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
Bloodjournal_title
Bloodauthors
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 KEdoi
10.1182/blood-2013-10-533604subject
Has Abstractpub_date
2015-01-08 00:00:00pages
296-303issue
2eissn
0006-4971issn
1528-0020pii
blood-2013-10-533604journal_volume
125pub_type
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