The role of the GATA2 transcriptional program in the development of acute myeloid leukemia

Myeloid dysplastic syndrome (MDS) and acute myeloid leukemia (AML) are aggressive forms of blood cancer that are still fatal in more than 50% of patients. Familial forms of MDS/AML have very poor cure rates. Germline mutations in GATA2, resulting in haploinsufficiency of the transcription factor GATA2 (Gata2 in animals) is the most commonly mutated gene in childhood MDS/AML. Between 36-71% of patients with germline mutations in GATA2 develop AML. Although the disease initiating mutation is known, it is unclear how GATA2 haploinsufficiency predisposes to leukemia and contributes to the progression to MDS/AML. Because GATA2 is pivotal for hematopoietic stem cell (HSC) generation in the embryo, the disease-driving defects likely already affect the hematopoietic system during fetal development. Therefore, we hypothesize that the defect in the hematopoietic system of patients with a GATA2 haploinsufficiency in newly generated HSCs or in amplifying HSCs contributes to leukemia predisposition. We have performed RNA sequencing on WT and Gata2+/- mouse embryonic and adult phenotypic HSCs and found that Gata2 transcriptional levels normalize during HSC development. Despite this normalization, the transcriptome of WT and Gata2+/- adult bone marrow HSCs is still transcriptionally different. This points to an underlying epigenetic reprogramming during the embryonic stages. We have found that cell cycle and metabolic signatures are different in embryonic HSCs compared to WT. We will further dissect these phenotypes in the zebrafish model in which we have generated a knockout of gata2b and several reporter lines to study these processes in vivo.