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Updated: Jul 12, 2025

Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration
08:41

Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration

Published on: December 27, 2024

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Ataxia-telangiectasia mutated ( Atm ) disruption sensitizes spatially-directed H3.3K27M/TP53 diffuse midline gliomas

Avani Mangoli, Sophie Wu, Harrison Q Liu

    Biorxiv : the Preprint Server for Biology
    |October 31, 2023
    PubMed

    Insights

    Targeting the ATM kinase enhances radiation therapy for diffuse midline gliomas (DMGs) with p53 mutations. This approach shows promise for treating these lethal brain tumors, particularly those with specific genetic alterations.

    Area of Science:

    • Neuro-oncology
    • Cancer Genetics
    • Radiation Oncology

    Background:

    • Diffuse midline gliomas (DMGs) are aggressive pediatric brain tumors.
    • Key mutations include p53 inactivation and H3K27M oncohistone variants.
    • These mutations alter cellular responses to DNA damage, offering therapeutic targets.

    Purpose of the Study:

    • To develop and utilize a genetically accurate mouse model of DMGs.
    • To investigate the role of ATM kinase in DMG radiosensitivity.
    • To identify mechanisms of radiation resistance in p53-mutant DMGs.

    Main Methods:

    • RCAS/tv-a retroviral system and Cre recombinase for targeted gene modification in mice.
    • Generation of primary murine DMG models with specific p53 and H3K27M mutations.
    • Pharmacologic and genetic inhibition of ATM kinase.
    • Spatial in situ transcriptomics for molecular profiling.

    Main Results:

    • Disruption of ATM kinase significantly enhanced the efficacy of focal brain irradiation in p53-mutant DMGs.
    • Survival was extended in mice treated with combined ATM inhibition and radiation.
    • Transactivation-independent p53 activity was identified as a mediator of radiosensitivity.

    Conclusions:

    • Targeting ATM kinase is a promising strategy to enhance radiation therapy for p53-mutant DMGs.
    • This approach may not be effective for p53-wildtype DMGs.
    • The developed mouse models provide a valuable platform for studying DMG resistance mechanisms and therapeutic strategies.

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