title: Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas.
abstract: Point mutations at Arg132 of the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase 1 (IDH1) occur frequently in gliomas and result in a gain of function to produce the "oncometabolite" D-2-hydroxyglutarate (D-2HG). The mutated IDH1 allele is usually associated with a wild-type IDH1 allele (heterozygous) in cancer. Here, we identify 2 gliomas that underwent loss of the wild-type IDH1 allele but retained the mutant IDH1 allele following tumor progression from World Health Organization (WHO) grade III anaplastic astrocytomas to WHO grade IV glioblastomas. Intratumoral D-2HG was 14-fold lower in the glioblastomas lacking wild-type IDH1 than in glioblastomas with heterozygous IDH1 mutations. To characterize the contribution of wild-type IDH1 to cancer cell D-2HG production, we established an IDH1-mutated astrocytoma (IMA) cell line from a WHO grade III anaplastic astrocytoma. Disruption of the wild-type IDH1 allele in IMA cells by gene targeting resulted in an 87-fold decrease in cellular D-2HG levels, showing that both wild-type and mutant IDH1 alleles are required for D-2HG production in glioma cells. Expression of wild-type IDH1 was also critical for mutant IDH1-associated D-2HG production in the colorectal cancer cell line HCT116. These insights may aid in the development of therapeutic strategies to target IDH1-mutated cancers.
authors.affiliation: The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, and The Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA. hai.yan@duke.edu
authors.forename: Genglin
authors.initials: G
authors.lastname: Jin
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Reitman
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Duncan
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.forename: David M
authors.initials: DM
authors.lastname: Gooden
authors.forename: B Ahmed
authors.initials: BA
authors.lastname: Rasheed
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.forename: Giselle Y
authors.initials: GY
authors.lastname: Lopez
authors.forename: Yiping
authors.initials: Y
authors.lastname: He
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
mesh_terms: D001254:Astrocytoma / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005838:Genotype; D005909:Glioblastoma / Q000235:genetics; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D009154:Mutation
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase