title: Bcl2 overexpression rescues the hematopoietic stem cell defects in Ku70-deficient mice by restoration of quiescence.
abstract: DNA repair is essential for hematopoietic stem cell (HSC) maintenance. Ku70 is a key component of the nonhomologous end-joining pathway, which is the major pathway for DNA double-strand break repair. We find that HSCs from Ku70-deficient mice are severely defective in self-renewal, competitive repopulation, and bone marrow (BM) hematopoietic niche occupancy and that loss of quiescence results in a dramatic defect in the maintenance of Ku70-deficient HSCs. Interestingly, although overexpression of Bcl2 does not rescue the severe combined immunodeficiency phenotype in Ku70-deficient mice, overexpression of Bcl2 in Ku70-deficient HSCs almost completely rescued the impaired HSC quiescence, repopulation, and BM hematopoietic niche occupancy capacities. Together, our data indicate that the HSC maintenance defect of Ku70-deficient mice is due to the loss of HSC quiescent populations, whereas overexpression of Bcl2 rescues the HSC defect in Ku70-deficient mice by restoration of quiescence. Our study uncovers a novel role of Bcl2 in HSC quiescence regulation.
authors.affiliation: Case Comprehensive Cancer Center, National Center for Regenerative Medicine, Seidman Cancer Center, University Hospitals Case Medical Center and Case Western Reserve University, Cleveland, OH.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Qing
authors.forename: Zhengqi
authors.initials: Z
authors.lastname: Wang
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Bunting
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019254:Genes, bcl-2 / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D016130:Immunophenotyping; D000072200:Ku Autoantigen; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055153:Stem Cell Niche / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen