Abdelfattah, A;
Habib, A;
Thomas, LA;
Menendez-Gonzalez, JB;
Almotiri, A;
Alqahtani, H;
Lawson, H;
... Rodrigues, NP; + view all
(2025)
Impaired DNA damage responses and inflammatory signaling underpin hematopoietic stem cell defects in Gata2 haploinsufficiency.
Stem Cell Reports
, 20
(8)
, Article 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.
| Type: | Article |
|---|---|
| Title: | Impaired DNA damage responses and inflammatory signaling underpin hematopoietic stem cell defects in Gata2 haploinsufficiency |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.stemcr.2025.102596 |
| Publisher version: | https://doi.org/10.1016/j.stemcr.2025.102596 |
| Language: | English |
| Additional information: | © 2025 The Authors. Published by Elsevier Inc. on behalf of International Society for Stem Cell Research. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | DNA damage response, GATA2 haploinsufficiency, hematopoietic stem cells, inflammation, pre-leukemia, Animals, GATA2 Transcription Factor, Haploinsufficiency, Hematopoietic Stem Cells, Mice, Signal Transduction, DNA Damage, Inflammation, Repressor Proteins, Cell Differentiation, Genomic Instability |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10213112 |
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