Induction of sarcomas by mutant IDH2

  1. Craig B. Thompson1,12
  1. 1Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
  2. 2Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
  3. 3Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York 10065, USA;
  4. 4Division of Hematology/Oncology, Weill Cornell Medical College, New York, New York 10065, USA;
  5. 5Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
  6. 6Donald B. and Catherine C. Marron Cancer Metabolism Center,
  7. 7Bioinformatics Core,
  8. 8Orthopaedic Surgery Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
  9. 9Howard Hughes Medical Institute, New York, New York 10065, USA;
  10. 10Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
    • 11 Present address: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.

    Abstract

    More than 50% of patients with chondrosarcomas exhibit gain-of-function mutations in either isocitrate dehydrogenase 1 (IDH1) or IDH2. In this study, we performed genome-wide CpG methylation sequencing of chondrosarcoma biopsies and found that IDH mutations were associated with DNA hypermethylation at CpG islands but not other genomic regions. Regions of CpG island hypermethylation were enriched for genes implicated in stem cell maintenance/differentiation and lineage specification. In murine 10T1/2 mesenchymal progenitor cells, expression of mutant IDH2 led to DNA hypermethylation and an impairment in differentiation that could be reversed by treatment with DNA-hypomethylating agents. Introduction of mutant IDH2 also induced loss of contact inhibition and generated undifferentiated sarcomas in vivo. The oncogenic potential of mutant IDH2 correlated with the ability to produce 2-hydroxyglutarate. Together, these data demonstrate that neomorphic IDH2 mutations can be oncogenic in mesenchymal cells.

    Keywords

    Footnotes

    • Received July 16, 2013.
    • Accepted August 16, 2013.

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