@article{f32df5a1e4014ad584aa9f4ddca6de48,
title = "The Spindle Assembly Checkpoint Is Required for Hematopoietic Progenitor Cell Engraftment",
abstract = "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. 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.",
keywords = "SAC, genome stability, hematopoiesis, hematopoietic progenitor cells, hematopoietic stem cells, micronuclei, mitotic checkpoint, reversine, spindle assembly checkpoint",
author = "Andreas Brown and Johannes Pospiech and Karina Eiwen and Baker, {Darren J.} and Bettina Moehrle and Vadim Sakk and Kalpana Nattamai and Mona Vogel and Ani Grigoryan and Hartmut Geiger",
note = "Funding Information: We thank the FACS core at Ulm University for cell sorting and the Central Animal Facility of Ulm University as well as the Comprehensive Mouse and Cancer Core at CCHMC for help with mouse experiments. We are grateful to Stephan Stilgenbauer and Hans J{\"o}rg Fehling for providing p53 KO mice and Steven Taylor for anti-BUBR1/BUB1 antibodies. We thank the core facility confocal microscopy for providing assistance with imaging. Furthermore, we thank Nicola Martin, Gina Marka, and Karin Soller for technical assistance and all members of the group for discussions. Work in the laboratory of H.G. was supported by the Deutsche Forschungsgemeinschaft SFB 1074 and SFB 1149 , the Excellence-Initiative of the Baden-W{\"u}rttemberg Foundation , the Edward P. Evans Foundation , and the National Institute of Health , AG040118 , DK104814 , and AG05065 . A.B. was supported by a Bausteinprogramm of the Medical Faculty of Ulm University . Funding Information: We thank the FACS core at Ulm University for cell sorting and the Central Animal Facility of Ulm University as well as the Comprehensive Mouse and Cancer Core at CCHMC for help with mouse experiments. We are grateful to Stephan Stilgenbauer and Hans J?rg Fehling for providing p53 KO mice and Steven Taylor for anti-BUBR1/BUB1 antibodies. We thank the core facility confocal microscopy for providing assistance with imaging. Furthermore, we thank Nicola Martin, Gina Marka, and Karin Soller for technical assistance and all members of the group for discussions. Work in the laboratory of H.G. was supported by the Deutsche Forschungsgemeinschaft SFB 1074 and SFB 1149, the Excellence-Initiative of the Baden-W?rttemberg Foundation, the Edward P. Evans Foundation, and the National Institute of Health, AG040118, DK104814, and AG05065. A.B. was supported by a Bausteinprogramm of the Medical Faculty of Ulm University. Publisher Copyright: {\textcopyright} 2017 The Authors",
year = "2017",
month = nov,
day = "14",
doi = "10.1016/j.stemcr.2017.09.017",
language = "English (US)",
volume = "9",
pages = "1359--1368",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "5",
}