ArticleThe Journal of clinical investigation2022
H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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58 citing papers in PubMed, 83 citations in OpenAlex.
- Pamiparib as consolidation treatment after concurrent chemoradiotherapy of limited-stage small cell lung cancer: a single-arm, open-label phase 2 trial.Radiation oncology (London, England) · 2024Trial
- Review
- cGAS-STING pathway modulation: A new hope for neural regeneration.Neural regeneration research · 2026Article
- Potent anti-tumor preclinical efficacy of B7-H3 CAR-T cells in H3G34-mutant, Diffuse Hemispheric Glioma.Neuro-oncology · 2026Article
- Integrated high-resolution copy number and histomolecular analysis of diffuse hemispheric glioma, H3 G34-mutant reveals universal TP53 abnormalities.Brain pathology (Zurich, Switzerland) · 2026Article
- Male germ cell-specific deletion ofZoological research · 2026Article
- "Targeting NF-κB epigenetic activation and DNA repair deficiency in G34-mutant pediatric diffuse hemispheric glioma with nanoparticles combining PARP inhibition and immune stimulation mediated by CpG dinucleotides".bioRxiv : the preprint server for biology · 2026Article
- G34R cancer mutation alters the conformational ensemble and dynamics of the histone H3.3 tails.Nucleic acids research · 2026Article
- STING signaling pathway: An oasis in the glioblastoma immune desert.Theranostics · 2026Review
- Case Report: Identification of rareFrontiers in oncology · 2026Article
- Overcoming immunotherapy barriers in pediatric brain tumors: epigenetic strategies.Frontiers in oncology · 2026Review
- Illuminating radiogenomic signatures in pediatric-type diffuse gliomas: insights into molecular, clinical, and imaging correlations. Part I: high-grade group.La Radiologia medica · 2025Review
- H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition.Neuro-oncology · 2025Article
- Novel Strategies for Improved Treatment of O6-Methylguanine-DNA Methyltransferase Promoter-Methylated Glioma.Medical research archives · 2025Article
- A review of diffuse hemispheric glioma, H3 G34-mutant disease development, DNA repair, microenvironment, and treatments on the horizon.NPJ precision oncology · 2025Review
- Review
- Current Landscape of Preclinical Models for Pediatric Gliomas: Clinical Implications and Future Directions.Cancers · 2025Review
- Outcomes From a Contemporary Mono-Institutional Cohort of Histone-Mutant Diffuse Hemispheric Glioma: A Rare and Aggressive Pediatric-Type High-Grade Primary Brain Tumor.Brain tumor research and treatment · 2025Article
- Review
- The STING Signaling: A Novel Target for Central Nervous System Diseases.Cellular and molecular neurobiology · 2025Review
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26 authors at 5 institutions in 2 countries.
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Abstract
Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation led to the downregulation of DNA repair pathways. This resulted in enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG led to the accumulation of extrachromosomal DNA, which activated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG-bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier-permeable PARP inhibitor pamiparib and the cell-cycle checkpoint CHK1/2 inhibitor AZD7762), and these combinations resulted in long-term survival for approximately 50% of the mice. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induced immune-mediated therapeutic efficacy in G34-mutant pHGG.
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