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1345 Ionizing Radiation Induces Hematopoietic Stem Cell Senescence and Long-Term Bone Marrow Suppression in a p16Ink4a/Arf-Independent manner  

Program: Oral and Poster Abstracts
Session: 508. Bone Marrow Failure: Poster I
Saturday, December 10, 2011, 5:30 PM-7:30 PM
Hall GH (San Diego Convention Center)

Lijian Shao, MD, PhD1, Wei Feng, MD1*, Hongliang Li, MD, PhD1*, Yong Wang, MD, PhD2, Norman Sharpless, MD, PhD3 and Daohong Zhou, MD1

1Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR
2Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC
3Medicine and Genetics, Lineberger Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC

Many patients receiving chemotherapy and/or ionizing radiation (IR) develop residual (or long-term) bone marrow (BM) injury that can not only limit the success of cancer treatment but also adversely affect their quality of life. Although residual BM injury has been largely attributed to the induction of hematopoietic stem cell (HSC) senescence, neither the molecular mechanisms by which chemotherapy and/or IR induce HSC senescence have been clearly defined, nor has an effective treatment been developed to ameliorate the injury. The Ink4a-Arf locus encodes two important tumor suppressors, p16Ink4a (p16) and Arf. Both of them have been implicated in mediating the induction of cellular senscence in a variety of cells including HSCs. Therefore, we examined the role of p16 and/or Arf in IR-induced HSC senescence and long-term BM suppression using a total body irradiation (TBI) mouse model. The results from our studies show that exposure of wild-type (WT) mice to a sublethal dose (6 Gy) of TBI induces HSC senescence and long-term BM suppression. The induction of HSC senescence is not associated with a reduction in telemore length in HSCs and their progeny, but is associated with significant increases in the production of reactive oxygen species (ROS), the expression of p16 and Arf mRNA, and the activity of senescence-associated β-galacotosidase (SA-β-gal) in HSCs. However, genetical deletion of Ink4a and/or Arf has no effect on TBI-induced HSC senescence, as HSCs from the Ink4a and/or Arf knockout mice after exposure to TBI exhibit similar changes as those seen in the cells from irradiated WT mice in comparison with the cells from un-irradiated mice with correspondent genotypes. In addition, TBI-induced long-term BM suppression is also not attenuated by the deletion of the Ink4a and/or Arf genes. These findings suggest that IR induces HSC senescence and long-term BM suppression in a p16Ink4a/Arf-independent manner. 

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH