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Induction of sarcomas by mutant IDH2

Item Type:Article
Title:Induction of sarcomas by mutant IDH2
Creators Name:Lu, C. and Venneti, S. and Akalin, A. and Fang, F. and Ward, P.S. and Dematteo, R.G. and Intlekofer, A.M. and Chen, C. and Ye, J. and Hameed, M. and Nafa, K. and Agaram, N.P. and Cross, J.R. and Khanin, R. and Mason, C.E. and Healey, J.H. and Lowe, S.W. and Schwartz, G.K. and Melnick, A. and Thompson, C.B.
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:Isocitrate Dehydrogenase Mutation, 2-Hydroxyglutarate, Differentiation, Contact Inhibition, Tumorigenesis, DNA Methylation, Chondrosarcoma, Animals, Mice
Source:Genes & Development
ISSN:0890-9369
Publisher:Cold Spring Harbor Laboratory Press (U.S.A.)
Volume:27
Number:18
Page Range:1986-1998
Date:15 September 2013
Official Publication:https://doi.org/10.1101/gad.226753.113
PubMed:View item in PubMed

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