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ResearchIn-Press PreviewNeuroscienceOncology Open Access | 10.1172/JCI179395

Disruption of Ataxia-telangiectasia mutated kinase enhances radiation therapy efficacy in spatially-directed diffuse midline glioma models

Avani Mangoli,1 Vennesa Valentine,2 Spencer Maingi,2 Sophie R. Wu,2 Harrison Q. Liu,2 Michael Aksu,3 Vaibhav Jain,3 Bronwen E. Foreman,2 Joshua A. Regal,2 Loren B. Weidenhammer,2 Connor E. Stewart,2 Maria E. Guerra Garcia,2 Emily Hocke,2 Karen Abramson,3 Tal Falick Michaeli,1 Nerissa T. Williams,2 Lixia Luo,2 Megan Romero,4 Katherine Deland,2 Samantha Gadd,5 Eita Uchida,5 Laura Attardi,6 Kouki Abe,5 Rintaro Hashizume,5 David M. Ashley,1 Oren J. Becher,4 David G. Kirsch,7 Simon G. Gregory,3 and Zachary J. Reitman2

1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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1The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, United States of America

2Department of Radiation Oncology, Duke University, Durham, United States of America

3The Preston Robert Tisch Brain Tumor Center Omics Program, Duke University, Durham, United States of America

4Department of Pediatric Hematology Oncology, Mount Sinai Kravis Children’s Hospital, New York, United States of America

5Department of Pediatrics, University of Alabama at Birmingham, Birmingham, United States of America

6Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, United States of America

7Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

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Published April 17, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI179395.
Copyright © 2025, Mangoli et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 17, 2025 - Version history
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Abstract

Diffuse midline gliomas (DMGs) are lethal brain tumors characterized by p53-inactivating mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress. We used RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce native H3.3K27M mutations in a lineage- and spatially-directed manner. We generated primary mouse tumors that recapitulate human DMG. Disrupting ataxia-telangiectasia mutated kinase (ATM) enhanced the efficacy of radiation therapy in murine and patient-derived DMG models which increased survival. Microscopy-based in situ sequencing was used to spatially resolve transcriptional profiles in >750,000 single cells with or without ATM disruption and radiation therapy, revealing altered immune-neoplastic and endothelial cell interactions after treatment. An allelic series of primary murine DMG models with different p53 mutations confirmed that transactivation-independent p53 activity is a key mediator of radiosensitivity after ATM disruption. Our findings contribute primary DMG mouse models with deep profiling and reveal the mechanisms of treatment response to an actionable therapeutic strategy.

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graphical abstract
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