期刊
CELL STEM CELL
卷 11, 期 1, 页码 36-49出版社
CELL PRESS
DOI: 10.1016/j.stem.2012.05.013
关键词
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资金
- AFMF (Association Francaise de la Maladie de Fanconi)
- FARF (Fanconi Anemia Research Fund)
- Agence Nationale de la Recherche (ANR) Genopath
- National Institutes of Health (NIH) [P01HL048546, RC4DK090913, R01DK43889]
- NIH/NHLB [P01HL048546-16]
- Association pour la Recherche contre le Cancer (ARC)
- Association Laurette Fugain
Fanconi anemia (FA) is an inherited DNA repair deficiency syndrome. FA patients undergo progressive bone marrow failure (BMF) during childhood, which frequently requires allogeneic hematopoietic stem cell transplantation. The pathogenesis of this BMF has been elusive to date. Here we found that FA patients exhibit a profound defect in hematopoietic stem and progenitor cells (HSPCs) that is present before the onset of clinical BMF. In response to replicative stress and unresolved DNA damage, p53 is hyperactivated in FA cells and triggers a late p21(Cdkn1a)-dependent G0/G1 cell-cycle arrest. Knockdown of p53 rescued the HSPC defects observed in several in vitro and in vivo models, including human FA or FA-like cells. Taken together, our results identify an exacerbated p53/p21 physiological response to cellular stress and DNA damage accumulation as a central mechanism for progressive HSPC elimination in FA patients, and have implications for clinical care.
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