Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells.
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.
Institute of Hematology (IUH), Université Paris-Diderot, Sorbonne Paris Cité 75010, France.
Raphael
R
Ceccaldi
Kalindi
K
Parmar
Enguerran
E
Mouly
Marc
M
Delord
Jung Min
JM
Kim
Marie
M
Regairaz
Marika
M
Pla
Nadia
N
Vasquez
Qing-Shuo
QS
Zhang
Corinne
C
Pondarre
Régis
R
Peffault de Latour
Eliane
E
Gluckman
Marina
M
Cavazzana-Calvo
Thierry
T
Leblanc
Jérôme
J
Larghero
Markus
M
Grompe
Gérard
G
Socié
Alan D
AD
D'Andrea
Jean
J
Soulier
D000293:Adolescent; D000328:Adult; D053687:Adult Stem Cells / Q000378:metabolism / Q000473:pathology; D000375:Aging / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology; D005199:Fanconi Anemia / Q000378:metabolism* / Q000473:pathology*; D052218:Fanconi Anemia Complementation Group C Protein / Q000172:deficiency / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints; D059565:G2 Phase Cell Cycle Checkpoints; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007223:Infant; D051379:Mice; D008875:Middle Aged; D016196:S Phase; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D016159:Tumor Suppressor Protein p53