Modelling GATA2 haploinsufficiency driven immunodeficiency and myelodysplastic syndromes /acute myeloid leukaemia

Abstract

HSCs are entirely responsible for the continuous replenishment of short-lived blood cells to preserve haematopoietic homeostasis. GATA2, a zinc-finger transcription factor, is highly expressed within HSPCs and operates different aspects of HSC functions in the embryonic and adult haematopoietic system. Since either low or high GATA2 expression is involved in leukaemogenesis, the balanced expression of GATA2 is therefore indispensable for retaining normal haematopoiesis. Acquired ASXL1 mutations are recurrently existent in MDS/AML patients harbouring inherited GATA2 mutations. While GATA2 haploinsufficiency causes BM failure disorders that can predispose to myeloid malignancies, little information is known about affected HSPC compartments and underlying molecular mechanisms in this context. With the intention to mimic inherited and acquired GATA2 haploinsufficiency disorders, conditional knockout mice models were employed to elucidate the impact of Gata2 haploinsufficiency on adult HSPCs and haematopoiesis. Analysis of young Gata2 haploinsufficient mice utilising a pan haematopoietic Vav-iCre approach revealed a reduction in HSCs, MPPs, MPP4 (LMPPs), early erythroid-progenitors (Pre-MegE/Pre-CFU-E), myeloid-progenitors (Pre-GM/GMP) and megakaryocyte-subpopulations (Pre-MegE/MkPs/megakaryocytes/platelets), but an increase in MPP2. The reduced HSC numbers were associated with increased cellular quiescence and apoptosis rates. The abundance of HSCs, MPPs, LMPPs and CLPs was decreased in aged Gata2+/fl;Vav-iCre+ mice although aged HSCs became more proliferative than young HSCs. Acute loss of Gata2 heterozygote applying the inducible Mx1-Cre model exhibited attenuation in HSCs frequency with an increase in the number of quiescent HSCs. Functionally, acute and chronic ablation of Gata2 haploinsufficiency resulted in a severe defect in long-term multi-lineage reconstitution and self-renewal capacities of adult HSCs post-transplantation. The DNA damage repair and proinflammatory signalling were the most affected biological pathways in Gata2 haploinsufficient HSCs. Cooperative haploinsufficient mice of Gata2 and Asxl1 (Gata2+/fl;Asxl1+/fl;Vav-iCre+) showed increased HSCs proliferation and decreased HSCs survival, which led to impaired long-term engraftment capability of HSCs and ultimately depleted HSCs pool during stress haematopoiesis. Together, Gata2 haploinsufficiency interrupts HSCs survival, proliferation, self-renewal, and maintenance. Thus, biallelic expression of Gata2 is essentially required for preserving adult HSPCs homeostasis