title: Down-regulation of the RUNX1-target gene NR4A3 contributes to hematopoiesis deregulation in familial platelet disorder/acute myelogenous leukemia.
abstract: 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 2 FPD/AML pedigrees with 2 distinct RUNX1 germline mutations, that is, 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.
authors: Inserm, U1009, Villejuif, France.
authors: Dominique
authors: D
authors: Bluteau
authors: Laure
authors: L
authors: Gilles
authors: Morgane
authors: M
authors: Hilpert
authors: Iléana
authors: I
authors: Antony-Debré
authors: Chloe
authors: C
authors: James
authors: Najet
authors: N
authors: Debili
authors: Valerie
authors: V
authors: Camara-Clayette
authors: Orianne
authors: O
authors: Wagner-Ballon
authors: Veronique
authors: V
authors: Cordette-Lagarde
authors: Thomas
authors: T
authors: Robert
authors: Hugues
authors: H
authors: Ripoche
authors: Patrick
authors: P
authors: Gonin
authors: Sabina
authors: S
authors: Swierczek
authors: Josef
authors: J
authors: Prchal
authors: William
authors: W
authors: Vainchenker
authors: Remi
authors: R
authors: Favier
authors: Hana
authors: H
authors: Raslova
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002999:Clone Cells / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010981:Platelet Storage Pool Deficiency / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D011987:Receptors, Steroid / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D055815:Young Adult
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C490412:NR4A3 protein, human; C493728:RUNX1 protein, human; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone