Leukemia (LEUKEMIA)

Publications in this journal

• Article: APR-246-induced cytotoxicity is related to induction of oxidative stress and activation of the HO-1/NRF2 axis in leukemia cells

  D Ali, DK Mohammad, K Jonsson-Videsäter, BF Nore, C Paul, S. Lehmann
  Leukemia 06/2013; Submitted.
• Article: ATL cells recognize self class II andtigens: implication to leukemogenesis

  Matsuoka M, Nishimura Y
  Leukemia 02/2013;
• Article: A new classification ofsubtypes of adult T-cell leukemia based on prognosis of the disease.

  Shirono K
  Leukemia 02/2013;
• Article: Recurrent involvement of ring-type zinc finger genes in complex molecular rearrangements in childhood acute myelogeneous leukemia with translocation t(10;11)(p12;q23)

  Ghosh S, Bartenhagen C, Okpanyi V, Gombert M, Binder V, Teigler-Schlegel A, Bradtke J, Röttgers S, Dugas M, Borkhardt A
  Leukemia 01/2013;
• Article: AMPK inhibition enhances apoptosis in MLL-rearranged pediatric B-acute lymphoblastic leukemia cells

  Accordi B, Galla L, Milani G, Curtarello M, Serafin V, Lissandron V, Viola G, Te Kronnie G, De Maria R, Petricoin EF 3rd, Liotta LA, Indraccolo S, Basso G
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  ABSTRACT: The serine/threonine kinase AMP-activated protein kinase (AMPK) and its downstream effectors, including endothelial nitric oxide synthase and BCL-2, are hyperactivated in B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) cells with MLL gene rearrangements. We investigated the role of activated AMPK in supporting leukemic cell survival and evaluated AMPK as a potential drug target. Exposure of leukemic cells to the commercial AMPK inhibitor compound C resulted in massive apoptosis only in cells with MLL gene rearrangements. These results were confirmed by targeting AMPK with specific short hairpin RNAs. Compound C-induced apoptosis was associated with mitochondrial membrane depolarization, reactive oxygen species production, cytochrome c release and caspases cleavage, indicating intrinsic apoptosis pathway activation. Treatment with low concentrations of compound C resulted in a strong antileukemic activity, together with cytochrome c release and cleavage of caspases and poly(ADP-ribose) polymerase, also in MLL-rearranged primary BCP-ALL samples. Moreover, AMPK inhibition in MLL-rearranged cell lines synergistically enhanced the antiproliferative effects of vincristine, daunorubicin, cytarabine, dexamethasone and L-asparaginase in most of the evaluated conditions. Taken together, these results indicate that the activation of the AMPK pathway directly contributes to the survival of MLL-rearranged BCP-ALL cells and AMPK inhibitors could represent a new therapeutic strategy for this high-risk leukemia.
  Leukemia 11/2012;
• Article: Clinical significance of CD81 expression by clonal plasma cells in high-risk smoldering and symptomatic multiple myeloma patients

  Paiva B, Gutiérrez NC, Chen X, Vídriales MB, Montalbán MÁ, Rosiñol L, Oriol A, Martínez-López J, Mateos MV, López-Corral L, [......], Bengoechea E, Terol MJ, de Paz R, Martin A, Hernández J, Orfao A, Lahuerta JJ, Bladé J, Pandiella A, Miguel JF
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  ABSTRACT: The presence of CD19 in myelomatous plasma cells (MM-PCs) correlates with adverse prognosis in multiple myeloma (MM). Although CD19 expression is upregulated by CD81, this marker has been poorly investigated and its prognostic value in MM remains unknown. We have analyzed CD81 expression by multiparameter flow cytometry in MM-PCs from 230 MM patients at diagnosis included in the Grupo Español de Mieloma (GEM)05>65 years trial as well as 56 high-risk smoldering MM (SMM). CD81 expression was detected in 45% (103/230) MM patients, and the detection of CD81(+) MM-PC was an independent prognostic factor for progression-free (hazard ratio=1.9; P=0.003) and overall survival (hazard ratio=2.0; P=0.02); this adverse impact was validated in an additional series of 325 transplant-candidate MM patients included in the GEM05 <65 years trial. Moreover, CD81(+) SMM (n=34/56, 57%) patients had a shorter time to progression to MM (P=0.02). Overall, our results show that CD81 may have a relevant role in MM pathogenesis and represent a novel adverse prognostic marker in myeloma.
  Leukemia 08/2012; 26(8):1862-9.
• Article: EVI-1 modulates leukemogenic potential and apoptosis sensitivity in human acute lymphoblastic leukemia

  Martina Konantz, Maya C. Andre, Martin Ebinger, Matthias Grauer, Hui Wang, Sarah Grzy-wna, Oliver C. Rothfuss, Simon Lehle, Olga S. Kustikova, Helmut R. Salih, Rupert Handgret-inger, Falko Fend, Christopher Baum, Lothar Kanz, Leticia Quintanilla-Martinez, Klaus Schulze-Osthoff, Frank Essmann, Claudia Lengerke
  Leukemia 07/2012;
• Article: Successful xenografts of AML3 samples in immune deficient NOD/shi-SCID IL2Rγ−/− mice

  patel
  Leukemia 06/2012;
• Article: Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomideOpen

  A Lopez-Girona, D Mendy, T Ito, K Miller, A K Gandhi, J Kang, S Karasawa, G Carmel, P Jackson, M Abbasian, A Mahmoudi, B Cathers, E Rychak, S Gaidarova, R Chen, P H Schafer, H Handa, T O Daniel, J F Evans, R Chopra
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  ABSTRACT: Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN–DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBNYW/AA. Overexpression of CRBN wild-type protein, but not CRBNYW/AA mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21WAF-1 expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.Keywords: cereblon; myeloma; lenalidomide; pomalidomide; immunomodulatory; antiproliferative
  Leukemia 05/2012;
• Article: 5-Azacitidine in aggressive myelodysplastic syndromes regulates chromatin structure at PU.1 gene and cell differentiation capacity

  N Curik, P Burda, K Vargova, V Pospisil, M Belickova, P Vlckova, F Savvulidi, E Necas, H Hajkova, C Haskovec, J Cermak, M Krivjanska, M Trneny, P Laslo, A Jonasova, T Stopka
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  ABSTRACT: Epigenetic 5-azacitidine (AZA) therapy of high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) represents a promising, albeit not fully understood, approach. Hematopoietic transcription factor PU.1 is dynamically regulated by upstream regulatory element (URE), whose deletion causes downregulation of PU.1 leading to AML in mouse. In this study a significant group of the high-risk MDS patients, as well as MDS cell lines, displayed downregulation of PU.1 expression within CD34+ cells, which was associated with DNA methylation of the URE. AZA treatment in vitro significantly demethylated URE, leading to upregulation of PU.1 followed by derepression of its transcriptional targets and onset of myeloid differentiation. Addition of colony-stimulating factors (CSFs; granulocyte-CSF, granulocyte–macrophage-CSF and macrophage-CSF) modulated AZA-mediated effects on reprogramming of histone modifications at the URE and cell differentiation outcome. Our data collectively support the importance of modifying the URE chromatin structure as a regulatory mechanism of AZA-mediated activation of PU.1 and induction of the myeloid program in MDS.Keywords: PU.1; 5-azacitidine; MDS; AML; cytokines; differentiation
  Leukemia 02/2012; 26(8):1804-1811.
• Article: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor bindingOpen

  A Ptasinska, S A Assi, D Mannari, S R James, D Williamson, J Dunne, M Hoogenkamp, M Wu, M Care, H McNeill, P Cauchy, M Cullen, R M Tooze, D G Tenen, B D Young, P N Cockerill, D R Westhead, O Heidenreich, C Bonifer
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  ABSTRACT: The t(8;21) translocation fuses the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape, we measured genome-wide RUNX1- and RUNX1/ETO-bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end, we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal, and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML.Keywords: acute myeloid leukemia; RUNX1/ETO; epigenetic regulation; chromatin; integrated analysis of high-throughput data
  Leukemia 02/2012; 26(8):1829-1841.
• Article: Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia

  M Hofmann, L Gro|[szlig]|e-Hovest, T N|[uuml]|bling, E Py|[zdot, M L Bamberg, S Aulwurm, H-J B|[uuml]|hring, K Schwartz, S P Haen, K Schilbach, H-G Rammensee, H R Salih, G Jung
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  ABSTRACT: The therapeutic efficacy of humanized or chimeric second-generation antitumor antibodies is clearly established, but often limited. In recent years, defined modifications of the glycosylation pattern or the amino-acid sequence of the human immunoglobulin G1 Fc part have resulted in the development of third-generation antibodies with improved capability to recruit Fc receptor-bearing effector cells. The first antibodies of this kind, currently evaluated in early clinical trials, are directed against lymphoma-associated antigens. Fc-engineered antibodies targeting myeloid leukemia are not yet available. We here report on the generation and preclinical characterization of an Fc-optimized antibody directed to the FMS-related tyrosine kinase 3 (FLT3), an antigen expressed on the leukemic blasts of all investigated patients with acute myeloid leukemia (AML). This antibody, termed 4G8SDIEM, mediated markedly enhanced cellular cytotoxicity against FLT3-expressing cell lines as well as blasts of AML patients. FLT3 expression levels on AML cells varied between 300 and 4600 molecules/cell and, in most cases, were substantially higher than those detected on normal hematopoietic precursor cells and dendritic cells (approximately 300 molecules/cell). Antibody-mediated cytotoxicity against these normal cells was not detectable. 4G8SDIEM has been produced in pharmaceutical quality in a university-owned production unit and is currently used for the treatment of leukemia patients.Keywords: FLT3; AML; optimized antibody; tumor immunotherapy; ADCC
  Leukemia 01/2012; 26(6):1228-1237.
• Article: Hematopoietic cell transplantation for primary plasma cell leukemia: results from the Center for International Blood and Marrow Transplant Research

  A Mahindra, M E Kalaycio, J Vela-Ojeda, D H Vesole, M-J Zhang, P Li, J R Berenson, J M Bird, A Dispenzieri, J L Gajewski, [......], S Lonial, J Mikhael, G A Milone, R Munker, R Nath, S Saccaro, L Bik To, D T Vogl, B Wirk, P Hari
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  ABSTRACT: There are limited data on hematopoietic cell transplantation (HCT) in primary plasma cell leukemia (pPCL), an aggressive plasma cell disorder. We report outcomes of 147 patients with pPCL receiving autologous (n=97) or allogeneic (n=50) HCT within 18 months after diagnosis between 1995 and 2006. Median age was 56 years and 48 years for autologous HCT and allogeneic HCT, respectively. Progression-free survival (PFS) at 3 years was 34% (95% confidence interval (CI), 23–46%) in the autologous group and 20% (95% CI, 10–34%) in the allogeneic group. Cumulative incidence of relapse at 3 years was 61% (95% CI, 48–72%) in the autologous group and 38% (95% CI, 25–53%) in the allogeneic group. Overall survival (OS) at 3 years was 64% (95% CI, 52–75%) in the autologous group and 39% (95% CI, 26–54%) in the allogeneic group. Non-relapse mortality (NRM) at 3 years was 5% (95% CI, 1–11%) in the autologous group and 41% (95% CI, 28–56%) in the allogeneic group. The encouraging OS after autologous HCT, establishes the safety and feasibility of this consolidative treatment option after initial induction therapy for pPCL. Allogeneic HCT, although associated with a significantly lower relapse rate, carries a much higher risk of NRM and no OS benefit.Keywords: primary plasma cell leukemia; stem cell transplant; overall survival
  Leukemia 10/2011; 26(5):1091-1097.