Impaired DNA damage responses and inflammatory signaling underpin hematopoietic stem cell defects in Gata2 haploinsufficiency

Abdelfattah, Ali, Habib, Ahmad, Thomas, Leigh-anne, Menendez-Gonzalez, Juan Bautista, Almotiri, Alhomidi, Alqahtani, Hind, Lawson, Hannah, Taha, Sarab, Steadman, Millie, Athalye, Radhika, Gibbs, Alex, Alzahrani, Hamed, Alshahrani, Ali, Cato, Alice, Giles, Peter ORCID: https://orcid.org/0000-0003-3143-6854, 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 2025. Impaired DNA damage responses and inflammatory signaling underpin hematopoietic stem cell defects in Gata2 haploinsufficiency. Stem Cell Reports 20 (8) , 102596. 10.1016/j.stemcr.2025.102596

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Abstract

Clinical GATA2 haploinsufficiency results in immunodeficiency that evolves to leukemia. How GATA2 haploinsufficiency disrupts the functionality of hematopoietic stem/progenitor cells (HSCs/HSPCs) to facilitate pre-leukemia development is poorly defined. Using a hematopoietic-specific conditional mouse model of Gata2 haploinsufficiency, we identified pervasive defects in HSPC differentiation in young adult Gata2 haploinsufficient mice and perturbed HSC self-renewal following transplantation. These alterations aligned with deregulated global DNA damage responses and inflammatory cell signaling from Gata2 haploinsufficient HSCs. We also discovered genetic interplay between Gata2 and Asxl1, a secondary mutation leading to leukemia in GATA2 deficiency syndromes. HSCs from young adult compound Gata2/Asxl1 haploinsufficient mice were hyperproliferative, functionally compromised after transplantation, and displayed a broad pre-leukemia transcriptomic program. Thus, Gata2 haploinsufficiency triggers HSC genomic instability. Our data further suggest that secondary mutations like ASXL1 exploit this impaired HSC genomic integrity to nurture a pre-leukemic state in GATA2 haploinsufficiency syndromes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Schools > Biosciences Research Institutes & Centres > European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	Cell Press
ISSN:	2213-6711
Date of First Compliant Deposit:	9 July 2025
Date of Acceptance:	7 July 2025
Last Modified:	19 Aug 2025 10:47
URI:	https://orca.cardiff.ac.uk/id/eprint/179671

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