Details

Autor(en) / Beteiligte

• GENGLIN JIN
• REITMAN, Zachary J
• BIGNER, Darell D
• HAI YAN
• DUNCAN, Christopher G
• SPASOJEVIC, Ivan
• GOODEN, David M
• AHMED RASHEED, B
• RUI YANG
• LOPEZ, Giselle Y
• YIPING HE
• MCLENDON, Roger E

Titel

Disruption of Wild-Type IDH1 Suppresses D-2-Hydroxyglutarate Production in IDH1-Mutated Gliomas

Ist Teil von

• Cancer research (Chicago, Ill.), 2013-01, Vol.73 (2), p.496-501

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2013

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.