Abstract PR02: Integrated metabolic and epigenomic reprograming by H3K27M mutations in diffuse intrinsic pontine gliomas

Media type: E-Article

Title: Abstract PR02: Integrated metabolic and epigenomic reprograming by H3K27M mutations in diffuse intrinsic pontine gliomas

Contributor: Chung, Chan; Sweha, Stefan; Pratt, Drew; Tamrazi, Benita; Panwalkar, Pooja; Banda, Adam; Bayliss, Jill; Hawes, Debra; Yang, Fusheng; Lee, Ho-Joon; Shan, Mengrou; Cieslik, Marcin; Qin, Tingting; Werner, Christian; Wahl, Daniel; Lyssiotis, Costas; Yadav, Viveka Nand; Koschmann, Carl; Chinnaiyan, Arul; Blüml, Stefan; Judkins, Alexander; Venneti, Sriram

Published: American Association for Cancer Research (AACR), 2020

Language: English

DOI: 10.1158/1538-7445.epimetab20-pr02

ISSN: 0008-5472; 1538-7445

Keywords: Cancer Research ; Oncology

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Description: Abstract H3K27M-midline gliomas are fatal tumors that mainly harbor H3.3K27M mutations resulting in global H3K27me3 reduction that impacts neuroglial-differentiation. However, the exact mechanisms by which H3.3K27M mutations promote cancer are poorly understood. Metabolic reprogramming is a hallmark of cancer and we hypothesized that H3.3K27M mutations can reprogram metabolism to support uncontrolled growth. We demonstrate that H3.3K27M-mutant cells show elevated levels of critical enzymes related to glycolysis and TCA cycle metabolism including hexokinase-2, isocitrate dehydrogenase (IDH)-1 and glutamate dehydrogenase. H3.3K27M cells also demonstrated enhanced glycolysis, glutamine and TCA-cycle metabolism accompanied by increased alpha-ketoglutarate (α-KG) production. Mutant IDH (mIDH)1/2 converts α-KG to D-2-hydroxyglutarate (D-2HG). D-2HG increases H3K27me3 by inhibiting α-KG’s function to drive H3K27-demethylases. We discovered that H3.3K27M cells use α-KG in an opposing manner to maintain low H3K27me3. Inhibiting enzymes related to α-KG generation including hexokinase-2, glutamate-dehydrogenase and wild type-IDH1 increased global H3K27me3, altered chromatin accessibility at neuroglial-differentiation factors, lowered tumor cell proliferation, and increased overall survival in vivo in two independent H3.3K27M animal models (p&lt; 0.0001). H3K27M and mIDH1 were mutually exclusive in-patient tumor samples and D-2HG treatment or forced-mIDH1 expression in H3.3K27M cells increased global H3K27me3 and cell death. Finally, H3.3K27M and mIDH1 were synthetic lethal in vitro. Our data suggest that H3.3K27M and mIDH1 hijack a critical and conserved metabolic pathway in opposing manners to regulate global H3K27me3. These results have implications for understanding the pathogenesis of fatal H3K27M-gliomas and for developing therapeutic strategies by disruption of an integrated metabolic/epigenetic-axis. Citation Format: Chan Chung, Stefan Sweha, Drew Pratt, Benita Tamrazi, Pooja Panwalkar, Adam Banda, Jill Bayliss, Debra Hawes, Fusheng Yang, Ho-Joon Lee, Mengrou Shan, Marcin Cieslik, Tingting Qin, Christian Werner, Daniel Wahl, Costas Lyssiotis, Viveka Nand Yadav, Carl Koschmann, Arul Chinnaiyan, Stefan Blüml, Alexander Judkins, Sriram Venneti. Integrated metabolic and epigenomic reprograming by H3K27M mutations in diffuse intrinsic pontine gliomas [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PR02.

Access State: Open Access

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