Bone Marrow Failure in Fanconi Anemia Is Triggered by an Exacerbated p53/p21 DNA Damage Response that Impairs Hematopoietic Stem and Progenitor Cells

被引：260

作者：

Ceccaldi, Raphael ^{[1
,2
,3
,4
]}

Parmar, Kalindi ^{[10
]}

Mouly, Enguerran ^{[1
]}

Delord, Marc ^{[1
]}

Kim, Jung Min ^{[10
]}

Regairaz, Marie ^{[1
,2
,3
]}

Pla, Marika ^{[1
,5
]}

Vasquez, Nadia ^{[4
]}

Zhang, Qing-Shuo ^{[11
]}

Pondarre, Corinne ^{[12
]}

de Latour, Regis Peffault ^{[6
]}

Gluckman, Eliane ^{[6
]}

Cavazzana-Calvo, Marina ^{[13
]}

Leblanc, Thierry ^{[14
]}

Larghero, Jerome ^{[1
,5
,8
,9
]}

Grompe, Markus ^{[11
]}

Socie, Gerard ^{[1
,6
,7
]}

D'Andrea, Alan D. ^{[10
]}

Soulier, Jean ^{[1
,2
,3
,4
]}

机构：

[1] Univ Paris Diderot, Sorbonne Paris Cite, Inst Hematol IUH, Paris 75010, France

[2] St Louis Hosp, INSERM, U944, F-75010 Paris, France

[3] St Louis Hosp, CNRS, UMR7212, F-75010 Paris, France

[4] St Louis Hosp, APHP, Hematol Lab, F-75010 Paris, France

[5] St Louis Hosp, INSERM, UMRS 940, F-75010 Paris, France

[6] St Louis Hosp, APHP, Hematol Transplantat Dept, F-75010 Paris, France

[7] St Louis Hosp, INSERM, U728, F-75010 Paris, France

[8] St Louis Hosp, APHP, Cell Therapy Unit, F-75010 Paris, France

[9] St Louis Hosp, APHP, CIC BT501, F-75010 Paris, France

[10] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA

[11] Oregon Hlth & Sci Univ, Oregon Stem Cell Ctr, Portland, OR 97239 USA

[12] Hosp Civils Lyon, Inst Pediat Hematol & Oncol, F-69008 Lyon, France

[13] Hop Necker Enfants Malad, INSERM, U768, F-75015 Paris, France

[14] Robert Debre Hosp, Dept Pediat Hematol, F-75019 Paris, France

来源：

CELL STEM CELL | 2012年 / 11卷 / 01期

基金：

美国国家卫生研究院;

关键词：

TNF-ALPHA; P53; CANCER; REPAIR; PATHWAY; SENESCENCE; FANCD2; DEFICIENCY; CHECKPOINT; COOPERATE;

D O I：

10.1016/j.stem.2012.05.013

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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.

引用

页码：36 / 49

页数：14

共 68 条

[11] CHK1 inhibition as a strategy for targeting fanconi anemia (FA) DNA repair pathway deficient tumors [J].

Chen, Clark C. ;

Kennedy, Richard D. ;

Sidi, Samuel ;

Look, A. Thomas ;

D'Andrea, Alan .

MOLECULAR CANCER, 2009, 8

[12] Hematopoietic stem cell quiescence maintained by p21cip1/waf1 [J].

Cheng, T ;

Rodrigues, N ;

Shen, HM ;

Yang, YG ;

Dombkowski, D ;

Sykes, M ;

Scadden, DT .

SCIENCE, 2000, 287 (5459) :1804-1808

[13] p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis [J].

Chin, L ;

Artandi, SE ;

Shen, Q ;

Tam, A ;

Lee, SL ;

Gottlieb, GJ ;

Greider, CW ;

DePinho, RA .

CELL, 1999, 97 (04) :527-538

[14] The genetic and molecular basis of Fanconi anemia [J].

de Winter, Johan P. ;

Joenje, Hans .

MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, 2009, 668 (1-2) :11-19

[15] DNA interstrand crosslink repair and cancer [J].

Deans, Andrew J. ;

West, Stephen C. .

NATURE REVIEWS CANCER, 2011, 11 (07) :467-480

[16] Reversal of senescence in mouse fibroblasts through lentiviral in suppression of p53 [J].

Dirac, AMG ;

Bernards, R .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (14) :11731-11734

[17] Inherited aplastic anaemias/bone marrow failure syndromes [J].

Dokal, Inderjeet ;

Vulliamy, Tom .

BLOOD REVIEWS, 2008, 22 (03) :141-153

[18] Fanconi anaemia: new strategies [J].

Dufour, C. ;

Svahn, J. .

BONE MARROW TRANSPLANTATION, 2008, 41 (Suppl 2) :S90-S95

[19] TNF-α and IFN-γ are overexpressed in the bone marrow of Fanconi anemia patients and TNF-α suppresses erythropoiesis in vitro [J].

Dufour, C ;

Corcione, A ;

Svahn, J ;

Haupt, R ;

Poggi, V ;

Béka'ssy, AN ;

Scimè, R ;

Pistorio, A ;

Pistoia, V .

BLOOD, 2003, 102 (06) :2053-2059

[20] Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis [J].

Freie, B ;

Li, XX ;

Ciccone, SLM ;

Nawa, K ;

Cooper, S ;

Vogelweid, C ;

Schantz, L ;

Haneline, LS ;

Orazi, A ;

Broxmeyer, HE ;

Lee, SH ;

Clapp, DW .

BLOOD, 2003, 102 (12) :4146-4152

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