Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 5, Pages 2007-2020Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI78124
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Funding
- Sidney Kimmel Cancer Research Foundation
- University of Michigan Comprehensive Cancer Center
- D. Dan and Betty Kahn Foundation
- NIH [RO1-AI091627, R37-HD30428, P30-CA46592]
- University of Michigan's Medical Scientist Training Program [GM07863]
- Center for Organogenesis [HD 007505]
- Cellular and Molecular Biology Program [GM 007315]
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Rapidly cycling fetal and neonatal hematopoietic stem cells (HSCs) generate a pool of quiescent adult HSCs after establishing hematopoiesis in the bone marrow. We report an essential role for the trithorax group gene absent, small, or homeotic 1-like (Ash1l) at this developmental transition. Emergence and expansion of Ash1l-deficient fetal/neonatal HSCs were preserved; however, in young adult animals, HSCs were profoundly depleted. Ash1l-deficient adult HSCs had markedly decreased quiescence and reduced cyclin-dependent kinase inhibitor 1b/c (Cdkn1b/1c) expression and failed to establish long-term trilineage bone marrow hematopoiesis after transplantation to irradiated recipients. Wild-type HSCs could efficiently engraft when transferred to unirradiated, Ash1l-deficient recipients, indicating increased availability of functional HSC niches in these mice. Ash1l deficiency also decreased expression of multiple Hox genes in hematopoietic progenitors. Ash1l cooperated functionally with mixed-lineage leukemia 1 (Mll1), as combined loss of Ash1l and Mll1, but not isolated Ash1l or Mll1 deficiency, induced overt hematopoietic failure. Our results uncover a trithorax group gene network that controls quiescence, niche occupancy, and self-renewal potential in adult HSCs.
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