Induction of sarcomas by mutant IDH2.
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.
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
Chao
C
Lu
Sriram
S
Venneti
Altuna
A
Akalin
Fang
F
Fang
Patrick S
PS
Ward
Raymond G
RG
Dematteo
Andrew M
AM
Intlekofer
Chong
C
Chen
Jiangbin
J
Ye
Meera
M
Hameed
Khedoudja
K
Nafa
Narasimhan P
NP
Agaram
Justin R
JR
Cross
Raya
R
Khanin
Christopher E
CE
Mason
John H
JH
Healey
Scott W
SW
Lowe
Gary K
GK
Schwartz
Ari
A
Melnick
Craig B
CB
Thompson
D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D002454:Cell Differentiation; D002460:Cell Line; D002813:Chondrosarcoma / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D014183:Transplantation, Heterologous
D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase
2-hydroxyglutarate; DNA methylation; chondrosarcoma; contact inhibition; differentiation; isocitrate dehydrogenase mutation; tumorigenesis