Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Article has an altmetric score of 1

Spontaneous abrogation of the G2 DNA damage checkpoint has clinical benefits but promotes leukemogenesis in Fanconi anemia patients

  • Text
  • PDF
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

×

Figure 6

Low expression of CHK1, but not CHK2, in the leukemic cells from MDS/AML FA patients (n = 4).

Options: View larger image (or click on image) Download as PowerPoint
Low expression of CHK1, but not CHK2, in the leukemic cells from MDS/AML...
Leukemic cells were purified by CD34+ selection; the clonality and high purity of the blast cell fraction was demonstrated in all of the 4 MDS/AML FA patients by array-CGH profiling, which detected chromosomal alterations (data not shown). Data from classical FA patient PHA-stimulated PBLs are indicated as reference (several samples were reanalyzed with consistent results). Leukemic cells from a series of non-FA patients (n = 15) with AML were analyzed as malignant reference. RQ-PCR copy number values are expressed using the ΔCT method relative to a housekeeping gene (reverse log2 scale). Mean values are indicated by horizontal bars. Statistical analyses were performed using the non-parametric test Wilcoxon test (**P < 0.001). As expected from published data in MDS and AML in non-FA patients (32), very low levels of CHK1 transcripts were also found in the non-FA AML cells. Each symbol represents a patient.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Highlighted by 1 platforms
78 readers on Mendeley
See more details