Gata2 as a Crucial Regulator of Stem Cells in Adult Hematopoiesis and Acute Myeloid Leukemia

Abstract

Summary: Subversion of transcription factor (TF) activity in hematopoietic stem/progenitor cells (HSPCs) leads to the development of therapy-resistant leukemic stem cells (LSCs) that drive fulminant acute myeloid leukemia (AML). Using a conditional mouse model where zinc-finger TF Gata2 was deleted specifically in hematopoietic cells, we show that knockout of Gata2 leads to rapid and complete cell-autonomous loss of adult hematopoietic stem cells. By using short hairpin RNAi to target GATA2, we also identify a requirement for GATA2 in human HSPCs. In Meis1a/Hoxa9-driven AML, deletion of Gata2 impedes maintenance and self-renewal of LSCs. Ablation of Gata2 enforces an LSC-specific program of enhanced apoptosis, exemplified by attenuation of anti-apoptotic factor BCL2, and re-instigation of myeloid differentiation––which is characteristically blocked in AML. Thus, GATA2 acts as a critical regulator of normal and leukemic stem cells and mediates transcriptional networks that may be exploited therapeutically to target key facets of LSC behavior in AML. : Leukemic stem cells (LSCs) underpin therapy resistance and poor prognosis for patients with acute myeloid leukemia (AML). In this article Rodrigues and colleagues show that zinc-finger transcription factor Gata2 acts as an indispensable regulator of adult hematopoiesis and that inhibition of Gata2 in AML LSCs promotes apoptosis and myeloid differentiation. Thus, targeting the GATA2 transcriptional network in AML may facilitate development of novel therapies to abolish LSCs. Keywords: hematopoiesis, acute myeloid leukemia, leukemic stem cells, transcription factor, GATA2, BCL2