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Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner.

Authors: Lijian L. Shao, Wei W. Feng, Hongliang H. Li, David D. Gardner, Yi Y. Luo, Yong Y. Wang, Lingbo L. Liu, Aimin A. Meng, Norman E NE. Sharpless, Daohong D. Zhou
Published: 03/12/2014, Blood


Exposure to total body irradiation (TBI) induces not only acute hematopoietic radiation syndrome but also long-term or residual bone marrow (BM) injury. This residual BM injury is mainly attributed to permanent damage to hematopoietic stem cells (HSCs), including impaired self-renewal, decreased long-term repopulating capacity, and myeloid skewing. These HSC defects were associated with significant increases in production of reactive oxygen species (ROS), expression of p16(Ink4a) (p16) and Arf mRNA, and senescence-associated β-galacotosidase (SA-β-gal) activity, but not with telomere shortening or increased apoptosis, suggesting that TBI induces residual BM injury via induction of HSC premature senescence. This suggestion is supported by the finding that SA-β-gal(+) HSC-enriched LSK cells showed more pronounced defects in clonogenic activity in vitro and long-term engraftment after transplantation than SA-β-gal(-) LSK cells isolated from irradiated mice. However, genetic deletion of p16 and/or Arf had no effect on TBI-induced residual BM suppression and HSC senescence, because HSCs from irradiated p16 and/or Arf knockout (KO) mice exhibited changes similar to those seen in HSCs from wild-type mice after exposure to TBI. These findings provide important new insights into the mechanism by which TBI causes long-term BM suppression (eg, via induction of premature senescence of HSCs in a p16-Arf-independent manner).

© 2014 by The American Society of Hematology.
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