Too little is too much: Leukemogenesis in the Gata2 syndrome

GATA2 is a transcription factor required for the generation/maintenance of hematopoietic stem cells. Strikingly, up to 75% of GATA2 haploinsufficient individuals develop myelodysplastic syndromes with a high risk of progression to leukemia. As the mechanism behind it is unknown, we aimed at deciphering how GATA2 haploinsufficiency drives leukemogenesis. We hypothesized that GATA2 haploinsufficiency either directly induces leukemia or provokes bone marrow failure, which later develops into secondary leukemia. To test these hypotheses, we analyzed the oncogenic potential of Gata2+/- in proliferation assays and after mutagen treatment. In parallel we assessed their susceptibility to provoke bone marrow failure by subjecting them to different cell stresses (ageing, transplantations). We discovered that Gata2+/- cells produced premalignant cells in vitro and accelerated leukemogenesis in vivo. Transplantation of Gata2+/- cells resulted in bone marrow failure. Our results show that Gata2 haploinsufficiency drives on the one hand leukemogenesis and on the other hand fuels bone marrow failure. We are now investigating the link and the mechanism behind this intriguing paradoxal behavior.