Jones Morgan, Chase Jennifer, Brinkmeier Michelle, Xu Jing, Weinberg Daniel N, Schira Julien, Friedman Ann, Malek Sami, Grembecka Jolanta, Cierpicki Tomasz, Dou Yali, Camper Sally A, Maillard Ivan
J Clin Invest. 2015 May;125(5):2007-20. doi: 10.1172/JCI78124. Epub 2015 Apr 13.
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.
快速循环的胎儿和新生儿造血干细胞（HSCs）在骨髓中建立造血功能后会产生一批静止的成年造血干细胞。我们报告了三体组基因缺失、小或同源异型1样（Ash1l）在这一发育转变过程中的重要作用。Ash1l缺陷型胎儿/新生儿造血干细胞的出现和扩增得以保留；然而，在年轻成年动物中，造血干细胞被严重消耗。Ash1l缺陷型成年造血干细胞的静止状态明显降低，细胞周期蛋白依赖性激酶抑制剂1b/c（Cdkn1b/1c）表达减少，在移植到受照射受体后无法建立长期三系骨髓造血。野生型造血干细胞转移到未受照射的Ash1l缺陷型受体时能够有效植入，表明这些小鼠中功能性造血干细胞龛的可用性增加。Ash1l缺陷还会降低造血祖细胞中多个Hox基因的表达。Ash1l在功能上与混合谱系白血病1（Mll1）协同作用，因为Ash1l和Mll1的联合缺失而非单独的Ash1l或Mll1缺陷会导致明显的造血功能衰竭。我们的研究结果揭示了一个三体组基因网络，该网络控制成年造血干细胞的静止状态、龛占据和自我更新潜力。
