한빛사논문
Chan Chung1,6, Stefan R. Sweha1,2, Drew Pratt1,6, Benita Tamrazi3, Pooja Panwalkar1,6, Adam Banda1,6, Jill Bayliss1,6, Debra Hawes4, Fusheng Yang4, Ho-Joon Lee5, Mengrou Shan5, Marcin Cieslik6,7, Tingting Qin8, Christian K. Werner9, Daniel R. Wahl9, Costas A. Lyssiotis5, Zhiguo Bian10, J. Brad Shotwell10, Viveka Nand Yadav11, Carl Koschmann11, Arul M. Chinnaiyan6,7, Stefan Blüml3, Alexander R. Judkins4, Sriram Venneti1,6,11,12,*
1Laboratory 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
2Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
3Department of Radiology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA
4Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
5Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
6Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
7Michigan Center for Translational Pathology, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA
8Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
9Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
10Centralized Medicinal Chemistry, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA
11Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA
12Lead Contact
*Corresponding author
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.
KEYWORDS : histone mutation, DIPG, metabolism, epigenetics, H3K27me3, glycolysis, glutaminolysis, α-KG, IDH mutation, D-2HG, histone methylation
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