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

Publication date: Available online 1 August 2019Source: Stem Cell ReportsAuthor(s): Juan Bautista Menendez-Gonzalez, Milica Vukovic, Ali Abdelfattah, Lubaid Saleh, Alhomidi Almotiri, Leigh-anne Thomas, Aloña Agirre-Lizaso, Aleksandra Azevedo, Ana Catarina Menezes, Giusy Tornillo, Sarah Edkins, Kay Kong, Peter Giles, Fernando Anjos-Afonso, Alex Tonks, Ashleigh S. Boyd, Kamil R. Kranc, Neil P. RodriguesSummarySubversion 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.Graphical Abstract
Source: Stem Cell Reports - Category: Stem Cells Source Type: research