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 Venneti & 15 others Jacqueline Brosnan-Cashman, Alan Keith 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

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

Fingerprint

alpha-Thalassemia
X-Linked Genes
Epigenomics
Glioma
DNA Damage
Intellectual Disability
Tumor Suppressor Proteins
Up-Regulation
Mutation
Neoplasms
DNA End-Joining Repair
Ataxia Telangiectasia
Checkpoint Kinase 2
Isocitrate Dehydrogenase
Survival
Genomic Instability
Radiation Tolerance
Gene Silencing
Genetic Therapy
Phosphotransferases

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Núñez, F. J., Mendez, F. M., Kadiyala, P., Alghamri, M. S., Savelieff, M. G., Garcia-Fabiani, M. B., ... 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

IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response. / Núñez, Felipe J.; Mendez, Flor M.; Kadiyala, Padma; Alghamri, Mahmoud S.; Savelieff, Masha G.; Garcia-Fabiani, Maria B.; Haase, Santiago; Koschmann, Carl; Calinescu, Anda Alexandra; Kamran, Neha; Saxena, Meghna; Patel, Rohin; Carney, Stephen; Guo, Marissa Z.; Edwards, Marta; Ljungman, Mats; Qin, Tingting; Sartor, Maureen A.; Tagett, Rebecca; Venneti, Sriram; Brosnan-Cashman, Jacqueline; Meeker, Alan Keith; Gorbunova, Vera; Zhao, Lili; Kremer, Daniel M.; Zhang, Li; Lyssiotis, Costas A.; Jones, Lindsey; Herting, Cameron J.; Ross, James L.; Hambardzumyan, Dolores; Hervey-Jumper, Shawn; Figueroa, Maria E.; Lowenstein, Pedro R.; Castro, Maria G.

In: Science translational medicine, Vol. 11, No. 479, eaaq1427, 13.02.2019.

Research output: Contribution to journalArticle

Núñez, FJ, Mendez, FM, Kadiyala, P, Alghamri, MS, Savelieff, MG, Garcia-Fabiani, MB, Haase, S, Koschmann, C, Calinescu, AA, Kamran, N, Saxena, M, Patel, R, Carney, S, Guo, MZ, Edwards, M, Ljungman, M, Qin, T, Sartor, MA, Tagett, R, Venneti, S, Brosnan-Cashman, J, Meeker, AK, Gorbunova, V, Zhao, L, Kremer, DM, Zhang, L, Lyssiotis, CA, Jones, L, Herting, CJ, Ross, JL, Hambardzumyan, D, Hervey-Jumper, S, Figueroa, ME, Lowenstein, PR & Castro, MG 2019, 'IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response', Science translational medicine, vol. 11, no. 479, eaaq1427. https://doi.org/10.1126/scitranslmed.aaq1427
Núñez FJ, Mendez FM, Kadiyala P, Alghamri MS, Savelieff MG, Garcia-Fabiani MB et al. IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response. Science translational medicine. 2019 Feb 13;11(479). eaaq1427. https://doi.org/10.1126/scitranslmed.aaq1427
Núñez, Felipe J. ; Mendez, Flor M. ; Kadiyala, Padma ; Alghamri, Mahmoud S. ; Savelieff, Masha G. ; Garcia-Fabiani, Maria B. ; Haase, Santiago ; Koschmann, Carl ; Calinescu, Anda Alexandra ; Kamran, Neha ; Saxena, Meghna ; Patel, Rohin ; Carney, Stephen ; Guo, Marissa Z. ; Edwards, Marta ; Ljungman, Mats ; Qin, Tingting ; Sartor, Maureen A. ; Tagett, Rebecca ; Venneti, Sriram ; Brosnan-Cashman, Jacqueline ; Meeker, Alan Keith ; Gorbunova, Vera ; Zhao, Lili ; Kremer, Daniel M. ; Zhang, Li ; Lyssiotis, Costas A. ; Jones, Lindsey ; Herting, Cameron J. ; Ross, James L. ; Hambardzumyan, Dolores ; Hervey-Jumper, Shawn ; Figueroa, Maria E. ; Lowenstein, Pedro R. ; Castro, Maria G. / IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response. In: Science translational medicine. 2019 ; Vol. 11, No. 479.
@article{8fe9919445864afbba6c0f0ac1885150,
title = "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. 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.",
author = "N{\'u}{\~n}ez, {Felipe J.} and Mendez, {Flor M.} and Padma Kadiyala and Alghamri, {Mahmoud S.} and Savelieff, {Masha G.} and Garcia-Fabiani, {Maria B.} and Santiago Haase and Carl Koschmann and Calinescu, {Anda Alexandra} and Neha Kamran and Meghna Saxena and Rohin Patel and Stephen Carney and Guo, {Marissa Z.} and Marta Edwards and Mats Ljungman and Tingting Qin and Sartor, {Maureen A.} and Rebecca Tagett and Sriram Venneti and Jacqueline Brosnan-Cashman and Meeker, {Alan Keith} and Vera Gorbunova and Lili Zhao and Kremer, {Daniel M.} and Li Zhang and Lyssiotis, {Costas A.} and Lindsey Jones and Herting, {Cameron J.} and Ross, {James L.} and Dolores Hambardzumyan and Shawn Hervey-Jumper and Figueroa, {Maria E.} and Lowenstein, {Pedro R.} and Castro, {Maria G.}",
year = "2019",
month = "2",
day = "13",
doi = "10.1126/scitranslmed.aaq1427",
language = "English (US)",
volume = "11",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "479",

}

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 Keith

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.

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

VL - 11

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 479

M1 - eaaq1427

ER -