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(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-CD48-CD150+and LSK-CD34-Flt3-populations in the bone marrow and a reduction in quiescent cells in G0Surprisingly, the loss of classically defined HSCs did not affect mouse viability, and there was no recovery of the LSK-CD48-CD150+and LSK-CD34-Flt3-populations 15 to 18 months afterMozdeletion. Clonal analysis of myeloid progenitors, which produce short-lived granulocytes, demonstrate that these are derived from cells that had undergone recombination at theMozlocus 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.
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
Bilal N
BN
Sheikh
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
Yuqing
Y
Yang
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
Jaring
J
Schreuder
Manufacturing Commonwealth Scientific and Industrial Research Organisation, Clayton, VIC, Australia; and.|Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia.
Susan K
SK
Nilsson
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
Rebecca
R
Bilardi
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
Sebastian
S
Carotta
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
Helen M
HM
McRae
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Donald
D
Metcalf
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
Anne K
AK
Voss
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
Tim
T
Thomas
D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation; D016922:Cellular Senescence; D003114:Colony-Forming Units Assay; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010641:Phenotype; D016192:Resting Phase, Cell Cycle; D033581:Stem Cell Transplantation
D015415:Biomarkers; D051548:Histone Acetyltransferases; C511438:MOZ protein, mouse; C045073:Cre recombinase; D019426:Integrases