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

165 Citations (Scopus)

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

Fingerprint

Fanconi Anemia
Hematopoietic Stem Cells
DNA Damage
Bone Marrow
DNA Repair-Deficiency Disorders
G1 Phase Cell Cycle Checkpoints
Hematopoietic Stem Cell Transplantation

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Cite this

Bone marrow failure in fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. / Ceccaldi, Raphael; Parmar, Kalindi; Mouly, Enguerran; Delord, Marc; Kim, Jung Min; Regairaz, Marie; Pla, Marika; Vasquez, Nadia; Zhang, Qing-Shuo; Pondarre, Corinne; Peffault De Latour, Régis; Gluckman, Eliane; Cavazzana-Calvo, Marina; Leblanc, Thierry; Larghero, Jérôme; Grompe, Markus; Socié, Gérard; D'Andrea, Alan D.; Soulier, Jean.

In: Cell Stem Cell, Vol. 11, No. 1, 06.07.2012, p. 36-49.

Research output: Contribution to journalArticle

Ceccaldi, R, Parmar, K, Mouly, E, Delord, M, Kim, JM, 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, AD & 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, vol. 11, no. 1, pp. 36-49. https://doi.org/10.1016/j.stem.2012.05.013
Ceccaldi, Raphael ; Parmar, Kalindi ; Mouly, Enguerran ; Delord, Marc ; Kim, Jung Min ; Regairaz, Marie ; Pla, Marika ; Vasquez, Nadia ; Zhang, Qing-Shuo ; Pondarre, Corinne ; Peffault De Latour, Régis ; Gluckman, Eliane ; Cavazzana-Calvo, Marina ; Leblanc, Thierry ; Larghero, Jérôme ; Grompe, Markus ; Socié, Gérard ; D'Andrea, Alan D. ; Soulier, Jean. / Bone marrow failure in fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. In: Cell Stem Cell. 2012 ; Vol. 11, No. 1. pp. 36-49.
@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 Qing-Shuo Zhang 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",
year = "2012",
month = "7",
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",

}

TY - JOUR

T1 - Bone marrow failure in fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells

AU - Ceccaldi, Raphael

AU - Parmar, Kalindi

AU - Mouly, Enguerran

AU - Delord, Marc

AU - Kim, Jung Min

AU - Regairaz, Marie

AU - Pla, Marika

AU - Vasquez, Nadia

AU - Zhang, Qing-Shuo

AU - Pondarre, Corinne

AU - Peffault De Latour, Régis

AU - Gluckman, Eliane

AU - Cavazzana-Calvo, Marina

AU - Leblanc, Thierry

AU - Larghero, Jérôme

AU - Grompe, Markus

AU - Socié, Gérard

AU - D'Andrea, Alan D.

AU - Soulier, Jean

PY - 2012/7/6

Y1 - 2012/7/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84863625900&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863625900&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2012.05.013

DO - 10.1016/j.stem.2012.05.013

M3 - Article

C2 - 22683204

AN - SCOPUS:84863625900

VL - 11

SP - 36

EP - 49

JO - Cell Stem Cell

JF - Cell Stem Cell

SN - 1934-5909

IS - 1

ER -