Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas.
| dc.contributor.author | Jin, Genglin | |
| dc.contributor.author | Reitman, Zachary J | |
| dc.contributor.author | Duncan, Christopher G | |
| dc.contributor.author | Spasojevic, Ivan | |
| dc.contributor.author | Gooden, David M | |
| dc.contributor.author | Rasheed, B Ahmed | |
| dc.contributor.author | Yang, Rui | |
| dc.contributor.author | Lopez, Giselle Y | |
| dc.contributor.author | He, Yiping | |
| dc.contributor.author | McLendon, Roger E | |
| dc.contributor.author | Bigner, Darell D | |
| dc.contributor.author | Yan, Hai | |
| dc.date.accessioned | 2019-01-02T22:36:02Z | |
| dc.date.available | 2019-01-02T22:36:02Z | |
| dc.date.issued | 2013-01 | |
| dc.date.updated | 2019-01-02T22:36:01Z | |
| dc.description.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. | |
| dc.identifier | 0008-5472.CAN-12-2852 | |
| dc.identifier.issn | 0008-5472 | |
| dc.identifier.issn | 1538-7445 | |
| dc.identifier.uri | ||
| dc.language | eng | |
| dc.publisher | American Association for Cancer Research (AACR) | |
| dc.relation.ispartof | Cancer research | |
| dc.relation.isversionof | 10.1158/0008-5472.CAN-12-2852 | |
| dc.subject | Cell Line, Tumor | |
| dc.subject | Humans | |
| dc.subject | Glioma | |
| dc.subject | Astrocytoma | |
| dc.subject | Glioblastoma | |
| dc.subject | Brain Neoplasms | |
| dc.subject | Glutarates | |
| dc.subject | Isocitrate Dehydrogenase | |
| dc.subject | Genotype | |
| dc.subject | Mutation | |
| dc.title | Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas. | |
| dc.type | Journal article | |
| duke.contributor.orcid | Reitman, Zachary J|0000-0002-9122-9550 | |
| duke.contributor.orcid | Spasojevic, Ivan|0000-0001-9890-6246 | |
| duke.contributor.orcid | Lopez, Giselle Y|0000-0001-5435-6668 | |
| duke.contributor.orcid | McLendon, Roger E|0000-0001-6682-4588 | |
| duke.contributor.orcid | Bigner, Darell D|0000-0001-5548-4899 | |
| duke.contributor.orcid | Yan, Hai|0000-0001-9509-8431 | |
| pubs.begin-page | 496 | |
| pubs.end-page | 501 | |
| pubs.issue | 2 | |
| pubs.organisational-group | School of Medicine | |
| pubs.organisational-group | Duke | |
| pubs.organisational-group | Duke Cancer Institute | |
| pubs.organisational-group | Institutes and Centers | |
| pubs.organisational-group | Pathology | |
| pubs.organisational-group | Clinical Science Departments | |
| pubs.organisational-group | Pharmacology & Cancer Biology | |
| pubs.organisational-group | Basic Science Departments | |
| pubs.organisational-group | Surgery | |
| pubs.organisational-group | Neurosurgery | |
| pubs.organisational-group | Medicine, Medical Oncology | |
| pubs.organisational-group | Medicine | |
| pubs.organisational-group | Faculty | |
| pubs.publication-status | Published | |
| pubs.volume | 73 |