TitleInduction of sarcomas by mutant IDH2.
Publication TypeJournal Article
Year of Publication2013
AuthorsLu, Chao, Venneti Sriram, Akalin Altuna, Fang Fang, Ward Patrick S., Dematteo Raymond G., Intlekofer Andrew M., Chen Chong, Ye Jiangbin, Hameed Meera, Nafa Khedoudja, Agaram Narasimhan P., Cross Justin R., Khanin Raya, Mason Christopher E., Healey John H., Lowe Scott W., Schwartz Gary K., Melnick Ari, and Thompson Craig B.
JournalGenes Dev
Volume27
Issue18
Pagination1986-98
Date Published2013 Sep 15
ISSN1549-5477
KeywordsAnimals, Bone Neoplasms, Cell Differentiation, Cell Line, Chondrosarcoma, CpG Islands, DNA Methylation, Female, Gene Expression Regulation, Neoplastic, Genome, Glutarates, Humans, Isocitrate Dehydrogenase, Mesenchymal Stem Cells, Mice, Mice, Nude, Mutation, Transplantation, Heterologous
Abstract

<p>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.</p>

DOI10.1101/gad.226753.113
Alternate JournalGenes Dev
PubMed ID24065766
PubMed Central IDPMC3792475
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 CA168802 / CA / NCI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States