2. Academic Validation
  3. Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome

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

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. stephen.mack@stjude.org.
  • 23 Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA. stephen.mack@stjude.org.
  • 24 Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. sameer.agnihotri@pitt.edu.
  • 25 John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. sameer.agnihotri@pitt.edu.
  • 26 Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA. sameer.agnihotri@pitt.edu.
PMID: 35422502 DOI: 10.1038/s43018-022-00348-3
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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