TY - JOUR
T1 - IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response
AU - Núñez, Felipe J.
AU - Mendez, Flor M.
AU - Kadiyala, Padma
AU - Alghamri, Mahmoud S.
AU - Savelieff, Masha G.
AU - Garcia-Fabiani, Maria B.
AU - Haase, Santiago
AU - Koschmann, Carl
AU - Calinescu, Anda Alexandra
AU - Kamran, Neha
AU - Saxena, Meghna
AU - Patel, Rohin
AU - Carney, Stephen
AU - Guo, Marissa Z.
AU - Edwards, Marta
AU - Ljungman, Mats
AU - Qin, Tingting
AU - Sartor, Maureen A.
AU - Tagett, Rebecca
AU - Venneti, Sriram
AU - Brosnan-Cashman, Jacqueline
AU - Meeker, Alan
AU - Gorbunova, Vera
AU - Zhao, Lili
AU - Kremer, Daniel M.
AU - Zhang, Li
AU - Lyssiotis, Costas A.
AU - Jones, Lindsey
AU - Herting, Cameron J.
AU - Ross, James L.
AU - Hambardzumyan, Dolores
AU - Hervey-Jumper, Shawn
AU - Figueroa, Maria E.
AU - Lowenstein, Pedro R.
AU - Castro, Maria G.
N1 - Publisher Copyright:
Copyright © American Association for the Advancement of Science 2019.
PY - 2019/2/13
Y1 - 2019/2/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85061613649&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061613649&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aaq1427
DO - 10.1126/scitranslmed.aaq1427
M3 - Article
C2 - 30760578
AN - SCOPUS:85061613649
SN - 1946-6234
VL - 11
JO - Science translational medicine
JF - Science translational medicine
IS - 479
M1 - eaaq1427
ER -