Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome

  • Nat Cancer. 2022 May;3(5):629-648. doi: 10.1038/s43018-022-00348-3.
Brian J Golbourn  1  2 ,  Matthew E Halbert  1  2 ,  Katharine Halligan  1  3 ,  Srinidhi Varadharajan  4 ,  Brian Krug  5  6 ,  Nneka E Mbah  7 ,  Nisha Kabir  5  8 ,  Ann-Catherine J Stanton  1  2 ,  Abigail L Locke  1 ,  Stephanie M Casillo  1  2 ,  Yanhua Zhao  4 ,  Lauren M Sanders  9 ,  Allison Cheney  9  10 ,  Steven J Mullett  11 ,  Apeng Chen  1  2  12 ,  Michelle Wassell  1  2 ,  Anthony Andren  7 ,  Jennifer Perez  1  2 ,  Esther P Jane  1  2 ,  Daniel R David Premkumar  1  2 ,  Robert F Koncar  1  2 ,  Shideh Mirhadi  13 ,  Lauren H McCarl  1  2 ,  Yue-Fang Chang  1 ,  Yijen L Wu  14 ,  Taylor A Gatesman  1  2 ,  Andrea F Cruz  1  2 ,  Michal Zapotocky  15 ,  Baoli Hu  1  2 ,  Gary Kohanbash  1  2 ,  Xiuxing Wang  16 ,  Alenoush Vartanian  17 ,  Michael F Moran  13 ,  Frank Lieberman  18 ,  Nduka M Amankulor  1 ,  Stacy G Wendell  11 ,  Olena M Vaske  9  10 ,  Ashok Panigrahy  19 ,  James Felker  20 ,  Kelsey C Bertrand  21 ,  Claudia L Kleinman  5  8 ,  Jeremy N Rich  1 ,  Robert M Friedlander  1 ,  Alberto Broniscer  2  3 ,  Costas Lyssiotis  7 ,  Nada Jabado  5  6 ,  Ian F Pollack  1  2 ,  Stephen C Mack  22  23 ,  Sameer Agnihotri  24  25  26
Affiliations
  • 1. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 2. John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • 3. Pediatrics, Division of Hematology-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • 4. Baylor College of Medicine, Texas Children's Cancer and Hematology Centers, Dan L. Duncan Cancer Center, Houston, TX, USA.
  • 5. Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
  • 6. Department of Pediatrics, McGill University, The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
  • 7. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 8. Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, Canada.
  • 9. Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA, USA.
  • 10. University of California Santa Cruz Genomics Institute, Santa Cruz, CA, USA.
  • 11. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 12. State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, PR China.
  • 13. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 14. Department of Developmental Biology, University of Pittsburgh and Rangos Research Center Animal Imaging Core, Pittsburgh, PA, USA.
  • 15. Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
  • 16. Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
  • 17. Department of Pharmacy, UPMC Shadyside, Pittsburgh, PA, USA.
  • 18. Department of Neurology, Adult Neurooncology Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
  • 19. Department of Radiology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • 20. Pediatric Neuro-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • 21. Department of Pediatric Hematology and Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 22. Baylor College of Medicine, Texas Children's Cancer and Hematology Centers, Dan L. Duncan Cancer Center, Houston, TX, USA. [email protected].
  • 23. Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA. [email protected].
  • 24. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].
  • 25. John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 26. Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
Abstract

Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain Tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these Tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these Tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin MARK of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.

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