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

Abstract

Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1^R132H) are younger at diagnosis and live longer. <i>IDH1</i> mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53 <i>(TP53</i>) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (<i>ATRX</i>). 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, <i>TP53</i> and <i>ATRX</i> 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 <i>ATRX</i> and <i>TP53</i> 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.