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Mutant IDH is sufficient to initiate enchondromatosis in mice
Open accessAbstract
Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to d-2-hydroxyglutarate (d-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.
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“Furthermore, a knock-in of a mutant IDH1 allele into normal hematopoietic cells and into chondrocytes in vivo triggers an aberrant expansion of targeted cell lineages (Hirata et al., 2015; Sasaki et al., 2012).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Hirata et al., 2015
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Metadata
- Authors
- Hirata, M., Sasaki, M., Cairns, R. A., Inoue, S., Puviindran, V., Li, W. Y., Snow, B. E., Jones, L. D., Wei, Q., Sato, S., Tang, Y. J., Nadesan, P., Rockel, J., Whetstone, H., Poon, R., Weng, A., Gross, S., Straley, K., Gliser, C., Xu, Y., Wunder, J., Mak, T. W., & Alman, B. A.
- Affiliations
- Hospital for Sick Children (CA)
- University Health Network (CA)
- Duke University (US)
- Agios Pharmaceuticals, Cambridge, MA 02139;
- Agios Pharmaceuticals (United States) (US)
- Chempartner, Shanghai 201203, China; and
- Mount Sinai Hospital (CA)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-02-17
- Volume
- 112
- Issue
- 9
- Pages
- 2829-2834
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4352794
- OpenAlex
- W2137307574
- Cited by
- 115
- References
- 39
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 7 · 2023: 11 · 2022: 6 · 2021: 16 · 2020: 11 · 2019: 13 · 2018: 8 · 2017: 12 · 2016: 15 · 2015: 6
- FWCI
- 11.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (R0 AR066765 01)
- Gouvernement du Canada | Canadian Institutes of Health Research (MOP 125884)
- Topics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone Tumor Diagnosis and Treatments
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
- Keywords
- enchondromatosis, isocitrate dehydrogenase, IDH2 mutation, 2-hydroxyglutarate, chondrosarcoma, growth plate, chondrocyte hypertrophy, type II collagen, conditional knock-in mice, tumor initiation, cartilaginous tumors
- MeSH terms
- Animals, Enchondromatosis, Glutarates, Humans, Isocitrate Dehydrogenase, Mice, Mutant Strains, Gene Expression Regulation, Enzymologic, Chondrocytes, Amino Acid Substitution, Mutation, Missense, Collagen Type II, Mice
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