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

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.