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Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas. Jin, Genglin Reitman, Zachary J Duncan, Christopher G Spasojevic, Ivan Gooden, David M Rasheed, B Ahmed Yang, Rui Lopez, Giselle Y He, Yiping McLendon, Roger E Bigner, Darell D Yan, Hai 2019-01-02T22:36:02Z 2019-01-02T22:36:02Z 2013-01
dc.identifier 0008-5472.CAN-12-2852
dc.identifier.issn 0008-5472
dc.identifier.issn 1538-7445
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.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 Reitman, Zachary J|0393328 Spasojevic, Ivan|0104047 Rasheed, B Ahmed|0095847 Lopez, Giselle Y|0339145 He, Yiping|0536362 McLendon, Roger E|0112103 Bigner, Darell D|0083494 Yan, Hai|0303449 2019-01-02T22:36:01Z
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
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

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