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

Bilal N. Sheikh, Yuqing Yang, Jaring Schreuder, Susan K. Nilsson, Rebecca Bilardi, Sebastian Carotta, Helen M. McRae, Donald Metcalf, Anne K. Voss and Tim Thomas

Key Points

  • MOZ deletion in adult mice leads to a rapid loss of cells with HSC cell surface immuno-phenotype and transplantation ability.

  • Absence of classically defined HSCs for an extended period does not substantially affect steady-state hematopoiesis.

Abstract

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 (Moz/Kat6a/Myst3) 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 G0. 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 Moz deletion. Clonal analysis of myeloid progenitors, which produce short-lived granulocytes, demonstrate that these are derived from cells that had undergone recombination at the Moz 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.

  • Submitted October 20, 2015.
  • Accepted September 14, 2016.
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