden)] [Clinical Pharmacology, Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Joensson, Jan-Ingvar, E-mail: Jan-ingvar.jonsson@liu.se [Experimental Hematology Unit, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden)] [Experimental Hematology Unit, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Hallbeck, Anna-Lotta, E-mail: Anna-Lotta.Hallbeck@lio.se [Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden) [Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Department of Oncology, County Council of Ostergoetland, Linkoeping (Sweden); Walz, Thomas M., E-mail: Thomas.Walz@lio.se [Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden); Department of Oncology, County Council of Ostergoetland, Linkoeping (Sweden)

    2011-07-08

    Highlights: {yields} Canertinib induces caspase-mediated apoptosis in T-cell leukemia cells in vitro. {yields} Canertinib mediates activation of the intrinsic apoptotic pathway. {yields} Canertinib induces apoptosis in an ErbB receptor independent manner. {yields} Lymphocyte specific proteins as well as survival kinases are inhibited. {yields} Canertinib may act as a multi-kinase inhibiting drug in human T-cell malignancies. -- Abstract: Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 {mu}M caused accumulation of Jurkat cells in the G{sub 1} cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.

  9. A cytotoxic NK-cell line (NK-92) for ex vivo purging of leukemia from blood.

    PubMed

    Klingemann, H G; Wong, E; Maki, G

    1996-05-01

    Myeloablative chemo-/radiotherapy supported by transplantation of autologous bone marrow or blood progenitor cells for acute leukemia, lymphoma, or myeloma continues to be associated with a high relapse rate because of the infusion of malignant stem cells and the lack of an in vivo graft-vs.-leukemia (GVL) effect. Although various methods of purging are established for marrow, purging procedures for blood progenitor cell preparations have not been widely used primarily because of the technical challenges to process a higher number of cells. As a broadly applicable method for immunological purging, we tested whether highly cytotoxic cells from a natural killer (NK) cell line characterized previously (NK-92) could be used for immunological purging of blood preparations. The NK-92 cell line, which was established from a patient with non-Hodgkin's lymphoma, can lyse in vitro a broad range of leukemia, lymphoma, and myeloma cell lines even at very low effector:target (E:T) ratios; this lysis is superior to cytotoxicity obtained from normal peripheral blood mononuclear cells (PBMCs) stimulated for 4 days with interleukin (IL)-2. In an attempt to quantitate the purging achievable with NK-92 cells, normal PBMCs were spiked with 10% K562 cells that had been transfected with the neo(r) marker gene (K562-neo(r). Various numbers of NK-92 cells were then added to the cell mixtures, which were incubated for 4 or 48 hours at 37 degrees C with or without IL-2 (500 U/mL). In order to prevent their proliferation, NK-92 cells were irradiated with 1000 cGy (cesium source). This radiation dose was determined to suppress proliferation of NK-92 cells, but at the same time maintain full cytotoxic activity. After co-culture, the cells were plated in methylcellulose containing 0.8 mg/mL G418. The number of surviving K562-neo(r) colonies was counted under the microscope 7 days later and the results were considered a quantitative readout for the purging efficacy of NK-92 cells. No neomycin-resistant K562 colonies could be detected up to a ratio of NK-92:K562-neo(r) cells of 5:1 (effective NK-92:PBMC ratio of 0.5:1). The presence or absence of IL-2 during the culture period did not affect the results. At this ratio of NK-92:PBMC, the growth of normal clonogenic hematopoietic progenitor cells was not compromised as determined by a standard methylcellulose assay. Considering that K562 is a rapidly proliferating cell line and that the input number of K562 cells (10%) tested here was high, the data suggest that the cytotoxic NK-92 clone (after irradiation to prevent proliferation) could be used effectively for immunological ex vivo purging without compromising hematopoietic cell function. PMID:9118301

  10. Differential Bone Marrow Homing Capacity of VLA4 and CD38 High Expressing Chronic Lymphocytic Leukemia Cells

    Microsoft Academic Search

    Gabriele Brachtl; Karine Sahakyan; Ursula Denk; Tamara Girbl; Beate Alinger; Sebastian W. Hofbauer; Daniel Neureiter; Josefina Piñón Hofbauer; Alexander Egle; Richard Greil; Tanja Nicole Hartmann

    2011-01-01

    BackgroundVLA-4 and CD38 predict a poor clinical outcome in chronic lymphocytic leukemia (CLL). We used CLL samples with discordant VLA-4\\/CD38 risk to address their individual roles in human bone marrow infiltration (BM), CLL cell homing to murine BM, and in supportive CLL cell-stromal cell interactions.MethodsVLA-4, CD38, and Ki-67 expression was measured in CLL cells from peripheral blood (PB) and bone

  11. Induction of apoptosis in human leukemia K562 cells by cyclic lipopeptide from Bacillus subtilis natto T-2

    Microsoft Academic Search

    C. L. Wang; T. B. Ng; F. Yuan; Z. K. Liu; F. Liu

    2007-01-01

    A new cyclic lipopeptide (CLP) purified from Bacillus subtilis natto T-2 dose dependently inhibited growth in human leukemia K562 cells. The results of fluorescent staining indicated that CLP brought about apoptosis in K562 cells. Flow cytometric analysis also demonstrated that CLP caused dose-dependent apoptosis of K562 cells through cell arrest at G1 phase. Western blotting revealed that CLP-induced apoptosis in

  12. Response of Human Myeloid Leukemia Cells to Various Sources of Colony stimulating Activity and Phytohemagglutinin-conditioned Medium1

    Microsoft Academic Search

    Raymond Taetle; Alendry Caviles; James Koziol

    The response of human myeloid leukemia cells to various sources of colony-stimulating activity (CSA) and media condi tioned by phytohemagglutinin-stimulated mononuclear cells (PHA-LCM) was investigated in liquid and colony culture. PHA- LCM, placenta-conditioned medium, GCT cell line-conditioned medium, leukocyte-conditioned medium, and partially purified CSA for human and murine cells were tested for ability to support growth of granulocyte-macrophage colonies from

  13. [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. PMID:25423753

  14. [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. PMID:25507476

  15. Age and Modified European LeukemiaNet Classification to Predict Transplant Outcomes: An Integrated Approach for Acute Myelogenous Leukemia Patients Undergoing Allogeneic Stem Cell Transplantation.

    PubMed

    Oran, Betül; Jimenez, Antonio M; De Lima, Marcos; Popat, Uday R; Bassett, Roland; Andersson, Borje S; Borthakur, Gautam; Bashir, Qaiser; Chen, Julianne; Ciurea, Stefan O; Jabbour, Elias; Cortes, Jorge; Kebriaei, Partow; Khouri, Issa F; Qazilbash, Muzaffar H; Ravandi, Farhad; Rondon, Gabriela; Lu, Xinyan; Shpall, Elizabeth J; Champlin, Richard E

    2015-08-01

    We evaluated the prognostic significance of a modified European LeukemiaNet (ELN) classification for patients with acute myelogenous leukemia (AML) undergoing hematopoietic stem cell transplantation (HSCT) while in first complete remission (CR1). We analyzed 464 AML patients with matched related (n = 211, 45.5%), matched unrelated (n = 176, 37.9%), and mismatched donors (n = 77, 16.6%). Patients were classified into 4 modified ELN risk groups (favorable, intermediate-I, intermediate-II, and adverse) separately for 354 patients age < 60 years and 110 patients age ? 60 years. In this modified version of ELN classification, patients with normal cytogenetic were classified by FLT3-ITD mutational status: favorable risk if FLT3-ITDwild and intermediate-I if FLT3-ITDmut. The best outcomes occurred in the ELN favorable and intermediate-II groups in younger AML patients and in the favorable and intermediate-I groups in older AML patients. Older AML patients had worse transplant outcomes within each modified ELN risk group except intermediate-I when compared with younger patients; leukemia-free survival at 3 years was 67.8% versus 49.8% in favorable, 53.4% versus 50.7% in intermediate-I, 65.7% versus 20.2% in intermediate-II, and 44.6% versus 23.8% in adverse group younger and older patients, respectively. Among lesion-specific abnormalities, del5q/-5 and abnl(17p) had the worse transplant outcomes, with 3-year leukemia-free survival rates of 18.4% and 20% in younger CR1 patients. In conclusion, the modified ELN prognostic classification developed for chemotherapy outcomes also identifies prognostic groups for HSCT, which is useful for a selection of patients for post-transplant strategies to improve outcomes. PMID:25840338

  16. Non-destructive Identification of Individual Leukemia Cells by Optical Trapping Raman Spectroscopy

    SciTech Connect

    Chan, J W; Taylor, D S; Lane, S; Zwerdling, T; Tuscano, J; Huser, T

    2007-03-05

    Currently, a combination of technologies is typically required to assess the malignancy of cancer cells. These methods often lack the specificity and sensitivity necessary for early, accurate diagnosis. Here we demonstrate using clinical samples the application of laser trapping Raman spectroscopy as a novel approach that provides intrinsic biochemical markers for the noninvasive detection of individual cancer cells. The Raman spectra of live, hematopoietic cells provide reliable molecular fingerprints that reflect their biochemical composition and biology. Populations of normal T and B lymphocytes from four healthy individuals, and cells from three leukemia patients were analyzed, and multiple intrinsic Raman markers associated with DNA and protein vibrational modes have been identified that exhibit excellent discriminating power for cancer cell identification. A combination of two multivariate statistical methods, principal component analysis (PCA) and linear discriminant analysis (LDA), was used to confirm the significance of these markers for identifying cancer cells and classifying the data. The results indicate that, on average, 95% of the normal cells and 90% of the patient cells were accurately classified into their respective cell types. We also provide evidence that these markers are unique to cancer cells and not purely a function of differences in their cellular activation.

  17. Targeting cholesterol synthesis increases chemoimmuno-sensitivity in chronic lymphocytic leukemia cells

    PubMed Central

    2014-01-01

    Background Cholesterol plays an important role in cancer development, drug resistance and chemoimmuno-sensitivity. Statins, cholesterol lowering drugs, can induce apoptosis, but also negatively interfere with CD-20 and rituximab-mediated activity. Our goal is to identify the alternative targets that could reduce cholesterol levels but do not interfere with CD-20 in chemo immunotherapy of chronic lymphocytic leukemia (CLL). Methods MEC-2 cells, a CLL cell line, and the peripheral blood mononuclear cells (PBMCs) from CLL patients were treated with cholesterol lowering agents, and analyzed the effect of these agents on cholesterol levels, CD-20 expression and distribution, and cell viability in the presence or absence of fludarabine, rituximab or their combinations. Results We found that MEC-2 cells treated with cholesterol lowering agents (BIBB-515, YM-53601 or TAK-475) reduced 20% of total cellular cholesterol levels, but also significantly promoted CD-20 surface expression. Furthermore, treatment of cells with fludarabine, rituximab or their combinations in the presence of BIBB-515, YM-53601 or TAK-475 enhanced MEC-2 cell chemoimmuno-sensitivity measured by cell viability. More importantly, these cholesterol lowering agents also significantly enhanced chemoimmuno-sensitivity of the PBMCs from CLL patients. Conclusion Our data demonstrate that BIBB-515, YM53601 and TAK-475 render chemoimmuno-therapy resistant MEC-2 cells sensitive to chemoimmuno-therapy and enhance CLL cell chemoimmuno-sensitivity without CD-20 epitope presentation or its downstream signaling. These results provide a novel strategy which could be applied to CLL treatment. PMID:25401046

  18. Adult T cell leukemia/lymphoma with lymphopenia in a Korean.

    PubMed

    Jeon, H J; Lee, M J; Jeong, Y K; Lee, D M; Oh, Y K; Kim, C W

    2000-04-01

    We experienced a case of adult T cell leukemia/lymphoma (ATLL) in a 48-year-old Korean female, who has never been abroad since birth and no history of blood transfusion. The patient had hypercalcemia and multiple lymphadenopathy. Histopathologic study of left cervical lymph node (LN) and bone marrow (BM) revealed that infiltrates of malignant lymphoid cells were composed of small, medium and large cells with pleomorphic nuclei. Smears of peripheral blood (PB) showed lymphopenia (16%) with the appearance of a few atypical lymphoid cells (less than 2%), but not the typical clover leaf cells seen in ATLL. Immunophenotypic study of LN and BM revealed T cell phenotype. PB showed increased CD4+ T cell (T(H), CD3/CD4+, 57%) and decreased CD8+ T cell counts (T(S), CD3/CD8+, 6.7%). The sera of the patient and her family were reactive for HTLV-I antibody. The specific sequences of pol, env, and tax of HTLV-I DNA were detected in the lymphoma cells and peripheral blood mononuclear cells (PBMC) using polymerase chain reaction. Ultrastructural examination of PBMC confirmed numerous type c virus particles in extracellular space. This case was an acute type of ATLL without overt leukemic features in PB. Despite chemotherapy and intensive conservative treatment, she died 3 months after admission. PMID:10803704

  19. Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

    PubMed Central

    Hartsink-Segers, Stefanie A.; Exalto, Carla; Allen, Matthew; Williamson, Daniel; Clifford, Steven C.; Horstmann, Martin; Caron, Huib N.; Pieters, Rob; Den Boer, Monique L.

    2013-01-01

    This study investigated Polo-like kinase 1, a mitotic regulator often over-expressed in solid tumors and adult hematopoietic malignancies, as a potential new target in the treatment of pediatric acute lymphoblastic leukemia. Polo-like kinase 1 protein and Thr210 phosphorylation levels were higher in pediatric acute lymphoblastic leukemia (n=172) than in normal bone marrow mononuclear cells (n=10) (P<0.0001). High Polo-like kinase 1 protein phosphorylation, but not expression, was associated with a lower probability of event-free survival (P=0.042) and was a borderline significant prognostic factor (P=0.065) in a multivariate analysis including age and initial white blood cell count. Polo-like kinase 1 was necessary for leukemic cell survival, since short hairpin-mediated Polo-like kinase 1 knockdown in acute lymphoblastic leukemia cell lines inhibited cell proliferation by G2/M cell cycle arrest and induced apoptosis through caspase-3 and poly (ADP-ribose) polymerase cleavage. Primary patient cells with a high Polo-like kinase 1 protein expression were sensitive to the Polo-like kinase 1-specific inhibitor NMS-P937 in vitro, whereas cells with a low expression and normal bone marrow cells were resistant. This sensitivity was likely not caused by Polo-like kinase 1 mutations, since only one new mutation (Ser335Arg) was found by 454-sequencing of 38 pediatric acute lymphoblastic leukemia cases. This mutation did not affect Polo-like kinase 1 expression or NMS-P937 sensitivity. Together, these results indicate a pivotal role for Polo-like kinase 1 in pediatric acute lymphoblastic leukemia and show potential for Polo-like kinase 1-inhibiting drugs as an addition to current treatment strategies for cases expressing high Polo-like kinase 1 levels. PMID:23753023

  20. Tetraspanin Family Member, CD82, Regulates Expression of EZH2 via Inactivation of p38 MAPK Signaling in Leukemia Cells

    PubMed Central

    Nishioka, Chie; Ikezoe, Takayuki; Yang, Jing; Yokoyama, Akihito

    2015-01-01

    Purpose We recently found that the tetraspanin family member, CD82, which is aberrantly expressed in chemotherapy-resistant CD34+/CD38? acute myelogenous leukemia (AML) cells, negatively regulates matrix metalloproteinase 9, and plays an important role in enabling CD34+/CD38? AML cells to adhere to the bone marrow microenvironment. This study explored novel functions of CD82 that contribute to AML progression. Materials and Methods We employed microarray analysis comparing the gene expression profiles between CD34+/CD38? AML cells transduced with CD82 shRNA and CD34+/CD38? AML cells transduced with control shRNA. Real-time RT-PCR and western blot analysis were performed to examine the effect of CD82 knockdown on the expression of the polycomb group member, enhancer of zeste homolog 2 (EZH2), in leukemia cells. A chromatin immunoprecipitation assay was performed to examine the effect of CD82 expression on the amount of EZH2 bound to the promoter regions of tumor suppressor genes in leukemia cells. We also utilized methylation-specific PCR to examine whether CD82 expression influences the methylation status of the tumor suppressor gene promoter regions in leukemia cells. Results Microarray analysis revealed that levels of EZH2 decreased after shRNA-mediated depletion of CD82 in CD34+/CD38? AML cells. Moreover, the antibody-mediated blockade of CD82 in leukemia cells lowered EZH2 expression via activation of p38 MAPK signaling, decreased the amount of EZH2 bound to the promoter regions of the tumor suppressor genes, and inhibited histone H3 lysine 27 trimethylation in these promoter regions, resulting in upregulation of the tumor suppressors at both the mRNA and protein levels. PMID:25955299

  1. Notch1 Contributes to Mouse T-Cell Leukemia by Directly Inducing the Expression of c-myc?

    PubMed Central

    Sharma, Vishva Mitra; Calvo, Jennifer A.; Draheim, Kyle M.; Cunningham, Leslie A.; Hermance, Nicole; Beverly, Levi; Krishnamoorthy, Veena; Bhasin, Manoj; Capobianco, Anthony J.; Kelliher, Michelle A.

    2006-01-01

    Recent work with mouse models and human leukemic samples has shown that gain-of-function mutation(s) in Notch1 is a common genetic event in T-cell acute lymphoblastic leukemia (T-ALL). The Notch1 receptor signals through a ?-secretase-dependent process that releases intracellular Notch1 from the membrane to the nucleus, where it forms part of a transcriptional activator complex. To identify Notch1 target genes in leukemia, we developed mouse T-cell leukemic lines that express intracellular Notch1 in a doxycycline-dependent manner. Using gene expression profiling and chromatin immunoprecipitation, we identified c-myc as a novel, direct, and critical Notch1 target gene in T-cell leukemia. c-myc mRNA levels are increased in primary mouse T-cell tumors that harbor Notch1 mutations, and Notch1 inhibition decreases c-myc mRNA levels and inhibits leukemic cell growth. Retroviral expression of c-myc, like intracellular Notch1, rescues the growth arrest and apoptosis associated with ?-secretase inhibitor treatment or Notch1 inhibition. Consistent with these findings, retroviral insertional mutagenesis screening of our T-cell leukemia mouse model revealed common insertions in either notch1 or c-myc genes. These studies define the Notch1 molecular signature in mouse T-ALL and importantly provide mechanistic insight as to how Notch1 contributes to human T-ALL. PMID:16954387

  2. The Synergistic Repressive Effect of NF-?B and JNK Inhibitor on the Clonogenic Capacity of Jurkat Leukemia Cells

    PubMed Central

    Liu, Xinli; Zhang, Jun; Li, Jing; Volk, Andrew; Breslin, Peter; Zhang, Jiwang; Zhang, Zhou

    2014-01-01

    Deregulation of Nuclear Transcription Factor-?B (NF-?B) and Jun N-terminal kinase (JNK) signaling is commonly detected in leukemia, suggesting an important role for these two signaling pathways in the pathogenesis of leukemia. In this study, using Jurkat cells, an acute T-lymphoblastic leukemia (T-ALL) cell line, we evaluated the effects of an NF-?B inhibitor and a JNK inhibitor individually and in combination on the proliferation, survival and clonogenic capacity of leukemic cells. We found that leukemic stem/progenitor cells (LSPCs) were more sensitive to NF-?B inhibitor treatment than were healthy hematopoietic stem/progenitor cells (HSPCs), as shown by a reduction in the clonogenic capacity of the former. Inactivation of NF-?B leads to the activation of JNK signaling in both leukemic cells and healthy HSPCs. Interestingly, JNK inhibitor treatment enhanced the repressive effects of NF-?B inhibitor on LSPCs but prevented such repression in HSPCs. Our data suggest that JNK signaling stimulates proliferation/survival in LSPCs but is a death signal in HSPCs. The combination of NF-?B inhibitor and JNK inhibitor might provide a better treatment for T-ALL leukemia by synergistically killing LSPCs while simultaneously preventing the death of normal HPCs. PMID:25526629

  3. Modulation of monocytic leukemia cell function and survival by high gradient magnetic fields and mathematical modeling studies.

    PubMed

    Zablotskii, Vitalii; Syrovets, Tatiana; Schmidt, Zoe W; Dejneka, Alexandr; Simmet, Thomas

    2014-03-01

    The influence of spatially modulated high gradient magnetic fields on cellular functions of human THP-1 leukemia cells is studied. We demonstrate that arrays of high-gradient micrometer-sized magnets induce i) cell swelling, ii) prolonged increased ROS production, and iii) inhibit cell proliferation, and iv) elicit apoptosis of THP-1 monocytic leukemia cells in the absence of chemical or biological agents. Mathematical modeling indicates that mechanical stress exerted on the cells by high magnetic gradient forces is responsible for triggering cell swelling and formation of reactive oxygen species followed by apoptosis. We discuss physical aspects of controlling cell functions by focused magnetic gradient forces, i.e. by a noninvasive and nondestructive physical approach. PMID:24439412

  4. microRNA-181a enhances cell proliferation in acute lymphoblastic leukemia by targeting EGR1.

    PubMed

    Verduci, Lorena; Azzalin, Gianluca; Gioiosa, Silvia; Carissimi, Claudia; Laudadio, Ilaria; Fulci, Valerio; Macino, Giuseppe

    2015-04-01

    Acute lymphoblastic leukemia (ALL) is an aggressive cancer that occurs in both children and adults. Starting from an integrated analysis of miRNA/mRNA expression profiles in 20 ALL patients, we identify a negative correlation between miR-181a and EGR1. Coherently, miR-181a over-expression in Jurkat T-ALL cells decreases EGR1 expression, increasing cell proliferation and enhancing the cell-cycle progression from G1 to S phase. We show that EGR1 is a new direct target of miR-181a. Our findings suggest that miR-181a behaves as an onco-miRNA in ALL by down-regulating EGR1. PMID:25740602

  5. Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

    ClinicalTrials.gov

    2014-09-30

    B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Lymphoblastic Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

  6. Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells

    SciTech Connect

    Fuchs, Dominik [Research Group Molecular Neuro-Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg (Germany) [Research Group Molecular Neuro-Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg (Germany); Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg (Germany); Daniel, Volker; Sadeghi, Mahmoud; Opelz, Gerhard [Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg (Germany)] [Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg (Germany); Naujokat, Cord, E-mail: cord.naujokat@med.uni-heidelberg.de [Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg (Germany)] [Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg (Germany)

    2010-04-16

    Leukemia stem cells are known to exhibit multidrug resistance by expression of ATP-binding cassette (ABC) transporters which constitute transmembrane proteins capable of exporting a wide variety of chemotherapeutic drugs from the cytosol. We show here that human promyeloblastic leukemia KG-1a cells exposed to the histone deacetylase inhibitor phenylbutyrate resemble many characteristics of leukemia stem cells, including expression of functional ABC transporters such as P-glycoprotein, BCRP and MRP8. Consequently, KG-1a cells display resistance to the induction of apoptosis by various chemotherapeutic drugs. Resistance to apoptosis induction by chemotherapeutic drugs can be reversed by cyclosporine A, which effectively inhibits the activity of P-glycoprotein and BCRP, thus demonstrating ABC transporter-mediated drug resistance in KG-1a cells. However, KG-1a are highly sensitive to apoptosis induction by salinomycin, a polyether ionophore antibiotic that has recently been shown to kill human breast cancer stem cell-like cells and to induce apoptosis in human cancer cells displaying multiple mechanisms of drug and apoptosis resistance. Whereas KG-1a cells can be adapted to proliferate in the presence of apoptosis-inducing concentrations of bortezomib and doxorubicin, salinomycin does not permit long-term adaptation of the cells to apoptosis-inducing concentrations. Thus, salinomycin should be regarded as a novel and effective agent for the elimination of leukemia stem cells and other tumor cells exhibiting ABC transporter-mediated multidrug resistance.

  7. Bone marrow derived mesenchymal stem cells from chronic myeloid leukemia t(9;22) patients are devoid of Philadelphia chromosome and support cord blood stem cell expansion

    Microsoft Academic Search

    Saengsuree Jootar; Nida Pornprasertsud; Sawang Petvises; Busaba Rerkamnuaychoke; Sinee Disthabanchong; Samart Pakakasama; Artit Ungkanont; Suradej Hongeng

    2006-01-01

    Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells. It is characterized at cytogenetic level by the Philadelphia (Ph) chromosome and at the molecular level by the BCR\\/ABL gene rearrangement. Bone marrow derived mesenchymal stem cells (MSCs) are also pluripotent stem cells that can differentiate into several mesenchymal tissues. To date, no study has been performed

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

    SciTech Connect

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

    2011-07-29

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

  9. [Effect of plasmacytoid dendritic cells activited by bacteria on spontaneous remission of leukemia].

    PubMed

    Li, Juan; Zhang, Lian-Sheng; Chai, Ye; Zeng, Peng-Yun; Wu, Chong-Yang; Yue, Ling-Ling; Bai, Jun; Hao, Zheng-Dong; Hu, Wan-Li; Chen, Hui-Ling; Guo, Xiao-Jia

    2014-10-01

    Spontaneous remission (SR) of leukemia is a rare event in clinic, which possibly correlated with severe infection and sepsis, but its exact mechanism has not been confirmed. Plasmacytoid dendritic cells (pDC) and myeloid dendritic cells (mDC) play a key role in innate and adaptive immunity respectively. A patient with severe infection of staphylococcus aureus acquired completely spontaneous remission (SR), moreover a increased number of pDC were observed, suggesting that bacteria-activated pDC may play an important role in SR. This study was purposed to explore if the bacteria can stimulate pDC successfully and get a functional pDC. Both pDC and mDC were isolated from freshly collected, leukocyte-rich buffy coats from healthy blood donor and leukemic patient with SR by using MACS and FACS. The pDC were cultured in RPMI 1640 medium and were stimulated with different kinds of bacteria and the expression of CD40, CD86 and HLA-DR on the cell surface was analyzed by flow cytometry. The cytokine (IFN-?, IL-12, IFN-?, IL-2, IL-4, IL-10) production was measured by using ELISA kits. The results showed that the stimulation with staphylococcus aureus and pseudomonas aeruginosa resulted in the maturation of pDC, which secrete a large number of IFN-? and promote the differentiation of naive CD4? T cells to Th1 cells. The activated pDC expressed high level of CD40 and CD86 and showed higher T cell stimulatory capacities. It is concluded that staphylococcus aureus and pseudomonas aeruginosa can activate pDC, the activated pDC secrete high quantity of IFN-?. This result suggests that bacteria stimulated pDC may play a key role in SR of leukemia following severe infections. PMID:25338574

  10. Cryptotanshinone enhances TNF-?-induced apoptosis in chronic myeloid leukemia KBM-5 cells.

    PubMed

    Kim, Ji-Hyun; Jeong, Soo-Jin; Kwon, Tae-Rin; Yun, Sun-Mi; Jung, Ji Hoon; Kim, Minseok; Lee, Hyo-Jung; Lee, Min-Ho; Ko, Seong Gyu; Chen, Chang-Yan; Kim, Sung-Hoon

    2011-07-01

    Cryptotanshinone is a biologically active compound from the root of Salvia miltiorrhiza. In the present study, we investigated the molecular mechanisms by which cryptotanshinone is in synergy with tumor necrosis factor-alpha (TNF-?) for the induction of apoptosis in human chronic myeloid leukemia (CML) KBM-5 cells. The co-treatment of cryptotanshinone with TNF-? reduced the viability of the cells [combination index (CI) < 1]. Concomitantly, the co-treatment of cryptotanshinone and TNF-? elicited apoptosis, manifested by enhanced the number of terminal deoxynucleotide transferase-mediated dUTP-nick-end labeling (TUNEL)-positive cells, the sub-G1 cell populations, and the activation of caspase-8 and -3, in comparison with the treatment with either drug alone. The treatment with cryptotanshinone further suppressed TNF-?-mediated expression of c-FLIP(L), Bcl-x(L), but the increased level of tBid (a caspase-8 substrate). Furthermore, cryptotanshinone activated p38 but not NF-?B in TNF-?-treated KBM-5 cells. The addition of a specific p38 MAPK inhibitor SB203580 significantly attenuated cryptotanshinone/TNF-?-induced apoptosis. The combination treatment of cryptotanshinone and TNF-? also stimulated the reactive oxygen species (ROS) generation. N-acetyl-L-cysteine (NAC, a ROS scavenger) was not only able to block cryptotanshinone/TNF-?-induced ROS production but also the activation of caspase-8 and p38 MAPK. Overall, our findings suggest that cryptotanshinone can sensitize TNF-?-induced apoptosis in human myeloid leukemia KBM-5 cells, which appears through ROS-dependent activation of caspase-8 and p38. PMID:21519916

  11. Mechanical Stimulation in Preventing Bone Density Loss in Patients Undergoing Donor Stem Cell Transplant

    ClinicalTrials.gov

    2012-07-05

    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); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Plasma Cell Neoplasm; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic 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; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage II Ovarian Epithelial Cancer; Stage II Ovarian Germ Cell Tumor; 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 Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Small Lymphocytic Lymphoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Breast Cancer; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3

  12. IL-32? inhibits monocytic differentiation of leukemia cells by attenuating expression of transcription factor PU.1

    PubMed Central

    Kim, Man Sub; Kang, Jeong-Woo; Park, Yun Sun; Lee, Dong Hun; Bak, Yesol; Kwon, Taeho; Yoon, Do-Young

    2015-01-01

    PU.1 is a key transcription factor regulating the myeloid differentiation. PU.1-induced monocytic differentiation into macrophage is also important for blood cancer development. Therefore, we chose THP-1 monocytic leukemia cells to investigate the function of a recently discovered IL-32?. Genetic analyses identified differences in the sequences of IL-32? and IL-32?. Using previously established cell lines that stably express IL-32? and IL-32? and cell lines transiently expressing IL-32?, we observed that expression of IL-32? inhibited phorbol 12-myristate 13-acetate (PMA)-induced monocytic differentiation in both THP-1 and HL-60 cells. IL-32? also suppressed expression of the macrophage cell surface markers, CD11b, CD18, and CD36. Interestingly, expression of IL-32? or IL-32? had no effect on the expression levels of cell cycle related factors. As a result, we concluded that these isoforms did not contribute to PMA-induced cell cycle arrest. IL-32? was found to modulate expression of PU.1, a transcription factor necessary for myeloid lineage commitment. Transient expression of PU.1 in THP-1/IL-32? cells rescued the observed differentiation defect. Additionally, transient expression of both CCAAT-enhancer-binding protein ? (C/EBP?) and PU.1 in THP-1/IL-32? cells exhibited synergistic effects in rescuing the differentiation defect. These observations indicate that intracellular IL-32? inhibits the differentiation of monocytes into macrophages by attenuating PU.1 expression. PMID:25726525

  13. Preapoptotic protease calpain-2 is frequently suppressed in adult T-cell leukemia.

    PubMed

    Ishihara, Makoto; Araya, Natsumi; Sato, Tomoo; Tatsuguchi, Ayako; Saichi, Naomi; Utsunomiya, Atae; Nakamura, Yusuke; Nakagawa, Hidewaki; Yamano, Yoshihisa; Ueda, Koji

    2013-05-23

    Adult T-cell leukemia (ATL) is one of the most aggressive hematologic malignancies caused by human T-lymphotropic virus type 1 (HTLV-1) infection. The prognosis of ATL is extremely poor; however, effective strategies for diagnosis and treatment have not been established. To identify novel therapeutic targets and diagnostic markers for ATL, we employed focused proteomic profiling of the CD4(+)CD25(+)CCR4(+) T-cell subpopulation in which HTLV-1-infected cells were enriched. Comprehensive quantification of 14?064 peptides and subsequent 2-step statistical analysis using 29 cases (6 uninfected controls, 5 asymptomatic carriers, 9 HTLV-1-associated myelopathy/tropical spastic paraparesis patients, 9 ATL patients) identified 91 peptide determinants that statistically classified 4 clinical groups with an accuracy rate of 92.2% by cross-validation test. Among the identified 17 classifier proteins, ?-II spectrin was drastically accumulated in infected T cells derived from ATL patients, whereas its digestive protease calpain-2 (CAN2) was significantly downregulated. Further cell cycle analysis and cell growth assay revealed that rescue of CAN2 activity by overexpressing constitutively active CAN2 (?(19)CAN2) could induce remarkable cell death on ATL cells accompanied by reduction of ?-II spectrin. These results support that proteomic profiling of HTLV-1-infected T cells could provide potential diagnostic biomarkers and an attractive resource of therapeutic targets for ATL. PMID:23538341

  14. Immunologic type of thyroid lymphoma in an adult T-cell leukemia endemic area in Japan.

    PubMed

    Ohsawa, M; Noguchi, S; Aozasa, K

    1995-04-01

    Our previous study showed that thyroid non-Hodgkin's lymphoma (TL) in an adult T-cell leukemia/lymphoma (ATL) non-endemic area were exclusively B-cell derived. The present study was carried out to examine whether TL in an ATL endemic area are also exclusively of B-cell type. Eight cases with TL admitted to the hospital situated in an ATL endemic area were studied: they were all female with an age range from 50 to 75 (median 67) years. Histologically four of the eight cases showed a follicular pattern. Immunophenotypic study revealed all but one case to be of B-cell nature: CD3-, 4-, 8-, 20+, 22+, 45RA+, 45RO-, L22-, L24+/-, L28+. Neoplastic cells in one case with the histology of diffuse large cell lymphoma showed a CD3+, 4+, 8-, 20-, 22-, 45RA-, 45RO+/-, L22-, L24-, L28-, indicating a helper T-cell phenotype. Genotypic study showed rearrangement of T-cell beta-chain receptor in this case. This case also had antibodies against HTLV-1 in the serum. This case shows that it is also possible to develop T-cell TL in an endemic ATL area. PMID:8580806