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

Menendez Gonzalez, Juan Bautista, Vukovic, Milica, Abdelfattah, Ali, Saleh, Lubaid, Almotiri, Alhomidi, Thomas, Leigh-anne, Agirre-Lizaso, Alona, Azevedo, Aleksandra, Menezes, Ana Catarina, Tornillo, Giusy, Edkins, Sarah ORCID: https://orcid.org/0000-0003-0717-1972, Kong, Kay, Giles, Peter ORCID: https://orcid.org/0000-0003-3143-6854, Anjos-Afonso, Fernando, Tonks, Alex ORCID: https://orcid.org/0000-0002-6073-4976, Boyd, Ashleigh S., Kranc, Kamil R. and Rodrigues, Neil P. ORCID: https://orcid.org/0000-0002-1925-7733 2019. Gata2 as a crucial regulator of stem cells in adult 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:	Advanced Research Computing @ Cardiff (ARCCA) Medicine Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License.
Publisher:	Elsevier
ISSN:	2213-6711
Date of First Compliant Deposit:	23 July 2019
Date of Acceptance:	5 July 2019
Last Modified:	24 Mar 2024 15:02
URI:	https://orca.cardiff.ac.uk/id/eprint/124412

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