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1.
Leukemia ; 23(11): 1989-98, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19587702

ABSTRACT

Adult and child B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) differ in terms of incidence and prognosis. These disparities are mainly due to the molecular abnormalities associated with these two clinical entities. A genome-wide analysis using oligo SNP arrays recently demonstrated that PAX5 (paired-box domain 5) is the main target of somatic mutations in childhood BCP-ALL being altered in 38.9% of the cases. We report here the most extensive analysis of alterations of PAX5 coding sequence in 117 adult BCP-ALL patients in the unique clinical protocol GRAALL-2003/GRAAPH-2003. Our study demonstrates that PAX5 is mutated in 34% of adult BCP-ALL, mutations being partial or complete deletion, partial or complete amplification, point mutation or fusion gene. PAX5 alterations are heterogeneous consisting in complete loss in 17%, focal deletions in 10%, point mutations in 7% and translocations in 1% of the cases. PAX5 complete loss and PAX5 point mutations differ. PAX5 complete loss seems to be a secondary event and is significantly associated with BCR-ABL1 or TCF3-PBX1 fusion genes and a lower white blood cell count.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , DNA-Binding Proteins/genetics , Fusion Proteins, bcr-abl/genetics , PAX5 Transcription Factor/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Proto-Oncogene Proteins/genetics , Adolescent , Adult , Antineoplastic Agents/therapeutic use , Benzamides , Clinical Trials, Phase II as Topic , Gene Dosage , Gene Rearrangement, T-Lymphocyte/genetics , Genomics , Haplotypes , Humans , Imatinib Mesylate , Immunoglobulin Heavy Chains/genetics , Immunophenotyping , Middle Aged , Multicenter Studies as Topic , Piperazines/therapeutic use , Point Mutation , Pre-B-Cell Leukemia Transcription Factor 1 , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prognosis , Prospective Studies , Pyrimidines/therapeutic use , Young Adult
2.
Leukemia ; 21(11): 2304-10, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17713555

ABSTRACT

Telomerase catalytic subunit (hTERT) exerts important cellular functions including telomere homeostasis, genetic stability, cell survival and perhaps differentiation. However, the nature of external or internal signals, which regulate hTERT expression in tissues, remains poorly understood. Thus, whereas it has been described that hTERT gene is regulated along the differentiation of primitive myeloid progenitors, the effect of specific cytokines on telomerase expression in each myeloid lineage is currently unknown. Based on these considerations, we have investigated hTERT expression in erythroid cells treated with erythropoietin (EPO) and transforming growth factor beta (TGFbeta), as putative positive and negative regulators, respectively. We describe here that EPO activates hTERT gene transcription in in vitro-expanded primary erythroid precursors as well as in UT7 erythroleukemia cells. In UT7 cells, this study shows also that EPO acts through a JAK2/STAT5/c-myc axis. In contrast, TGFbeta blocks EPO signaling downstream of c-myc induction through a Smad3-dependent mechanism. Finally, hTERT appears to be efficiently regulated by EPO and TGFbeta in an opposite way in erythropoietic cells, arguing for a role of telomerase in red blood cell production.


Subject(s)
Erythroid Precursor Cells/metabolism , Erythropoietin/metabolism , Gene Expression Regulation, Leukemic , Telomerase/biosynthesis , Transforming Growth Factor beta/metabolism , Antigens, CD34/biosynthesis , Apoptosis , Cell Line , Cell Line, Tumor , Cell Proliferation , Cell Survival , Humans , Models, Biological , Plasmids/metabolism , Proto-Oncogene Proteins c-myc/metabolism
3.
Leukemia ; 20(7): 1211-6, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16688229

ABSTRACT

Activation of the Wnt/beta-catenin pathway has recently been shown to be crucial to the establishment of leukemic stem cells in chronic myeloid leukemia. We sought to determine whether beta-catenin was correlated to clonogenic capacity also in the acute myeloid leukemia (AML) setting. Eighty-two patients were retrospectively evaluated for beta-catenin expression by Western blot. beta-Catenin was expressed (although at various protein levels) in 61% of patients, and was undetectable in the remaining cases. In our cohort, beta-catenin expression was correlated with the clonogenic proliferation of AML-colony forming cells (AML-CFC or CFU-L) in methylcellulose in the presence of 5637-conditioned medium, and more strikingly with self-renewing of leukemic cells, as assessed in vitro by a re-plating assay. In survival analyses, beta-catenin appeared as a new independent prognostic factor predicting poor event-free survival and shortened overall survival (both with P<0.05). Furthermore, variations in beta-catenin protein levels were dependent on post-transcriptional mechanisms involving the Wnt/beta-catenin pathway only in leukemic cells. Indeed, beta-catenin negative leukemic cells were found to increase beta-catenin in response to Wnt3a agonist in contrast to normal counterparts. Altogether, our data pave the way to the evaluation of Wnt pathway inhibition as a new rationale for eradicating the clonogenic pool of AML cells.


Subject(s)
Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Neoplastic Stem Cells/physiology , beta Catenin/genetics , Cell Line, Tumor , Clone Cells , Female , Gene Expression Regulation, Leukemic , Humans , Leukemia, Monocytic, Acute/metabolism , Leukemia, Monocytic, Acute/mortality , Leukemia, Monocytic, Acute/pathology , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myelomonocytic, Acute/metabolism , Leukemia, Myelomonocytic, Acute/mortality , Leukemia, Myelomonocytic, Acute/pathology , Male , Middle Aged , Neoplastic Stem Cells/pathology , Predictive Value of Tests , Prognosis , Retrospective Studies , Signal Transduction , Survival Analysis , Wnt Proteins/metabolism
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