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Gata2 as a crucial regulator of stem cells in hematopoiesis and acute myeloid leukemia

Menendez Gonzalez, Juan, Vukovic, Milica, Abdelfattah, Ali, Saleh, Lubaid, Almotiri, Alhomidi, Thomas, Leigh-Anne, Agirre-Lizaso, Alona, Azevedo, Aleksandra, Menezes, Ana Catarina, Tornillo, Giusy, Edkins, Sarah, Kong, Kay, Giles, Peter, Dos Anjos Afonso, Fernando, Tonks, Alex, Boyd, Ashleigh S, Kranc, Kamil R and Rodrigues, Neil P 2019. Gata2 as a crucial regulator of stem cells in hematopoiesis and acute myeloid leukemia. Stem Cell Reports 13 (2) , pp. 291-306. 10.1016/j.stemcr.2019.07.005

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Biosciences
Publisher: Elsevier
ISSN: 2213-6711
Date of First Compliant Deposit: 23 July 2019
Date of Acceptance: 12 June 2019
Last Modified: 30 Nov 2019 06:22
URI: http://orca-mwe.cf.ac.uk/id/eprint/124412

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