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Sci Transl Med. 2019 Feb 13;11(479). pii: eaaq1427. doi: 10.1126/scitranslmed.aaq1427.

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

Author information

1
Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
2
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
3
Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
4
Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
5
Department of Environmental Health Science, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
6
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
7
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
8
Departments of Pathology, Oncology and Urology, Johns Hopkins University, Baltimore, MD 21287, USA.
9
Department of Biology, University of Rochester, Rochester, NY 14627, USA.
10
Department of Biostatistics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
11
Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
12
Graduate Program in Chemical Biology, University of Michigan, Ann Arbor, MI 48109, USA.
13
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
14
Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA.
15
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
16
Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322, USA.
17
Graduate Division of Molecular and Systems Pharmacology, Emory University, Atlanta, GA 30322, USA.
18
Graduate Division of Cancer Biology, Emory University, Atlanta, GA 30322, USA.
19
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136-1000, USA.
20
Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. mariacas@med.umich.edu pedrol@med.umich.edu.

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.

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