IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition.
Mutations of IDH1 and IDH2, which produce the oncometabolite 2-hydroxyglutarate (2HG), have been identified in several tumors, including acute myeloid leukemia. Recent studies have shown that expression of the IDH mutant enzymes results in high levels of 2HG and a block in cellular differentiation that can be reversed with IDH mutant-specific small-molecule inhibitors. To further understand the role of IDH mutations in cancer, we conducted mechanistic studies in the TF-1 IDH2 R140Q erythroleukemia model system and found that IDH2 mutant expression caused both histone and genomic DNA methylation changes that can be reversed when IDH2 mutant activity is inhibited. Specifically, histone hypermethylation is rapidly reversed within days, whereas reversal of DNA hypermethylation proceeds in a progressive manner over the course of weeks. We identified several gene signatures implicated in tumorigenesis of leukemia and lymphoma, indicating a selective modulation of relevant cancer genes by IDH mutations. As methylation of DNA and histones is closely linked to mRNA expression and differentiation, these results indicate that IDH2 mutant inhibition may function as a cancer therapy via histone and DNA demethylation at genes involved in differentiation and tumorigenesis.
Agios Pharmaceuticals, Cambridge, MA.
Andrew
A
Kernytsky
Agios Pharmaceuticals, Cambridge, MA.
Fang
F
Wang
Agios Pharmaceuticals, Cambridge, MA.
Erica
E
Hansen
Agios Pharmaceuticals, Cambridge, MA.
Stefanie
S
Schalm
Agios Pharmaceuticals, Cambridge, MA.
Kimberly
K
Straley
Agios Pharmaceuticals, Cambridge, MA.
Camelia
C
Gliser
Agios Pharmaceuticals, Cambridge, MA.
Hua
H
Yang
Agios Pharmaceuticals, Cambridge, MA.
Jeremy
J
Travins
Agios Pharmaceuticals, Cambridge, MA.
Stuart
S
Murray
Agios Pharmaceuticals, Cambridge, MA.
Marion
M
Dorsch
Agios Pharmaceuticals, Cambridge, MA.
Sam
S
Agresta
Agios Pharmaceuticals, Cambridge, MA.
David P
DP
Schenkein
Agios Pharmaceuticals, Cambridge, MA.
Scott A
SA
Biller
Agios Pharmaceuticals, Cambridge, MA.
Shinsan M
SM
Su
Agios Pharmaceuticals, Cambridge, MA.
Wei
W
Liu
Agios Pharmaceuticals, Cambridge, MA.
Katharine E
KE
Yen
D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002853:Chromatography, Liquid; D019175:DNA Methylation / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D009154:Mutation; D010671:Phenylurea Compounds / Q000494:pharmacology; D025341:Principal Component Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D053719:Tandem Mass Spectrometry; D059467:Transcriptome / Q000187:drug effects*
C581155:AGI-6780; D004791:Enzyme Inhibitors; D006657:Histones; D010671:Phenylurea Compounds; D013449:Sulfonamides; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase