Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells
Morgan Jones, … , Sally A. Camper, Ivan Maillard
Morgan Jones, … , Sally A. Camper, Ivan Maillard
Published April 13, 2015
Citation Information: J Clin Invest. 2015;125(5):2007-2020. https://doi.org/10.1172/JCI78124.
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Research Article Hematology

Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells

Abstract

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.

Authors

Morgan Jones, Jennifer Chase, Michelle Brinkmeier, Jing Xu, Daniel N. Weinberg, Julien Schira, Ann Friedman, Sami Malek, Jolanta Grembecka, Tomasz Cierpicki, Yali Dou, Sally A. Camper, Ivan Maillard

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Figure 4

Ash1l-deficient fetal liver cells do not sustain long-term BM reconstitution after competitive transplantation.

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Ash1l-deficient fetal liver cells do not sustain long-term BM reconstit...
(A) Experimental strategy: Ash1l+/+or Ash1lGT/GT B6-CD45.2 E15.5 fetal liver was mixed with wild-type B6-CD45.1 competitor BM (1:1 ratio; 2.5 × 105 cells each) and injected into lethally irradiated (9 Gy) B6-CD45.1 recipients. (B) Analysis of peripheral blood 2–26 weeks after transplantation, showing a profound reduction of Ash1lGT/GT contribution to myeloid, B, and T lineage reconstitution (n = 10–11 mice per genotype; mean ± SD from 2 experiments). (C) CD45.2/CD45.1 chimerism in CD150+CD48–LSKs (LT-HSCs) 17–26 weeks after transplantation, showing markedly decreased fetal liver-derived Ash1lGT/GT LT-HSCs (wild-type n = 11, Ash1lGT/GT n = 10 mice, ***P < 0.001, t test; horizontal bars show the mean).