ClinicalGATA2deficiency syndromes arise from germline haploinsufficiency inducing mutations inGATA2, resulting in immunodeficiency that evolves to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). HowGATA2haploinsufficiency disrupts the function and transcriptional network of hematopoietic stem/progenitors (HSCs/HSPCs) to facilitate the shift from immunodeficiency to pre-leukemia is poorly characterised. Using a conditional mouse model harboring a single allele deletion ofGata2from the start of HSC developmentin utero, we identified pervasive defects in HSPC differentiation from young adultGata2haploinsufficient mice during B-cell development, early erythroid specification, megakaryocyte maturation to platelets and inflammatory cell generation.Gata2haploinsufficiency abolished HSC self-renewal and multi-lineage differentiation capacity. These functional alterations closely associated with deregulated DNA damage responses and inflammatory signalling conveyed fromGata2haploinsufficient HSCs. We identified genetic interplay betweenGata2andAsxl1, a driver of DNA damage and inflammation and, notably, a recurrent secondary mutation found inGATA2haploinsufficiency disease progression to MDS/AML. shRNA mediated knockdown ofAsxl1inGata2haploinsufficient HSPCs led to an enhanced differentiation blockin vitro. By analysis of HSCs from young adult compoundGata2/Asxl1haploinsufficient mice, we discovered hyperproliferation of double haploinsufficient HSCs, which were also functionally compromised in transplantation compared to their singleGata2 or Asxl1haploinsufficient counterparts. Through bothGata2/Asxl1dependent and unique transcriptional programs, HSCs from compoundGata2/Asxl1haploinsufficient fortified deregulated DNA damage responses and inflammatory signalling initiated inGata2haploinsufficient HSCs and established a broad pre-leukemic program. Our data reveal howGata2haploinsufficiency initially drives deregulation of HSC genome integrity and suggest the mechanisms of how secondary mutations likeASXL1take advantage of HSC genomic instability to nurture a pre-leukemic state inGATA2haploinsufficiency syndromes.