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CRISPR Editing of Mutant IDH1 R132H Induces a CpG Methylation-Low State in Patient-Derived Glioma Models of G-CIMP.

Publication ,  Journal Article
Moure, CJ; Diplas, BH; Chen, LH; Yang, R; Pirozzi, CJ; Wang, Z; Spasojevic, I; Waitkus, MS; He, Y; Yan, H
Published in: Mol Cancer Res
October 2019

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 IDH1R132H/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. IMPLICATIONS: These findings show that loss of the IDH1 mutation in malignant glioma cells leads to a pattern of DNA methylation alterations, and shows plausibility of IDH1 mutation loss being causally related to the gain of a G-CIMP-low-like phenotype.

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Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

October 2019

Volume

17

Issue

10

Start / End Page

2042 / 2050

Location

United States

Related Subject Headings

  • Transfection
  • Oncology & Carcinogenesis
  • Mutation
  • Isocitrate Dehydrogenase
  • Humans
  • Glioblastoma
  • Gene Knockdown Techniques
  • Developmental Biology
  • DNA Methylation
  • CpG Islands
 

Citation

APA
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MLA
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Moure, C. J., Diplas, B. H., Chen, L. H., Yang, R., Pirozzi, C. J., Wang, Z., … Yan, H. (2019). CRISPR Editing of Mutant IDH1 R132H Induces a CpG Methylation-Low State in Patient-Derived Glioma Models of G-CIMP. Mol Cancer Res, 17(10), 2042–2050. https://doi.org/10.1158/1541-7786.MCR-19-0309
Moure, Casey J., Bill H. Diplas, Lee H. Chen, Rui Yang, Christopher J. Pirozzi, Zhaohui Wang, Ivan Spasojevic, Matthew S. Waitkus, Yiping He, and Hai Yan. “CRISPR Editing of Mutant IDH1 R132H Induces a CpG Methylation-Low State in Patient-Derived Glioma Models of G-CIMP.Mol Cancer Res 17, no. 10 (October 2019): 2042–50. https://doi.org/10.1158/1541-7786.MCR-19-0309.
Moure CJ, Diplas BH, Chen LH, Yang R, Pirozzi CJ, Wang Z, et al. CRISPR Editing of Mutant IDH1 R132H Induces a CpG Methylation-Low State in Patient-Derived Glioma Models of G-CIMP. Mol Cancer Res. 2019 Oct;17(10):2042–50.
Moure, Casey J., et al. “CRISPR Editing of Mutant IDH1 R132H Induces a CpG Methylation-Low State in Patient-Derived Glioma Models of G-CIMP.Mol Cancer Res, vol. 17, no. 10, Oct. 2019, pp. 2042–50. Pubmed, doi:10.1158/1541-7786.MCR-19-0309.
Moure CJ, Diplas BH, Chen LH, Yang R, Pirozzi CJ, Wang Z, Spasojevic I, Waitkus MS, He Y, Yan H. CRISPR Editing of Mutant IDH1 R132H Induces a CpG Methylation-Low State in Patient-Derived Glioma Models of G-CIMP. Mol Cancer Res. 2019 Oct;17(10):2042–2050.

Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

October 2019

Volume

17

Issue

10

Start / End Page

2042 / 2050

Location

United States

Related Subject Headings

  • Transfection
  • Oncology & Carcinogenesis
  • Mutation
  • Isocitrate Dehydrogenase
  • Humans
  • Glioblastoma
  • Gene Knockdown Techniques
  • Developmental Biology
  • DNA Methylation
  • CpG Islands