Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas.
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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.
SubjectCell Line, Tumor
Published Version (Please cite this version)10.1158/0008-5472.CAN-12-2852
Publication InfoMcLendon, Roger; Yan, Hai; Bigner, Darell; He, Yiping; Spasojevic, Ivan; Rasheed, Ahmed; ... Yang, Rui (2013). Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas. Cancer research, 73(2). pp. 496-501. 10.1158/0008-5472.CAN-12-2852. Retrieved from https://hdl.handle.net/10161/17851.
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E. L. and Lucille F. Jones Cancer Research Professor, in the School of Medicine
The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS). There are over 16,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 80,000 cases of primary brain tumors were expected to
Associate Professor in Pathology
Assistant Professor in Pathology
I am a physician scientist with a clinical focus on neuropathology, and a research interest in brain tumors. Originally from Maryland, I completed my undergraduate training at the University of Maryland, completing degrees in Physiology and Neurobiology as well as Spanish Language and Literature. I subsequently came to Duke for my MD and PhD, and discovered a passion for brain tumor research, and quickly realized that this was my life's calling. After completing a residency and fellowship at the
Professor of Pathology
Brain tumors are diagnosed in more than 20,000 Americans annually. The most malignant neoplasm, glioblastoma, is also the most common. Similarly, brain tumors constitute the most common solid neoplasm in children and include astrocytomas of the cerebellum, brain stem and cerebrum as well as medulloblastomas of the cerebellum. My colleagues and I have endeavored to translate the bench discoveries of genetic mutations and aberrant protein expressions found in brain tumors to better understan
Assistant Professor in Pathology
Our lab is interested in identifying the specific genetic alterations associated with the genesis and progression of glial malignancies. Studies from our and other laboratories have shown that in adult glioblastomas, approximately 80% of the cases show loss of alleles on chromosome 10, and to a lesser extent on 9p, 17p, 19q and 22q. Amplification of epidermal growth factor receptor gene is detected in about a third of glioblastomas. The high incidence of loss of chromosome 10 alleles sug
Associate Professor in Medicine
Henry S. Friedman Professor of Neuro-Oncology in the School of Medicine
Our research activities center on the molecular genetics and biology of cancer with a focus on the identification, characterization, and therapeutic targeting of driver mutations involved in the genesis and progression of brain cancers. Gliomas are the most common type of primary brain tumor. Through genomic studies, we have identified mutations in IDH1 and IDH2 in 70% of progressive malignant gliomas. These are somatic missense mutations that alter a conserved arginine residue and gain a
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