New Insights into the Regulation of Hematopoietic Stem Cell Self-Renewal.

[摘要] Self-renewal is essential for stem cell maintenance. In the blood system, rare hematopoietic stem cells (HSCs) must maintain their self-renewal potential to sustain long-term homeostasis. HSC self-renewal is tightly regulated, as defective self-renewal can result in stem cell depletion and unrestricted self-renewal is a hallmark of leukemia. In this report, we describe two novel regulators of HSC self-renewal illustrative of the diverse mechanisms that sustain stable long-term blood formation.Absent, small, or homeotic 1-like (Ash1l) is a Trithorax group (TrG) member with a previously uncharacterized physiological function. The TrG is of interest in hematopoiesis, as Mixed-lineage leukemia 1, the prototypical TrG member, is required for HSC maintenance and frequently drives human leukemogenesis. Our work demonstrates that HSCs require Ash1l for establishing quiescence in the bone marrow, a fundamental process for preservation of HSC self-renewal. In the absence of Ash1l, HSCs become depleted in the young adult bone marrow, and HSC function is not detected in transplantation assays. Despite an apparent lack of functional HSCs, Ash1l-deficient mice do not progress to hematopoietic failure elucidating a paradoxical preservation of steady-state hematopoiesis despite a lack of transplantable HSC function. Additionally, we found that Ash1l cooperates non-redundantly with Mll1 to maintain hematopoietic homeostasis. This is reminiscent of the functional cooperativity that defines Drosophila TrG members and has not been demonstrated in mammals.Adrenocortical dysplasia (Acd), encodes Tpp1, a member of the telomere-protecting shelterin protein complex. Recent work implicates shelterin in a particularly aggressive form of the human bone marrow failure syndrome dyskeratosis congenita, though roles for shelterin proteins in hematopoietic homeostasis have not been fully defined. Our work indicates that Acd loss causes acute hematopoietic stem and progenitor cell depletion and severely impaired HSC self-renewal in transplantation assays. Though Acd deletion results in p53 target gene activation, p53 deletion is not sufficient to rescue Acd-deficient HSC function. This is contrary to models of Acd deficiency in other stem cell systems in which p53 inactivation largely rescues function. Our data suggest that HSCs are exquisitely sensitive to Acd loss and that shelterin proteins have previously undefined context-dependent functions in stem cell biology.

[发布机构] University of Michigan

[效力级别] telomere

[关键词] hematopoietic stem cells;telomere;shelterin;histone methyltransferase;quiescence;trithorax;Molecular;Cellular and Developmental Biology;Oncology and Hematology;Health Sciences;Cellular and Molecular Biology