Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response.

Authors: Núñez, Felipe J; Mendez, Flor M; Kadiyala, Padma; Alghamri, Mahmoud S; Savelieff, Masha G; Garcia-Fabiani, Maria B; Haase, Santiago; Koschmann, Carl; Calinescu, Anda-Alexandra; Kamran, Neha; Saxena, Meghna; Patel, Rohin; Carney, Stephen; Guo, Marissa Z; Edwards, Marta; Ljungman, Mats; Qin, Tingting; Sartor, Maureen A; Tagett, Rebecca; Venneti, Sriram; Brosnan-Cashman, Jacqueline; Meeker, Alan; Gorbunova, Vera; Zhao, Lili; Kremer, Daniel M; Zhang, Li; Lyssiotis, Costas A; Jones, Lindsey; Herting, Cameron J; Ross, James L; Hambardzumyan, Dolores; Hervey-Jumper, Shawn; Figueroa, Maria E; Lowenstein, Pedro R; Castro, Maria G

Published In Sci Transl Med, (2019 02 13)

Abstract: Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1R132H) are younger at diagnosis and live longer. IDH1 mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53 (TP53) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (ATRX). All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1R132H mutation. The current molecular classification of LGGs is based, partly, on the distribution of these mutations. We developed a genetically engineered mouse model harboring IDH1R132H, TP53 and ATRX inactivating mutations, and activated NRAS G12V. Previously, we established that ATRX deficiency, in the context of wild-type IDH1, induces genomic instability, impairs nonhomologous end-joining DNA repair, and increases sensitivity to DNA-damaging therapies. In this study, using our mouse model and primary patient-derived glioma cultures with IDH1 mutations, we investigated the function of IDH1R132H in the context of TP53 and ATRX loss. We discovered that IDH1R132H expression in the genetic context of ATRX and TP53 gene inactivation (i) increases median survival in the absence of treatment, (ii) enhances DNA damage response (DDR) via epigenetic up-regulation of the ataxia-telangiectasia-mutated (ATM) signaling pathway, and (iii) elicits tumor radioresistance. Accordingly, pharmacological inhibition of ATM or checkpoint kinases 1 and 2, essential kinases in the DDR, restored the tumors' radiosensitivity. Translation of these findings to patients with IDH1132H glioma harboring TP53 and ATRX loss could improve the therapeutic efficacy of radiotherapy and, consequently, patient survival.

PubMed ID: 30760578 Exiting the NIEHS site

MeSH Terms: Animals; Ataxia Telangiectasia Mutated Proteins/metabolism; Brain Neoplasms/genetics; Brain Neoplasms/pathology; Cell Differentiation; DNA Damage/genetics*; DNA Methylation/genetics; DNA Repair/genetics; Disease Models, Animal; Epigenesis, Genetic*; Gene Ontology; Genome; Glioma/genetics*; Glioma/pathology; Histones/metabolism; Humans; Isocitrate Dehydrogenase/genetics*; Mice; Mutation/genetics*; Oligodendroglia/pathology; Radiation Tolerance; Signal Transduction; Survival Analysis; Tumor Suppressor Proteins/genetics*; Up-Regulation/genetics*

Back
to Top