Characterization of cooperating mechanisms in GATA2 syndrome

Hematopoiesis is regulated by different transcription factors and cofactors that ensure a proper proliferation, differentiation and survival of immature hematopoietic stem and progenitor cells (HSPCs). Germline mutations in these genes can affect both their expression and their activity. GATA2 is a transcription factor where more than 400 germline pathogenic variants have been identified leading to variable hematological and non-hematological phenotypes with a high risk of developing MDS or AML. However, the underlying mechanisms of this malignant transformation remain unknown.

Hence, we aim to identify possible tumor suppressor genes promoting leukemogenesis in mice with GATA2 haploinsufficient hematopoietic system. Because of the association of GATA2 deficiency with monosomy 7, we are focusing on putative tumor suppressors located on human chromosome 7. First, we downregulate IKZF1 and EZH2 by transducing shRNA-expressing lentiviruses into Gata2+/- / WT HSPCs. Outcome parameters are the capacity to proliferate, differentiate and undergo apoptosis. These data will shed light on cooperating mechanisms in GATA2 haploinsufficiency for the predisposition to MDS/AML.

Publication History

Article published online:
17 May 2022