title: Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner.
abstract: 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).
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR;
authors.forename: Lijian
authors.initials: L
authors.lastname: Shao
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR;
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR; Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences (PUMC & CAMS), Tianjin, China;
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR;
authors.forename: David
authors.initials: D
authors.lastname: Gardner
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR;
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Pathology, Medical University of South Carolina, Charleston, SC; and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Medical University of South Carolina, Charleston, SC; and.
authors.forename: Lingbo
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences (PUMC & CAMS), Tianjin, China;
authors.forename: Aimin
authors.initials: A
authors.lastname: Meng
authors.affiliation: Department of Medicine and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR;
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects*; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D016615:Telomere / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D014916:Whole-Body Irradiation
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16