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Mutant IDH is sufficient to initiate enchondromatosis in mice.
Hirata, Makoto; Sasaki, Masato; Cairns, Rob A; Inoue, Satoshi; Puviindran, Vijitha; Li, Wanda Y; Snow, Bryan E; Jones, Lisa D; Wei, Qingxia; Sato, Shingo; Tang, Yuning J; Nadesan, Puviindran; Rockel, Jason; Whetstone, Heather; Poon, Raymond; Weng, Angela; Gross, Stefan; Straley, Kimberly; Gliser, Camelia; Xu, Yingxia; Wunder, Jay; Mak, Tak W; Alman, Benjamin A.
Afiliación
  • Hirata M; Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
  • Sasaki M; The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1;
  • Cairns RA; The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1;
  • Inoue S; The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1;
  • Puviindran V; Department of Orthopedic Surgery, Duke University, Durham, NC 27710;
  • Li WY; The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1;
  • Snow BE; The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1;
  • Jones LD; The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1;
  • Wei Q; Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
  • Sato S; Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
  • Tang YJ; Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
  • Nadesan P; Department of Orthopedic Surgery, Duke University, Durham, NC 27710;
  • Rockel J; Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
  • Whetstone H; Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
  • Poon R; Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
  • Weng A; Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
  • Gross S; Agios Pharmaceuticals, Cambridge, MA 02139;
  • Straley K; Agios Pharmaceuticals, Cambridge, MA 02139;
  • Gliser C; Agios Pharmaceuticals, Cambridge, MA 02139;
  • Xu Y; Chempartner, Shanghai 201203, China; and.
  • Wunder J; Department of Orthopedic Surgery, Mount Sinai Hospital, Toronto, ON, Canada, M5G 1X5.
  • Mak TW; The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1; tmak@uhnres.utoronto.ca benjamin.alman@sickkids.ca.
  • Alman BA; Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4; Department of Orthopedic Surgery, Duke University, Durham, NC 27710; tmak@uhnres.utoronto.ca benjamin.alman@sickkids.ca.
Proc Natl Acad Sci U S A ; 112(9): 2829-34, 2015 Mar 03.
Article en En | MEDLINE | ID: mdl-25730874
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación Enzimológica de la Expresión Génica / Condrocitos / Mutación Missense / Encondromatosis / Isocitrato Deshidrogenasa Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación Enzimológica de la Expresión Génica / Condrocitos / Mutación Missense / Encondromatosis / Isocitrato Deshidrogenasa Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos