Evidence map›Paper›PMID 32795401›Full record

ArticleCancer cell2020

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

Chan Chung, Stefan R Sweha, Drew Pratt, Benita Tamrazi, Pooja Panwalkar, Adam Banda, Jill Bayliss, Debra Hawes, Fusheng Yang, Ho-Joon Lee and 14 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer cell, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 109 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
109citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

109 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer.Frontiers in cell and developmental biology · 2021
    Pooled it
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  13. Brain tumor research and treatment · 2026
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49 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

24 authors.

Chan ChungLaboratory 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.
Stefan R SwehaLaboratory 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 School, Ann Arbor, MI 48109, USA.
Drew PrattLaboratory 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.
Benita TamraziDepartment of Radiology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
Pooja PanwalkarLaboratory 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.
Adam BandaLaboratory 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.
Jill BaylissLaboratory 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.
Debra HawesDepartment of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Fusheng YangDepartment of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Ho-Joon LeeDepartment of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Mengrou ShanDepartment of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Marcin CieslikDepartment 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.
Tingting QinDepartment of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Christian K WernerDepartment of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Daniel R WahlDepartment of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Costas A LyssiotisDepartment of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Zhiguo BianCentralized Medicinal Chemistry, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
J Brad ShotwellCentralized Medicinal Chemistry, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Viveka Nand YadavDepartment of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Carl KoschmannDepartment of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Arul M ChinnaiyanDepartment 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.
Stefan BlümlDepartment of Radiology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
Alexander R JudkinsDepartment of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Sriram VennetiLaboratory 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: svenneti@med.umich.edu.

Funding

Unravelling metabolic dependencies in H3K27M mutant DIPGR01NS110572 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Sriram Venneti · 2019 to 2026
$2.7M
De Novo Nucleotide Synthesis as a Mediator of Radiation Resistance and a Therapeutic Target in GlioblastomaK08CA234416 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI WAHL, DANIEL R · 2019 to 2023
$1.1M
Targeting ATRX-Deficient Pediatric GBMK08NS099427 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KOSCHMANN, CARL J · 2017 to 2021
$811k
NCI NIH HHS K08 CA234416NINDS NIH HHS K08 NS099427NINDS NIH HHS R01 NS110572
6 · The paper itself

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.

Indexed as

MutationAnimalsBrain Stem NeoplasmsCell Line, TumorDiffuse Intrinsic Pontine GliomaEpigenomicsGene Expression Regulation, NeoplasticGlycolysisHistonesHumansLysineMethylationMice, Inbred NODMice, KnockoutMice, NudeMice, SCIDHistonesLysineD-2HGDIPGepigeneticsglutaminolysisglycolysisH3K27me3histone methylationhistone mutationIDH mutationmetabolismα-KG

Identifiers

PMID32795401
PMCPMC7494613

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.