MOZ (KAT6A) is essential for the maintenance of classically defined adult hematopoietic stem cells.

Hematopoietic stem cells (HSCs) are conventionally thought to be at the apex of a hierarchy that produces all mature cells of the blood. The quintessential property of these cells is their ability to reconstitute the entire hematopoietic system of hemoablated recipients. This characteristic has enabled HSCs to be used to replenish the hematopoietic system of patients after chemotherapy or radiotherapy. Here, we use deletion of the monocytic leukemia zinc finger gene to examine the effects of removing HSCs. Loss of MOZ in adult mice leads to the rapid loss of HSCs as defined by transplantation. This is accompanied by a reduction of the LSK-CD48CD150 and LSK-CD34Flt3 populations in the bone marrow and a reduction in quiescent cells in G Surprisingly, the loss of classically defined HSCs did not affect mouse viability, and there was no recovery of the LSK-CD48CD150 and LSK-CD34Flt3 populations 15 to 18 months after deletion. Clonal analysis of myeloid progenitors, which produce short-lived granulocytes, demonstrate that these are derived from cells that had undergone recombination at the locus up to 2 years earlier, suggesting that early progenitors have acquired extended self-renewal. Our results establish that there are essential differences in HSC requirement for steady-state blood cell production compared with the artificial situation of reconstitution after transplantation into a hemoablated host. A better understanding of steady-state hematopoiesis may facilitate the development of novel therapies engaging hematopoietic cell populations with previously unrecognized traits, as well as characterizing potential vulnerability to oncogenic transformation.