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Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas.
Chung, Chan; Sweha, Stefan R; 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 K; Wahl, Daniel R; Lyssiotis, Costas A; Bian, Zhiguo; Shotwell, J Brad; Yadav, Viveka Nand; Koschmann, Carl; Chinnaiyan, Arul M; Blüml, Stefan; Judkins, Alexander R; Venneti, Sriram.
Afiliação
  • Chung C; 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 Schoo
  • Sweha SR; 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; Neuroscience Graduate Program, University of Michigan Medical
  • Pratt D; 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 Schoo
  • Tamrazi B; Department of Radiology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
  • Panwalkar P; 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 Schoo
  • Banda A; 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 Schoo
  • Bayliss J; 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 Schoo
  • Hawes D; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • Yang F; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • Lee HJ; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Shan M; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Cieslik M; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • Qin T; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Werner CK; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Wahl DR; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Lyssiotis CA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Bian Z; Centralized Medicinal Chemistry, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Shotwell JB; Centralized Medicinal Chemistry, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • Yadav VN; Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Koschmann C; Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Chinnaiyan AM; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • Blüml S; Department of Radiology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
  • Judkins AR; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • Venneti S; 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 Schoo
Cancer Cell ; 38(3): 334-349.e9, 2020 09 14.
Article em En | MEDLINE | ID: mdl-32795401
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Histonas / Neoplasias do Tronco Encefálico / Epigenômica / Glioma Pontino Intrínseco Difuso / Mutação Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Histonas / Neoplasias do Tronco Encefálico / Epigenômica / Glioma Pontino Intrínseco Difuso / Mutação Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article