Disruption of ataxia telangiectasia–mutated kinase enhances radiation therapy efficacy in spatially directed diffuse midline glioma models
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 recapitulated human DMG. Disrupting ataxia-telangiectasia mutated (ATM) kinase enhanced the efficacy of radiation therapy (RT) in murine and patient-derived DMG models and increased survival. Microscopy-based in situ sequencing was used to spatially resolve transcriptional profiles in more than 750,000 single cells with or without ATM disruption and RT, 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 was a key mediator of radiosensitivity after ATM disruption. We generated primary DMG mouse models and performed deep profiling that revealed mechanisms of response to ATM disruption and RT that can be utilized as a therapeutic strategy.
Authors
- Spencer M. Maingi
- Simon G. Gregory (ORCID: https://orcid.org/0000-0002-7805-1743)
- María E. Guerra García
- Eita Uchida (ORCID: https://orcid.org/0000-0002-3056-5446)
- Samantha Gadd (ORCID: https://orcid.org/0000-0001-5033-8585)
- Laura D. Attardi (ORCID: https://orcid.org/0000-0003-1782-9045)
- Loren B. Weidenhammer (ORCID: https://orcid.org/0009-0000-9127-7272)
- Harrison Q. Liu
- Rintaro Hashizume (ORCID: https://orcid.org/0000-0002-9373-7831)
- Emily Hocke (ORCID: https://orcid.org/0000-0002-0976-5814)
- Zachary J. Reitman (ORCID: https://orcid.org/0000-0002-9122-9550)
- Connor E. Stewart (ORCID: https://orcid.org/0000-0003-1115-2272)
- Vaibhav Jain (ORCID: https://orcid.org/0000-0002-8505-9778)
- Karen Abramson
- Joshua A. Regal (ORCID: https://orcid.org/0000-0001-5142-0978)
- David M. Ashley (ORCID: https://orcid.org/0000-0002-4754-5900)
- Michael Aksu
- Nerissa T. Williams (ORCID: https://orcid.org/0000-0003-0554-9222)
- Katherine Deland (ORCID: https://orcid.org/0009-0008-0739-7529)
- David G. Kirsch (ORCID: https://orcid.org/0000-0002-2086-205X)
- Sophie R. Wu
- Kouki Abe
- Avani Mangoli (ORCID: https://orcid.org/0000-0002-1695-9983)
- Bronwen Foreman (ORCID: https://orcid.org/0000-0002-4663-3917)
- Tal Falick Michaeli (ORCID: https://orcid.org/0000-0002-7733-9438)
- Oren J. Becher (ORCID: https://orcid.org/0000-0003-4016-8492)
- Lixia Luo (ORCID: https://orcid.org/0000-0002-9806-4074)
- Megan M. Romero
- Vennesa Valentine
Institutions
- Duke University (US)
- University of Toronto (CA)
- Princess Margaret Cancer Centre (CA)
- University of Alabama at Birmingham (US)
- Mount Sinai Hospital (US)
- Texas Neurology (US)
- Duke University Hospital (US)
- Pediatric Brain Tumor Foundation (US)
- Stanford University (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1172/jci179395
- Citations
- 3
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 4.88
Funders
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Pediatric Brain Tumor Foundation
- St. Baldrick's Foundation
- ChadTough Foundation
- Strong
- National Cancer Institute
- Hyundai Hope On Wheels