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细胞周期检查点激酶 1 对于胎儿和成人的造血功能至关重要。

Checkpoint kinase 1 is essential for fetal and adult hematopoiesis.

机构信息

Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.

Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

出版信息

EMBO Rep. 2019 Aug;20(8):e47026. doi: 10.15252/embr.201847026. Epub 2019 Jun 17.

DOI:10.15252/embr.201847026
PMID:31379128
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6680171/
Abstract

Checkpoint kinase 1 (CHK1) is critical for S-phase fidelity and preventing premature mitotic entry in the presence of DNA damage. Tumor cells have developed a strong dependence on CHK1 for survival, and hence, this kinase has developed into a promising drug target. Chk1 deficiency in mice results in blastocyst death due to G2/M checkpoint failure showing that it is an essential gene and may be difficult to target therapeutically. Here, we show that chemical inhibition of CHK1 kills murine and human hematopoietic stem and progenitor cells (HSPCs) by the induction of BCL2-regulated apoptosis. Cell death in HSPCs is independent of p53 but requires the BH3-only proteins BIM, PUMA, and NOXA. Moreover, Chk1 is essential for definitive hematopoiesis in the embryo. Noteworthy, cell death inhibition in HSPCs cannot restore blood cell formation as HSPCs lacking CHK1 accumulate DNA damage and stop dividing. Moreover, conditional deletion of Chk1 in hematopoietic cells of adult mice selects for blood cells retaining CHK1, suggesting an essential role in maintaining functional hematopoiesis. Our findings establish a previously unrecognized role for CHK1 in establishing and maintaining hematopoiesis.

摘要

细胞周期蛋白依赖性激酶 1（CHK1）对于 S 期保真度和防止 DNA 损伤时过早进入有丝分裂至关重要。肿瘤细胞的生存强烈依赖于 CHK1，因此，这种激酶已成为有前途的药物靶点。在小鼠中 Chk1 缺失会导致囊胚死亡，这是由于 G2/M 检查点失败，表明它是一个必需基因，可能难以进行治疗性靶向。在这里，我们表明，CHK1 的化学抑制通过诱导 BCL2 调节的细胞凋亡来杀死小鼠和人类造血干细胞和祖细胞（HSPCs）。HSPCs 中的细胞死亡不依赖于 p53，但需要 BH3 仅蛋白 BIM、PUMA 和 NOXA。此外，Chk1 对于胚胎中的确定性造血是必需的。值得注意的是，HSPCs 中的细胞死亡抑制不能恢复血细胞的形成，因为缺乏 CHK1 的 HSPCs 会积累 DNA 损伤并停止分裂。此外，在成年小鼠的造血细胞中条件性缺失 Chk1 会选择保留 CHK1 的血细胞，这表明其在维持功能性造血中具有重要作用。我们的发现确立了 CHK1 在建立和维持造血中的先前未知作用。

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