The Spindle Assembly Checkpoint Is Required for Hematopoietic Progenitor Cell Engraftment.
The Spindle Assembly Checkpoint Is Required for Hematopoietic Progenitor Cell Engraftment.
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DOI：
10.1016/j.stemcr.2017.09.017
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发表时间：
2017-11-14
影响因子：
5.9
通讯作者：
Geiger H
中科院分区：
文献类型：
--
作者：
Brown A;Pospiech J;Eiwen K;Baker DJ;Moehrle B;Sakk V;Nattamai K;Vogel M;Grigoryan A;Geiger H
纺锤体组装检查点在防止非整倍体和转化中起着关键作用。许多研究证明了癌细胞中这一检查点的受损。虽然白血病通常由转化的造血干细胞和祖细胞（HSPC）驱动，但这种原代细胞中纺锤体组装检查点的生物学还不是很清楚。在这里，我们揭示了检查点在小鼠祖细胞中是完全功能性的，并且在较小程度上在造血干细胞中是完全功能性的。我们发现，HSPCs逮捕在前中期和诱导p53依赖性细胞凋亡后，长期治疗抗有丝分裂药物。此外，检查点可以被化学和遗传废除，导致过早退出有丝分裂，随后强制G1期阻滞，并提高染色体损伤水平。我们最终证明，在HSPC中检查点废除后，造血功能受损，表现为分化潜力和移植能力的丧失，表明该检查点在HSPC和造血中的关键作用。HSPCs具有一个纺锤体检查点，在抗有丝分裂应激时被激活SAC废除导致过早的有丝分裂退出，染色体畸变和G1停滞检查点活性是祖细胞而不是干细胞功能所需的。在这份报告中，Andreas Brown和同事证明，循环造血干细胞和祖细胞激活纺锤体组装检查点作为对抗有丝分裂应激的反应。作者进一步揭示，抑制检查点会导致祖细胞功能受损，而对造血干细胞似乎不那么重要。
The spindle assembly checkpoint plays a pivotal role in preventing aneuploidy and transformation. Many studies demonstrate impairment of this checkpoint in cancer cells. While leukemia is frequently driven by transformed hematopoietic stem and progenitor cells (HSPCs), the biology of the spindle assembly checkpoint in such primary cells is not very well understood. Here, we reveal that the checkpoint is fully functional in murine progenitor cells and, to a lesser extent, in hematopoietic stem cells. We show that HSPCs arrest at prometaphase and induce p53-dependent apoptosis upon prolonged treatment with anti-mitotic drugs. Moreover, the checkpoint can be chemically and genetically abrogated, leading to premature exit from mitosis, subsequent enforced G1 arrest, and enhanced levels of chromosomal damage. We finally demonstrate that, upon checkpoint abrogation in HSPCs, hematopoiesis is impaired, manifested by loss of differentiation potential and engraftment ability, indicating a critical role of this checkpoint in HSPCs and hematopoiesis. HSPCs harbor a spindle checkpoint that is activated upon anti-mitotic stress SAC abrogation causes premature mitotic exit, chromosomal aberrations, and G1 arrest Checkpoint activity is required for functionality of progenitors but not stem cells In this report, Andreas Brown and colleagues demonstrate that cycling hematopoietic stem and progenitor cells activate the spindle assembly checkpoint as a response to anti-mitotic stress. The authors further reveal that inhibition of the checkpoint causes impairment of progenitor function, whereas it appears to be less crucial for hematopoietic stem cells.
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影响因子：
64.8
作者：
Wong, Terrence N.;Ramsingh, Giridharan;Young, Andrew L.;Miller, Christopher A.;Touma, Waseem;Welch, John S.;Lamprecht, Tamara L.;Shen, Dong;Hundal, Jasreet;Fulton, Robert S.;Heath, Sharon;Baty, Jack D.;Klco, Jeffery M.;Ding, Li;Mardis, Elaine R.;Westervelt, Peter;DiPersio, John F.;Walter, Matthew J.;Graubert, Timothy A.;Ley, Timothy J.;Druley, Todd E.;Link, Daniel C.;Wilson, Richard K.
通讯作者：
Wilson, Richard K.
影响因子：
64.8
作者：
Busch, Katrin;Klapproth, Kay;Rodewald, Hans-Reimer
通讯作者：
Rodewald, Hans-Reimer
影响因子：
20.3
作者：
Holyoake, T;Jiang, XY;Eaves, A
通讯作者：
Eaves, A
DOI：
10.1084/jem.20111490
发表时间：
2011-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dykstra B;Olthof S;Schreuder J;Ritsema M;de Haan G
通讯作者：
de Haan G
影响因子：
8.8
作者：
Moehrle BM;Nattamai K;Brown A;Florian MC;Ryan M;Vogel M;Bliederhaeuser C;Soller K;Prows DR;Abdollahi A;Schleimer D;Walter D;Milsom MD;Stambrook P;Porteus M;Geiger H
通讯作者：
Geiger H