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 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.

journal_name

Blood

journal_title

Blood

authors

Kernytsky A,Wang F,Hansen E,Schalm S,Straley K,Gliser C,Yang H,Travins J,Murray S,Dorsch M,Agresta S,Schenkein DP,Biller SA,Su SM,Liu W,Yen KE

doi

10.1182/blood-2013-10-533604

subject

Has Abstract

pub_date

2015-01-08 00:00:00

pages

296-303

issue

2

eissn

0006-4971

issn

1528-0020

pii

blood-2013-10-533604

journal_volume

125

pub_type

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