IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition.

ABSTRACT: 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 pr

SUBMITTER: Kernytsky A 

PROVIDER: S-EPMC4295919 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature