A Worldwide Support Network For Chronic Myelogenous Leukemia
Posted by rob on November 26, 2010 under Uncategorized | 
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Spontaneous remission in acute myelogenous leukemia evidenced by cytogenetic changes.
Ann Hematol. 2010 Nov 24;
Authors: Teng CJ, Yang CF, Gau JP, Liu JH, Hong YC, Liu CY, Yu YB, Hsiao LT, Wang WS, Tzeng CH
PMID: 21107840 [PubMed - as supplied by publisher]
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Pure erythroid leukemia: a reassessment of the entity using the 2008 World Health Organization classification.
Mod Pathol. 2010 Nov 19;
Authors: Liu W, Hasserjian RP, Hu Y, Zhang L, Miranda RN, Medeiros LJ, Wang SA
Pure erythroid leukemia (PEL) is rare, characterized by a neoplastic proliferation of erythroblasts. Given recent incorporation of molecular genetic findings and clinical features in the revised 2008 World Health Organization classification scheme of acute myeloid leukemia, we questioned if PEL still remains as a distinct subtype of acute myeloid leukemia. In this retrospective study, we identified 18 cases of acute leukemia with morphologic and immunophenotypic features of PEL. Following the current World Health Organization classification algorithm, these cases were classified as: 13 acute myeloid leukemia with myelodysplasia-related changes, 3 therapy-related acute myeloid leukemia, and 1 chronic myelogenous leukemia blast crisis, and one unclassifiable due to insufficient clinical information. All 16 cases with cytogenetic data harbored an extremely complex karyotype and the median overall survival of the 18 patients was 3 months (range, 1-7 months). This survival was significantly shorter than that of patients with acute erythroid leukemia, erythroid/myeloid subtype, or acute myeloid leukemia with myelodysplasia-related changes with erythroid predominance (P<0.001). PEL is characterized as a neoplastic erythroid hyperproliferation with maturation arrest. E-cadherin emerged as the most sensitive and specific marker for immature erythroblasts, and was helpful in distinguishing PEL from other erythroid proliferations. Our study showed that the criteria for acute myeloid leukemia in the 2008 World Health Organization system facilitate reclassification of PEL cases into other acute myeloid leukemia categories, mainly of acute myeloid leukemia with myelodysplasia-related changes. These new assigned categories fail to capture the distinct features of PEL, where the phenotype of PEL correlates with a very complex karyotype and an extremely aggressive clinical course.Modern Pathology advance online publication, 19 November 2010; doi:10.1038/modpathol.2010.194.
PMID: 21102413 [PubMed - as supplied by publisher]
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Persistent Activation of the Fyn/ERK Kinase Signaling Axis Mediates Imatinib Resistance in Chronic Myelogenous Leukemia Cells through Upregulation of Intracellular SPARC.
Cancer Res. 2010 Nov 23;
Authors: Fenouille N, Puissant A, Dufies M, Robert G, Jacquel A, Ohanna M, Deckert M, Pasquet JM, Mahon FX, Cassuto JP, Raynaud S, Tartare-Deckert S, Auberger P
SPARC is an extracellular matrix protein that exerts pleiotropic effects on extracellular matrix organization, growth factor availability, cell adhesion, differentiation, and immunity in cancer. Chronic myelogenous leukemia (CML) cells resistant to the BCR-ABL inhibitor imatinib (IM-R cells) were found to overexpress SPARC mRNA. In this study, we show that imatinib triggers SPARC accumulation in a variety of tyrosine kinase inhibitor (TKI)–resistant CML cell lines. SPARC silencing in IM-R cells restored imatinib sensitivity, whereas enforced SPARC expression in imatinib-sensitive cells promoted viability as well as protection against imatinib-mediated apoptosis. Notably, we found that the protective effect of SPARC required intracellular retention inside cells. Accordingly, SPARC was not secreted into the culture medium of IM-R cells. Increased SPARC expression was intimately linked to persistent activation of the Fyn/ERK kinase signaling axis. Pharmacologic inhibition of this pathway or siRNA-mediated knockdown of Fyn kinase resensitized IM-R cells to imatinib. In support of our findings, increased levels of SPARC mRNA were documented in blood cells from CML patients after 1 year of imatinib therapy compared with initial diagnosis. Taken together, our results highlight an important role for the Fyn/ERK signaling pathway in imatinib-resistant cells that is driven by accumulation of intracellular SPARC. Cancer Res; 70(23); 1-12. ©2010 AACR.
PMID: 21098700 [PubMed - as supplied by publisher]
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Declining lymphoid progenitor fitness promotes aging-associated leukemogenesis.
Proc Natl Acad Sci U S A. 2010 Nov 22;
Authors: Henry CJ, Marusyk A, Zaberezhnyy V, Adane B, Degregori J
Aging is associated with the functional decline of cells, tissues, and organs. At the same time, age is the single most important prognostic factor in the development of most human cancers, including chronic myelogenous and acute lymphoblastic leukemias initiated by Bcr-Abl oncogenic translocations. Prevailing paradigms attribute the association between aging and cancers to the accumulation of oncogenic mutations over time, because the accrual of oncogenic events is thought to be the rate-limiting step in initiation and progression of cancers. Conversely, aging-associated functional decline caused by both cell-autonomous and non-cell-autonomous mechanisms is likely to reduce the fitness of stem and progenitor cell populations. This reduction in fitness should be conducive for increased selection of oncogenic mutations that can at least partially alleviate fitness defects, thereby promoting the initiation of cancers. We tested this hypothesis using mouse hematopoietic models. Our studies indicate that the dramatic decline in the fitness of aged B-lymphopoiesis coincides with altered receptor-associated kinase signaling. We further show that Bcr-Abl provides a much greater competitive advantage to old B-lymphoid progenitors compared with young progenitors, coinciding with restored kinase signaling pathways, and that this enhanced competitive advantage translates into increased promotion of Bcr-Abl-driven leukemias. Moreover, impairing IL-7-mediated signaling is sufficient to promote selection for Bcr-Abl-expressing B progenitors. These studies support an unappreciated causative link between aging and cancer: increased selection of oncogenic mutations as a result of age-dependent alterations of the fitness landscape.
PMID: 21098275 [PubMed - as supplied by publisher]
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Myeloperoxidase-dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34+ Cells.
Mol Pharmacol. 2010 Nov 19;
Authors: Vlasova II, Feng WH, Goff JP, Giorgianni A, Do D, Gollin SM, Lewis DW, Kagan VE, Yalowich JC
Etoposide is a widely used anticancer drug successfully utilized for treatment of many types of cancer in children and adults. Its use, however, is associated with an increased risk of development of secondary acute myelogenous leukemia (t-AML) involving MLL gene (11q23) translocations. Previous studies demonstrated that the phenoxyl radical of etoposide can be produced by action of myeloperoxidase (MPO), an enzyme found in developing myeloid progenitor cells, the likely origin for myeloid leukemias. We hypothesized, therefore, that one-electron oxidation of etoposide by myeloperoxidase (MPO) to its phenoxyl radical is important for converting this anticancer drug to genotoxic and carcinogenic species in human CD34+ myeloid progenitor cells. In the present study, using EPR spectroscopy, we provide conclusive evidence for MPO-dependent formation of etoposide phenoxyl radicals in growth factor mobilized CD34+ cells isolated from human umbilical cord blood and demonstrate that MPO-induced oxidation of etoposide is amplified in the presence of phenol. Formation of etoposide radicals resulted in oxidation of endogenous thiols thus providing evidence for etoposide-mediated MPO-catalyzed redox cycling that may play a role in enhanced etoposide genotoxicity. In separate studies, etoposide-induced DNA damage and MLL gene rearrangements were demonstrated to be dependent in part on MPO activity in CD34+ cells. Together our results are consistent with the idea that MPO-dependent oxidation of etoposide in human hematopoetic CD34+ cells makes these cells especially prone to induction of etoposide-related acute myeloid leukemia.
PMID: 21097707 [PubMed - as supplied by publisher]
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Genetically modified donor leukocyte transfusion and Graft-versus-Leukemia effect after allogeneic stem cell transplantation.
Hum Gene Ther. 2010 Nov 23;
Authors: Borchers S, Provasi E, Benati C, Dammann E, Radrizzani M, Krons A, Kuehnau W, Schmidke J, von Neuhoff N, Stadler M, Ciceri F, Bonini C, Ganser A, Hertenstein B, Mischak-Weissinger EM
Seven patients with acute myeloid leukemia (AML) and two patients with chronic myelogenous leukemia (CML) were transplanted from HLA-identical sibling donors with CD34+-enriched stem cells (HSCT) without further immunosuppression. The myeloablative standard transplantation protocol was adapted to include transfusion of gene-modified donor T-cells after HSCT. Donor T-cells were transduced with the replication-deficient retrovirus SFCMM-3, which expresses the herpes simplex thymidine-kinase (HSV-Tk) and the truncated version of low affinity nerve growth factor receptor (?LNGFR) for selection and characterization of transduced cells. Transduced T-cells were detectable in all patients during follow-up for up to 5 years after transfusion. Proteomic screening for development of acute graft-versus-host disease (aGvHD) was applied to five of seven AML patients. No positivity for the aGVHD grade II specific proteomic pattern was observed. Only one patient developed aGvHD grade I. To date, 3 AML patients relapsed, one responded to the transfusion of 3 untransduced, escalating DLI from the original donor and is in complete remission. Two were re-transplanted with non-T-cell depleted peripheral blood stem cells from their original donors and died post re-transplantation from septic complications or relapse, respectively. In one CML-patient, loss of bcr-abl gene expression was observed following an expansion of transduced cells. Seven of nine patients are alive and in complete remission.
PMID: 21091264 [PubMed - as supplied by publisher]
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Targeted Blockage of Signal Transducer and Activator of Transcription 5 Signaling Pathway with Decoy Oligodeoxynucleotides Suppresses Leukemic K562 Cell Growth.
DNA Cell Biol. 2010 Nov 22;
Authors: Wang X, Zeng J, Shi M, Zhao S, Bai W, Cao W, Tu Z, Huang Z, Feng W
The protein signal transducer and activator of transcription 5 (STAT5) of the JAK/STAT pathway is constitutively activated because of its phosphorylation by tyrosine kinase activity of fusion protein BCR-ABL in chronic myelogenous leukemia (CML) cells. This study investigated the potential therapeutic effect of STAT5 decoy oligodeoxynucleotides (ODN) using leukemia K562 cells as a model. Our results showed that transfection of 21-mer-long STAT5 decoy ODN into K562 cells effectively inhibited cell proliferation and induced cell apoptosis. Further, STAT5 decoy ODN downregulated STAT5 targets bcl-xL, cyclinD1, and c-myc at both mRNA and protein levels in a sequence-specific manner. Collectively, these data demonstrate the therapeutic effect of blocking the STAT5 signal pathway by cis-element decoy for cancer characterized by constitutive STAT5 activation. Thus, our study provides support for STAT5 as a potential target downstream of BCR-ABL for CML treatment and helps establish the concept of targeting STAT5 by decoy ODN as a novel therapy approach for imatinib-resistant CML.
PMID: 21091189 [PubMed - as supplied by publisher]
