Somatic mutations in the hematopoietic transcription factor GATA1, leading to the production of a GATA1 variant (GATA1s) lacking its N-terminal domain, are a critical event in the development of Down syndrome (DS) associated transient myeloproliferative disease (TMD) and myeloid leukemia (ML-DS). Mice carrying Gata1s germline mutation exhibit a transient population of abnormal yolk sac/fetal liver megakaryocytic progenitors, hyperproliferating both in vitro and in vivo. However, either Gata1s mice alone or in conjunction with two DS mouse models (Ts65dn, Ts1Cje) fail to recapitulate human TMD or leukemia. Using a retroviral insertional mutagenesis screening in Gata1s fetal progenitors, we generated murine acute megakaryoblastic leukemia (AMKL) closely resembling human ML-DS. We demonstrate that retroviral integrations at the Evi1 and Plag1 loci cooperated with Gata1s in leukemogenesis. Through an integrated genomic approach, we show that restoration of full length Gata1 expression in these murine Gata1s AMKL blasts leads to downregulation of gene sets containing E2F target genes. In addition, most of these same gene sets are also enriched in Gata1s primary fetal liver-derived megakaryocytes compared to wild type megakaryocytes, in flow sorted human ML-DS leukemic blasts compared to sorted non-DS M7 leukemic blasts, and in ML-DS CMK cell line compared to other leukemic cell lines. Using a genetic approach, we could demonstrate that the hyperproliferative phenotype of Gata1s FL megakaryocytic progenitor cells can be rescued by broadly repressing the function of E2F factors. Additionally, the CMK cell line ceased to proliferate upon E2F inactivation. Thus, we discovered a new mechanism of GATA1 mediated growth regulation by controlling E2F function. GATA1s mutant protein contributes to leukemogenesis through insufficient repression of E2F targets, perturbing the coordination of proliferation and terminal differentiation. Our study reveals a previously unknown function of the N-terminal domain of GATA1 and adds a significant step towards our understanding of the role of GATA1 mutants in leukemogenesis.

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