Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, UK.
Cell Stem Cell. 2009 Dec 4;5(6):659-65. doi: 10.1016/j.stem.2009.11.001.
The regulatory pathways necessary for the maintenance of adult hematopoietic stem cells (HSCs) remain poorly defined. By using loss-of-function approaches, we report a selective and cell-autonomous requirement for the p300/CBP-binding transcriptional coactivator Cited2 in adult HSC maintenance. Conditional deletion of Cited2 in the adult mouse results in loss of HSCs causing multilineage bone marrow failure and increased lethality. In contrast, conditional ablation of Cited2 after lineage specification in lymphoid and myeloid lineages has no impact on the maintenance of these lineages. Additional deletion of Ink4a/Arf (encoding p16(Ink4a) and p19(Arf)) or Trp53 (encoding p53, a downstream target of p19(Arf)) in a Cited2-deficient background restores HSC functionality and rescues mice from bone marrow failure. Furthermore, we show that the critical role of Cited2 in primitive hematopoietic cells is conserved in humans. Taken together, our studies provide genetic evidence that Cited2 selectively maintains adult HSC functions, at least in part, via Ink4a/Arf and Trp53.
维持成体造血干细胞（HSCs）的调控途径仍未完全明确。通过使用功能丧失方法，我们报告了 p300/CBP 结合转录共激活因子 Cited2 在成体 HSC 维持中的选择性和细胞自主需求。在成年小鼠中条件性删除 Cited2 会导致 HSCs 的丧失，从而导致多谱系骨髓衰竭和死亡率增加。相比之下，在淋巴谱系和髓系谱系中谱系特异性删除 Cited2 对这些谱系的维持没有影响。在 Cited2 缺陷背景中进一步删除 Ink4a/Arf（编码 p16(Ink4a) 和 p19(Arf)）或 Trp53（编码 p53，p19(Arf)的下游靶点）可恢复 HSC 功能并使小鼠免于骨髓衰竭。此外，我们表明 Cited2 在原始造血细胞中的关键作用在人类中是保守的。综上所述，我们的研究提供了遗传证据，表明 Cited2 通过 Ink4a/Arf 和 Trp53 选择性地维持成体 HSC 的功能，至少部分如此。
