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 7

Genomic instability, DNA damage response, and stepwise oncogenesis — a model of stepwise progression to MDS/AML in patients with or without constitutive genetic instability.

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Genomic instability, DNA damage response, and stepwise oncogenesis — a m...
In FA patients, the first step is constitutive and leads to excess cell death related to the G2 checkpoint response; the attenuation phenomenon described here rescues cell survival and allows for the accumulation of additional oncogenic events that are favored by the genetic instability. In patients that are not genetically predisposed (non-FA patients), activation of oncogenes is associated with acquired genetic instability and induction of anticancer DNA damage response (6–8); further inactivation of this response, often by TP53 inactivation, allows cancer progression to late stages (6–8, 32, 44, 47). Notably, no TP53 mutation or deletion was observed in the 5 MDS/AML leukemia cases that developed in attenuated FA patients in our series (data not shown).