Bone marrow failure in fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells

Raphael Ceccaldi, Kalindi Parmar, Enguerran Mouly, Marc Delord, Jung Min Kim, Marie Regairaz, Marika Pla, Nadia Vasquez, Qing Shuo Zhang, Corinne Pondarre, Régis Peffault De Latour, Eliane Gluckman, Marina Cavazzana-Calvo, Thierry Leblanc, Jérôme Larghero, Markus Grompe, Gérard Socié, Alan D. D'Andrea, Jean Soulier

Research output: Contribution to journalArticle

172 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)36-49
Number of pages14
JournalCell Stem Cell
Volume11
Issue number1
DOIs
StatePublished - Jul 6 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Ceccaldi, R., Parmar, K., Mouly, E., Delord, M., Kim, J. M., Regairaz, M., Pla, M., Vasquez, N., Zhang, Q. S., Pondarre, C., Peffault De Latour, R., Gluckman, E., Cavazzana-Calvo, M., Leblanc, T., Larghero, J., Grompe, M., Socié, G., D'Andrea, A. D., & Soulier, J. (2012). Bone marrow failure in fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. Cell Stem Cell, 11(1), 36-49. https://doi.org/10.1016/j.stem.2012.05.013