期刊
MOLECULAR CANCER RESEARCH
卷 17, 期 10, 页码 2042-2050出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-19-0309
关键词
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资金
- NCI of the NIH [R01CA140316]
- NRSA Fellowship [F31CA203399, F30CA206423]
- NIH R01 grant [R01CA140316]
Mutations in isocitrate dehydrogenases 1 and 2 (IDH) occur in the majority of World Health Organization grade II and III gliomas. IDH1/2 active site mutations confer a neomorphic enzyme activity producing the oncometabolite D-2-hydroxyglutarate (D-2HG), which generates the glioma CpG island methylation phenotype (G-CIMP). While IDH1/2 mutations and G-CIMP are commonly retained during tumor recurrence, recent work has uncovered losses of the IDH1 mutation in a subset of secondary glioblastomas. Cooccurrence of the loss of the mutant allele with extensive methylation changes suggests a possible link between the two phenomena. Here, we utilize patient-derived IDH1(R132H/WT) glioma cell lines and CRISPR-Cas9-mediated gene knockout to model the genetic loss of IDH1(R132H), and characterize the effects of this deletion on DNA methylation. After D-2HG production has been abolished by deletions within the IDH1 alleles, these models show persistent DNA hypermethylation at seven CpG sites previously used to define G-CIMP-positivity in patient tumor samples. Despite these defining G-CIMP sites showing persistent hypermethylation, we observed a genome-wide pattern of DNA demethylation, enriched for CpG sites located within open sea regions of the genome, as well as in CpG-island shores of transcription start sites, after loss of D-2HG production. These results suggest that inhibition of D-2HG from genetic deletion of IDH alleles is not sufficient to reverse hypermethylation of all G-CIMP-defining CpG sites, but does result in more demethylation globally and may contribute to the formation of a G-CIMP-low-like phenotype.
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