@article{f37c42550b074ed8b7e5cd81aa57486c,
title = "Bone marrow failure in fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells",
abstract = "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.",
author = "Raphael Ceccaldi and Kalindi Parmar and Enguerran Mouly and Marc Delord and Kim, {Jung Min} and Marie Regairaz and Marika Pla and Nadia Vasquez and Zhang, {Qing Shuo} and Corinne Pondarre and {Peffault De Latour}, R{\'e}gis and Eliane Gluckman and Marina Cavazzana-Calvo and Thierry Leblanc and J{\'e}r{\^o}me Larghero and Markus Grompe and G{\'e}rard Soci{\'e} and D'Andrea, {Alan D.} and Jean Soulier",
note = "Funding Information: We are grateful to William Vainchenker, Jean-Claude Gluckman, and Hugues de Th{\'e} for helpful discussion. We thank Lucie Hernandez (Genomic facility, IUH), Niclas Setterblad (Plateau technique, IUH), Abigail Hamilton (DFCI), and Aur{\'e}lie Coquin (APHP, Saint-Louis Hospital) for their technical assistance; Eric Benedetti (OHSU) for maintaining the Fancd2/p53 mouse colony; Daniela Geromin at the Cellulotheque of Saint-Louis Hospital; and Patrizia Vinciguerra (DFCI) for her initial observations on the role of p53 in the cytokinesis failure of HSCs. We thank the patients and their families, and the AFMF (Association Fran{\c c}aise de la Maladie de Fanconi) and FARF (Fanconi Anemia Research Fund) for their support to J.S. and A.D.D., respectively, and the physicians and nurses from French pediatric, genetic, and/or hematological centers who have taken care of the patients. We also thank Joelle Roume, Laurence Loeuillet, Christine Francannet, and Anne-Marie Beaufrere, who referred FA fetus samples to our laboratory. Our center is supported by the French Government (Direction de l'Hospitalisation et de l'Organisation des Soins) as Centre de R{\'e}f{\'e}rence Maladies Rares “Aplasies M{\'e}dullaires Constitutionnelles” (coordination: G. Soci{\'e}), and by the “R{\'e}seau INCa des Maladies Cassantes de l'AND” (coordination: D. Stoppa-Lyonnet and A. Sarasin). This work was supported by a grant from the Agence Nationale de la Recherche (ANR) “Genopath” to J.S., and by grants of the National Institutes of Health (NIH) (P01HL048546, RC4DK090913, and R01DK43889 to A.D.D.) and NIH/NHLB (P01HL048546-16 to M.G.). R.C. was supported by a fellowship of the Association pour la Recherche contre le Cancer (ARC) and by the Association Laurette Fugain. ",
year = "2012",
month = jul,
day = "6",
doi = "10.1016/j.stem.2012.05.013",
language = "English (US)",
volume = "11",
pages = "36--49",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "1",
}