Dataset Information


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

ABSTRACT: Mutations of IDH1 (R132) and IDH2 (R172 and R140), which produce an oncometabolite 2-hydroxyglutarate (2HG), have been identified in several tumors including acute myeloid leukemia (AML). 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. Pathway enrichment analysis revealed several pathways involved 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 short-term histone demethylation and long-term DNA demethylation at genes involved in differentiation and tumorigenesis. TF-1 cells with and without IDH2/R140Q expression were treated with DMSO or AGI-6780, an inhibitor of IDH2/R140Q for 7 to 28 days. Genomic DNA was extracted and analyzed by the Illumina 450k Methylation array.

ORGANISM(S): Homo sapiens  

SUBMITTER: Andrew Kernytsky   Katharine Yen 

PROVIDER: E-GEOD-51352 | ArrayExpress | 2014-11-19



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