Contribution of the gata2 transcription factor to the development and progression of myeloid disorders

Résumé

The GATA2 transcription factor has an essential role in the proliferation and differentiation of hematopoietic cells. GATA2 contributes to myeloid malignancies through various mechanisms, including GATA2 overexpression in acute myeloid leukemia (AML), somatic GATA2 mutations in chronic myeloid leukemia in blast crisis and AML with biallelic CEBPA mutations, and germline mutations of GATA2, associated with four related familial syndromes that predispose to AML, among other myeloid malignancies. We hypothesized that deregulation of either GATA2 expression or GATA2 aberrant function caused by mutations could alter key downstream target genes, contributing to the pathogenesis of these diseases. Our general aim was to identify and functionally characterize novel target genes of the GATA2 transcription factor in AML, and to assess the effect of the GATA2 mutated proteins in the transcription of known target genes of GATA2. The results indicate that MYB is a key transcriptional target of GATA2 in AML, and that leukemic cells depend on MYB to maintain their proliferative phenotype. Moreover, MYB and GATA2 expression is positively correlated in three independent cohorts of patients with AML. On the other hand, human GATA2 contributes to its own transcription, and GATA2 mutations p.Thr354Met, p.Thr355del and p.Arg396Gln are unable to activate the GATA2 promoter, causing a haploinsufficiency that may be responsible for GATA2 deficit in affected individuals. Moreover, the expression of genes with important functions in myeloid development is deregulated in a patient with p.Arg396Gln mutation, including GATA2. Finally, in silico and in vitro studies indicate that p.Arg396Gln is unable to retain the immature phenotype of hematopoietic stem and progenitor cells, and that p.Arg396Gln might contribute to alter the leukocyte profile in affected individuals.