Document Detail

Down-regulation of the RUNX1-target gene NR4A3 contributes to hematopoiesis deregulation in familial platelet disorder/acute myelogenous leukemia (FPD/AML).
MedLine Citation:
PMID:  21725049     Owner:  NLM     Status:  Publisher    
RUNX1 encodes a DNA binding α-subunit of the core binding factor, a heterodimeric transcription factor. RUNX1 is a master regulatory gene in hematopoiesis and its disruption is one of the most common aberrations in acute leukemia. Inactivating or dominant-negative mutations in the RUNX1 gene have been also identified in pedigrees of familial platelet disorders with a variable propensity to develop acute myeloid leukemia (FPD/AML). We performed analysis of hematopoiesis from two FPD/AML pedigrees with two distinct RUNX1 germ line mutations, i.e. the R139X in a pedigree without AML and the R174Q mutation in a pedigree with AML. Both mutations induced a marked increase in the clonogenic potential of immature CD34(+)CD38(-) progenitors, with some self-renewal capacities observed only for R174Q mutation. This increased proliferation correlated with reduction in the expression of NR4A3, a gene previously implicated in leukemia development. We demonstrated that NR4A3 was a direct target of RUNX1 and that restoration of NR4A3 expression partially reduced the clonogenic potential of patient progenitors. We propose that the down-regulation of NR4A3 in RUNX1 mutated hematopoietic progenitors leads to an increase in the pool of cells susceptible to be hit by secondary leukemic genetic events.
Dominique Bluteau; Laure Gilles; Morgane Hilpert; Iléana Antony-Debré; Chloe James; Najet Debili; Valerie Camara-Clayette; Orianne Wagner-Ballon; Veronique Cordette-Lagarde; Thomas Robert; Hugues Ripoche; Patrick Gonin; Sabina Swierczek; Joseph Prchal; William Vainchenker; Remi Favier; Hana Raslova
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-7-1
Journal Detail:
Title:  Blood     Volume:  -     ISSN:  1528-0020     ISO Abbreviation:  -     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-7-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Institut National de la Sante et de la Recherche Medicale, U1009, Villejuif, France;
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