IDH1 R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response
IDH1 R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response
One sentence summaryMutant IDH1 acts as a tumor suppressor when co-expressed together with TP53 and ATRX inactivating mutations in glioma, inducing genomic stability, DNA repair and resistance to genotoxic therapies. AbstractGlioma patients whose tumors carry a mutation in the Isocitrate Dehydrogenase 1 (IDH1R132H) gene are younger at the time of diagnosis and survive longer. The molecular glioma subtype which we modelled, harbors IDH1R132H, tumor protein 53 (TP53) and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss. The impact of IDH1R132H on genomic stability, DNA damage response (DDR) and DNA repair in this molecular glioma subtype is unknown. We discovered that IDH1R132H expression in the genetic context of ATRX and TP53 inactivation: (i) increases median survival (MS), (ii) enhances DDR activity via epigenetic upregulation of Ataxia-telangiectasia mutated (ATM) signaling, and (iii) elicits tumor radioresistance. Pharmacological inhibition of ATM or checkpoint kinase 1 and 2 (CHK1/2), two essential kinases in the DDR pathways, restored tumors’ radiosensitivity. Translation of these findings for mlDH1 glioma patients could significantly improve the therapeutic efficacy of radiotherapy, and thus have a major impact on patient survival.
N¨2?ez Felipe J.、Mendez Flor M.、Kadiyala Padma、Savelieff Masha G.、Koschmann Carl、Kamran Neha、Carney Stephen、Garcia-Fabiani Maria B.、Hervey-Jumper Shawn、Figueroa Maria E.、Ljungman Mats、Sartor Maureen A.、Tagett Rebecca、Gorbunova Vera、Zhao Lili、Zhang Li、Ross James L.、Calinescu Anda-Alexandra、Venneti Sriram、Edwards Marta、Brosnan-Cashman Jacqueline、Meeker Alan、Lowenstein Pedro R.、Castro Maria G.、Patel Rohin、Qin Tingting、Alghamri Mahmoud S.、Guo Marissa Z.、Kremer Daniel M.、Lyssiotis Costas A.、Herting Cameron J.、Hambardzumyan Dolores、Haase Santiago、Jones Lindsey
Departments of Neurosurgery||Department of Cell and Developmental BiologyDepartment of Cell and Developmental BiologyDepartments of Neurosurgery||Department of Cell and Developmental BiologyDepartments of Neurosurgery||Department of Cell and Developmental BiologyDepartment of PediatricsDepartments of Neurosurgery||Department of Cell and Developmental BiologyDepartments of NeurosurgeryDepartments of Neurosurgery||Department of Cell and Developmental BiologyDepartments of NeurosurgeryDepartment of Pathology, University of Michigan Medical School||Sylvester Comprehensive Cancer Center, University of Miami Miller School of MedicineDepartment of Radiation Oncology, University of Michigan Medical School||Department of Environmental Health Science, School of Public Health, University of MichiganDepartment of Computational Medicine and Bioinformatics, University of MichiganDepartment of Computational Medicine and Bioinformatics, University of MichiganDepartment of Biology, University of RochesterDepartment of Biostatistics, University of Michigan Medical SchoolDepartment of Molecular and Integrative Physiology, University of MichiganDepartment of Pediatrics, Aflac Cancer and Blood Disorders Center, Children?ˉs Healthcare of Atlanta, Emory University School of Medicine||Graduate Division of Cancer Biology, Emory UniversityDepartments of NeurosurgeryDepartment of Pathology, University of Michigan Medical SchoolDepartments of Neurosurgery||Department of Cell and Developmental BiologyDepartments of Pathology, Oncology and Urology, Johns Hopkins UniversityDepartments of Pathology, Oncology and Urology, Johns Hopkins UniversityDepartments of Neurosurgery||Department of Cell and Developmental BiologyDepartments of Neurosurgery||Department of Cell and Developmental Biology||Lead contactDepartments of NeurosurgeryDepartment of Computational Medicine and Bioinformatics, University of MichiganDepartments of Neurosurgery||Department of Cell and Developmental BiologyDepartments of NeurosurgerySylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine||Graduate Program in Chemical Biology, University of MichiganSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine||Department of Molecular and Integrative Physiology, University of Michigan||Department of Internal Medicine, Division of Gastroenterology, University of MichiganDepartment of Pediatrics, Aflac Cancer and Blood Disorders Center, Children?ˉs Healthcare of Atlanta, Emory University School of Medicine||Graduate Division of Molecular and Systems Pharmacology, Emory UniversityDepartment of Pediatrics, Aflac Cancer and Blood Disorders Center, Children?ˉs Healthcare of Atlanta, Emory University School of MedicineDepartments of Neurosurgery||Department of Cell and Developmental BiologyDepartment of Pediatrics, Aflac Cancer and Blood Disorders Center, Children?ˉs Healthcare of Atlanta, Emory University School of Medicine
肿瘤学神经病学、精神病学基础医学
N¨2?ez Felipe J.,Mendez Flor M.,Kadiyala Padma,Savelieff Masha G.,Koschmann Carl,Kamran Neha,Carney Stephen,Garcia-Fabiani Maria B.,Hervey-Jumper Shawn,Figueroa Maria E.,Ljungman Mats,Sartor Maureen A.,Tagett Rebecca,Gorbunova Vera,Zhao Lili,Zhang Li,Ross James L.,Calinescu Anda-Alexandra,Venneti Sriram,Edwards Marta,Brosnan-Cashman Jacqueline,Meeker Alan,Lowenstein Pedro R.,Castro Maria G.,Patel Rohin,Qin Tingting,Alghamri Mahmoud S.,Guo Marissa Z.,Kremer Daniel M.,Lyssiotis Costas A.,Herting Cameron J.,Hambardzumyan Dolores,Haase Santiago,Jones Lindsey.IDH1 R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response[EB/OL].(2025-03-28)[2025-06-13].https://www.biorxiv.org/content/10.1101/389817.点此复制
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