ArticleThe Journal of clinical investigation2011
Spontaneous abrogation of the G₂DNA damage checkpoint has clinical benefits but promotes leukemogenesis in Fanconi anemia patients.
Article in The Journal of clinical investigation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 64 citations in OpenAlex.
- Insights and modulation of RNA polymerase-dependent R-loop and dsRNA in Fanconi anemia hematopoietic stem cells.JCI insight · 2026Article
- PUMA-induced apoptosis drives bone marrow failure and genomic instability in telomerase-deficient mice.Cell death and differentiation · 2026Article
- Comprehensive laboratory diagnosis of Fanconi anaemia: comparison of cellular and molecular analysis.Journal of medical genetics · 2023Article
- RUNX1 mutations mitigate quiescence to promote transformation of hematopoietic progenitors in Fanconi anemia.Leukemia · 2023Article
- Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia.The Journal of clinical investigation · 2022Article
- LNK (SH2B3) inhibition expands healthy and Fanconi anemia human hematopoietic stem and progenitor cells.Blood advances · 2022Article
- Cell senescence and malignant transformation in the inherited bone marrow failure syndromes: Overlapping pathophysiology with therapeutic implications.Seminars in hematology · 2022Review
- FANCD2 limits acetaldehyde-induced genomic instability during DNA replication in esophageal keratinocytes.Molecular oncology · 2021Article
- Beyond the Double-Strand Breaks: The Role of DNA Repair Proteins in Cancer Stem-Cell Regulation.Cancers · 2021Review
- SLFN11 promotes stalled fork degradation that underlies the phenotype in Fanconi anemia cells.Blood · 2021Article
- Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia.Frontiers in oncology · 2021Article
- Gene Editing of Hematopoietic Stem Cells: Hopes and Hurdles Toward Clinical Translation.Frontiers in genome editing · 2021Review
- Review
- Somatic genetic rescue in Mendelian haematopoietic diseases.Nature reviews. Genetics · 2019Review
- Lnk/Sh2b3 deficiency restores hematopoietic stem cell function and genome integrity in Fancd2 deficient Fanconi anemia.Nature communications · 2018Article
- A small molecule p53 activator attenuates Fanconi anemia leukemic stem cell proliferation.Stem cell research & therapy · 2018Article
- Article
- Fanconi anaemia and cancer: an intricate relationship.Nature reviews. Cancer · 2018Review
- Cell-Cycle-Specific Function of p53 in Fanconi Anemia Hematopoietic Stem and Progenitor Cell Proliferation.Stem cell reports · 2018Article
- Article
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Authors and funding
16 authors at 9 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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