Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas.

Cancer Cell

Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Michigan Medicine, University of Michigan, 3520E MSRB 1, 1150 West Medical Center Drive, Ann Arbor, MI 48109-41804, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address:

Published: September 2020

AI Article Synopsis

  • * Research indicates that these mutated cells undergo enhanced metabolic processes like glycolysis and glutaminolysis, leading to increased production of alpha-ketoglutarate (α-KG), which helps sustain the low H3K27me3 levels.
  • * Disrupting the metabolic pathways that maintain this epigenetic state shows promising results in improving survival in animal models, highlighting potential new therapeutic strategies for treating H3K27M DIPGs.

Article Abstract

H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. They mainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysis in H3.3K27M cells, tumors, and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and tricarboxylic acid cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/or glutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition of key enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatin accessibility, and prolonged survival in animal models. Previous studies have shown that mutant isocitrate-dehydrogenase (mIDH)1/2 glioma cells convert α-KG to D-2-hydroxyglutarate (D-2HG) to increase H3K27me3. Here, we show that H3K27M and IDH1 mutations are mutually exclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27M and mIDH1 hijack a conserved and critical metabolic pathway in opposing ways to maintain their preferred epigenetic state. Consequently, interruption of this metabolic/epigenetic pathway showed potent efficacy in preclinical models, suggesting key therapeutic targets for much needed treatments.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494613PMC
http://dx.doi.org/10.1016/j.ccell.2020.07.008DOI Listing

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