Spontaneous abrogation of the G2 DNA damage checkpoint has clinical benefits but promotes leukemogenesis in Fanconi anemia patients
Raphael Ceccaldi, … , Gérard Socié, Jean Soulier
Raphael Ceccaldi, … , Gérard Socié, Jean Soulier
Published December 22, 2010
Citation Information: J Clin Invest. 2011;121(1):184-194. https://doi.org/10.1172/JCI43836.
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Research Article

Spontaneous abrogation of the G2 DNA 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

Raphael Ceccaldi, Delphine Briot, Jérôme Larghero, Nadia Vasquez, Catherine Dubois d’Enghien, Delphine Chamousset, Maria-Elena Noguera, Quinten Waisfisz, Olivier Hermine, Corinne Pondarre, Thierry Leblanc, Eliane Gluckman, Hans Joenje, Dominique Stoppa-Lyonnet, Gérard Socié, Jean Soulier

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Figure 2

Clonality of attenuated FA cells.

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Clonality of attenuated FA cells. (A) Array-CGH showed clonal chromosoma...
(A) Array-CGH showed clonal chromosomal abnormalities in PHA-stimulated PBLs from an attenuated patient. MGG stains confirmed the activated lymphoblast morphology (original magnification, ×400). Arrows indicate copy number abnormalities. (B) X-linked–based analysis of clonality; female FA patients who were heterozygous for 1 or more of the 3 SNPs in the X chromosome were identified by direct sequencing of genomic DNA. Then, allelic X-linked inactivation was evaluated in a semiquantitative manner by sequencing PBL cDNA from these patients. The left panel shows balanced expression of the heterozygous MMP1 SNP in a healthy control and a classical FA patient, whereas skewed expression was detected in the attenuated and revertant patients (asterisks). The right panel summarizes the X-linked clonality data in heterozygous PBLs from healthy female controls (n = 11), attenuated patients (n = 5), revertants (n = 1), and classical FA subjects (n = 6). The percentage of skewing expression is quantified for each case, and median values are indicated by horizontal bars. The threshold for skewed unbalanced expression was arbitrarily fixed (dashed horizontal line). Each symbol represents a patient.