title: Spontaneous abrogation of the G₂DNA damage checkpoint has clinical benefits but promotes leukemogenesis in Fanconi anemia patients.
abstract: DNA damage checkpoints in the cell cycle may be important barriers against cancer progression in human cells. Fanconi anemia (FA) is an inherited DNA instability disorder that is associated with bone marrow failure and a strong predisposition to cancer. Although FA cells experience constitutive chromosomal breaks, cell cycle arrest at the G2 DNA damage checkpoint, and an excess of cell death, some patients do become clinically stable, and the mechanisms underlying this, other than spontaneous reversion of the disease-causing mutation, are not well understood. Here we have defined a clonal phenotype, termed attenuation, in which FA patients acquire an abrogation of the G2 checkpoint arrest. Attenuated cells expressed lower levels of CHK1 (also known as CHEK1) and p53. The attenuation could be recapitulated by modulating the ATR/CHK1 pathway, and CHK1 inhibition protected FA cells from cell death. FA patients who expressed the attenuated phenotype had mild bone marrow deficiency and reached adulthood, but several of them eventually developed myelodysplasia or leukemia. Better understanding of attenuation might help predict a patient's clinical course and guide choice of treatment. Our results also highlight the importance of evaluating the cellular DNA damage checkpoint and repair pathways in cancer therapies in general.
authors.affiliation: INSERM U944, Assistance Publique-Hôpitaux de Paris, Saint-Louis Hospital, Paris, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Ceccaldi
authors.forename: Delphine
authors.initials: D
authors.lastname: Briot
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.forename: Nadia
authors.initials: N
authors.lastname: Vasquez
authors.forename: Catherine
authors.initials: C
authors.lastname: Dubois d'Enghien
authors.forename: Delphine
authors.initials: D
authors.lastname: Chamousset
authors.forename: Maria-Elena
authors.initials: ME
authors.lastname: Noguera
authors.forename: Quinten
authors.initials: Q
authors.lastname: Waisfisz
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Corinne
authors.initials: C
authors.lastname: Pondarre
authors.forename: Thierry
authors.initials: T
authors.lastname: Leblanc
authors.forename: Eliane
authors.initials: E
authors.lastname: Gluckman
authors.forename: Hans
authors.initials: H
authors.lastname: Joenje
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.forename: Gérard
authors.initials: G
authors.lastname: Socié
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D002648:Child; D002675:Child, Preschool; D004249:DNA Damage; D005199:Fanconi Anemia / Q000150:complications* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D016195:G2 Phase / Q000235:genetics*; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000235:genetics; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D055815:Young Adult
chemical_list: D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1