Gata2 haploinsufficiency promotes proliferation and functional decline of HSCs with myeloid bias during aging

Abdelfattah, Ali Mahmoud, Hughes-Davies, Antonia, Clayfield, Liam Daniel, Menendez-Gonzalez, Juan Bautista, Almotiri, Alhomidi, Alotaibi, Badi, Tonks, Alex ORCID: https://orcid.org/0000-0002-6073-4976 and Rodrigues, Neil P ORCID: https://orcid.org/0000-0002-1925-7733 2021. Gata2 haploinsufficiency promotes proliferation and functional decline of HSCs with myeloid bias during aging. Blood Advances 5 (20) , pp. 4285-4290. 10.1182/bloodadvances.2021004726

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Abstract

During aging, hematopoietic stem cell (HSC) function wanes with important biological and clinical implications for benign and malignant hematology, and other co-morbidities, such as cardiovascular disease. However, the molecular mechanisms regulating HSC aging remain incompletely defined. GATA2 haploinsufficiency driven clinical syndromes initially result in primary immunodeficiencies and routinely evolve into hematologic malignancies on acquisition of further epigenetic mutations in both young and older patients. Using a conditional mouse model of Gata2 haploinsufficiency, we discover that during aging Gata2 promotes HSC proliferation, monocytosis, and loss of the common lymphoid progenitor. Aging of Gata2 haploinsufficient mice also offsets enhanced HSC apoptosis and decreased granulocyte-macrophage progenitor number normally observed in young Gata2 haploinsufficient mice. Transplantation of elderly Gata2 haploinsufficient HSCs impairs HSC function with evidence of myeloid bias. Our data demonstrate that Gata2 regulates HSC aging and suggest the mechanisms by which Gata2 mediated HSC aging has an impact on the evolution of malignancies in GATA2 haploinsufficiency syndromes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Additional Information:	Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Publisher:	American Society of Hematology
ISSN:	2473-9529
Date of First Compliant Deposit:	17 September 2021
Date of Acceptance:	10 June 2021
Last Modified:	20 Dec 2023 10:13
URI:	https://orca.cardiff.ac.uk/id/eprint/144134

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