Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress.

Liu Y, Aiello A, Zinkel SS
Cell Death Differ. 2012 19 (10): 1602-12

PMID: 22522598 · PMCID: PMC3438491 · DOI:10.1038/cdd.2012.38

Hematopoietic stem cells (HSCs) possess long-term self-renewal capacity and multipotent differentiative capacity, to maintain the hematopoietic system. Long-term hematopoietic homeostasis requires effective control of genotoxic damage to maintain HSC function and prevent propagation of deleterious mutations. Here we investigate the role of the BH3-only Bcl-2 family member Bid in the response of murine hematopoietic cells to long-term replicative stress induced by hydroxyurea (HU). The PI3-like serine/threonine kinase, ATR, initiates the DNA damage response (DDR) to replicative stress. The pro-apoptotic Bcl-2 family member, Bid, facilitates this response to replicative stress in hematopoietic cells, but the in vivo role of this DDR function of Bid has not been defined. Surprisingly, we demonstrate that long-term HU treatment expands wild-type myeloid progenitor cells (MPCs) and HSC-enriched Lin(-)Sca1(+)Kit(+) (LSK) cells to maintain bone marrow function as measured by long-term competitive repopulating ability. Bid-/- MPCs demonstrate increased sensitivity to HU and are depleted. Bid-/- LSK cells demonstrate increased mobilization manifest by increased Bromodeoxyuridine (BrdU) incorporation. Bid-/- MPCs and LSK cells are relatively depleted, however, and bone marrow from Bid-/- mice demonstrates decreased long-term competitive repopulating ability in both primary and secondary transplants. We thus describe a survival function of Bid in hematopoiesis in the setting of chronic replicative stress.

MeSH Terms (21)

Animals Antigens, Ly Antineoplastic Agents Apoptosis Ataxia Telangiectasia Mutated Proteins BH3 Interacting Domain Death Agonist Protein Cell Cycle Proteins DNA Repair Hematopoietic Stem Cells Hematopoietic Stem Cell Transplantation Hydroxyurea Membrane Proteins Methylcellulose Mice Mice, Inbred C57BL Mice, Knockout Myeloid Progenitor Cells Nucleotidyltransferases Oxidative Stress Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-kit

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