H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models
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 ther...
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-11-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI154229 |
| _version_ | 1827768194239037440 |
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| author | Santiago Haase Kaushik Banerjee Anzar A. Mujeeb Carson S. Hartlage Fernando M. Núñez Felipe J. Núñez Mahmoud S. Alghamri Padma Kadiyala Stephen Carney Marcus N. Barissi Ayman W. Taher Emily K. Brumley Sarah Thompson Justin T. Dreyer Caitlin T. Alindogan Maria B. Garcia-Fabiani Andrea Comba Sriram Venneti Visweswaran Ravikumar Carl Koschmann Ángel M. Carcaboso Maria Vinci Arvind Rao Jennifer S. Yu Pedro R. Lowenstein Maria G. Castro |
| author_facet | Santiago Haase Kaushik Banerjee Anzar A. Mujeeb Carson S. Hartlage Fernando M. Núñez Felipe J. Núñez Mahmoud S. Alghamri Padma Kadiyala Stephen Carney Marcus N. Barissi Ayman W. Taher Emily K. Brumley Sarah Thompson Justin T. Dreyer Caitlin T. Alindogan Maria B. Garcia-Fabiani Andrea Comba Sriram Venneti Visweswaran Ravikumar Carl Koschmann Ángel M. Carcaboso Maria Vinci Arvind Rao Jennifer S. Yu Pedro R. Lowenstein Maria G. Castro |
| author_sort | Santiago Haase |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:09:52Z |
| format | Article |
| id | doaj.art-86291c23bf8d4ccda5764eae5949072f |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:52Z |
| publishDate | 2022-11-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-86291c23bf8d4ccda5764eae5949072f2023-11-07T16:19:36ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-11-0113222H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma modelsSantiago HaaseKaushik BanerjeeAnzar A. MujeebCarson S. HartlageFernando M. NúñezFelipe J. NúñezMahmoud S. AlghamriPadma KadiyalaStephen CarneyMarcus N. BarissiAyman W. TaherEmily K. BrumleySarah ThompsonJustin T. DreyerCaitlin T. AlindoganMaria B. Garcia-FabianiAndrea CombaSriram VennetiVisweswaran RavikumarCarl KoschmannÁngel M. CarcabosoMaria VinciArvind RaoJennifer S. YuPedro R. LowensteinMaria G. CastroPediatric 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.https://doi.org/10.1172/JCI154229OncologyTherapeutics |
| spellingShingle | Santiago Haase Kaushik Banerjee Anzar A. Mujeeb Carson S. Hartlage Fernando M. Núñez Felipe J. Núñez Mahmoud S. Alghamri Padma Kadiyala Stephen Carney Marcus N. Barissi Ayman W. Taher Emily K. Brumley Sarah Thompson Justin T. Dreyer Caitlin T. Alindogan Maria B. Garcia-Fabiani Andrea Comba Sriram Venneti Visweswaran Ravikumar Carl Koschmann Ángel M. Carcaboso Maria Vinci Arvind Rao Jennifer S. Yu Pedro R. Lowenstein Maria G. Castro H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models The Journal of Clinical Investigation Oncology Therapeutics |
| title | H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models |
| title_full | H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models |
| title_fullStr | H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models |
| title_full_unstemmed | H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models |
| title_short | H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models |
| title_sort | h3 3 g34 mutations impair dna repair and promote cgas sting mediated immune responses in pediatric high grade glioma models |
| topic | Oncology Therapeutics |
| url | https://doi.org/10.1172/JCI154229 |
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