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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