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

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

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1 R132H ) 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 IDH1 R132H mutation. The current molecular classification of LGGs is based, partly, on the distribution of these mutations. We developed a genetically engineered mouse model harboring IDH1 R132H , 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 IDH1 R132H in the context of TP53 and ATRX loss. We discovered that IDH1 R132H 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 IDH1 132H glioma harboring TP53 and ATRX loss could improve the therapeutic efficacy of radiotherapy and, consequently, patient survival.

Original languageEnglish (US)
Article numbereaaq1427
JournalScience Translational Medicine
Volume11
Issue number479
DOIs
StatePublished - Feb 13 2019

ASJC Scopus subject areas

  • Medicine(all)

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    Núñez, F. J., Mendez, F. M., Kadiyala, P., Alghamri, M. S., Savelieff, M. G., Garcia-Fabiani, M. B., Haase, S., Koschmann, C., Calinescu, A. A., Kamran, N., Saxena, M., Patel, R., Carney, S., Guo, M. Z., Edwards, M., Ljungman, M., Qin, T., Sartor, M. A., Tagett, R., ... Castro, M. G. (2019). IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response. Science Translational Medicine, 11(479), [eaaq1427]. https://doi.org/10.1126/scitranslmed.aaq1427