Project description:Clinical GATA2 deficiency syndromes arise from germline haploinsufficiency inducing mutations in GATA2, resulting in immunodeficiency that evolves to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). How GATA2 haploinsufficiency disrupts the function and transcriptional network of hematopoietic stem/progenitors (HSCs/HSPCs) to facilitate the shift from immunodeficiency sequalae to pre-leukemia is poorly characterised. Using a conditional mouse model harboring a single allele deletion of Gata2 when HSCs emerge in utero, we identify pervasive defects in HSPC differentiation from young adult Gata2 haploinsufficient mice during B-cell maturation, early erythroid specification, megakaryocyte maturation to platelets and inflammatory cell generation. Gata2 haploinsufficiency abolishes HSC self-renewal and multi-lineage differentiation capacity following transplantation. These alterations closely associate with deregulated DNA damage responses and inflammatory signalling conveyed from Gata2 haploinsufficient HSCs. We also identify functional interplay between Gata2 and Asxl1, a driver of DNA damage and inflammation and, notably, a recurrent secondary mutation found in GATA2 haploinsufficiency disease progression to MDS/AML. shRNA mediated knockdown of Asxl1 in Gata2 haploinsufficient HSPCs led to a differentiation block in committed progenitor formation beyond that in Gata2 haploinsufficient HSPCs. By analysis of HSCs from young adult compound Gata2/Asxl1 haploinsufficient mice, we discover hyperproliferation of double haploinsufficent HSCs, which are also functionally compromised in transplantation compared to their single haploinsufficient counterparts. Through both Gata2/Asxl1 dependent and unique transcriptional programs, HSCs from young adult compound Gata2/Asxl1 haploinsufficient mice fortify deregulated DNA damage responses and inflammatory signalling in HSCs initiated in Gata2 haploinsufficient mice and establish a broad pre-leukemic program. Our data reveal how Gata2 haploinsufficiency initially drives deregulation of HSC genome integrity and suggest the mechanisms of how secondary mutations like ASXL1 take advantage of HSC genomic instability to nurture a pre-leukemic state in GATA2 haploinsufficiency syndromes.

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Co-mutation of asxl1 and IDH2R172K induces leukemogenesis via epigenetic activation of MAPK /AP-1 pathway in leukemic stem cells

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