Idh mutation impairs histone demethylation and results in a block to cell differentiation

ABSTRACT Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic

property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate1,2,3,4,5,6. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for

lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression

profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone

methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation _in vitro_. Introduction of

either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated

with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone

repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased

H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during

adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation

and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells. Access through your institution Buy or subscribe This is a preview of

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ONCOGENIC DRIVERS DURING THE PROGRESSION OF IDH-MUTANT GLIOMAS Article 21 November 2024 LOSS OF MAT2A COMPROMISES METHIONINE METABOLISM AND REPRESENTS A VULNERABILITY IN H3K27M MUTANT GLIOMA

BY MODULATING THE EPIGENOME Article 14 April 2022 HDAC1 AND HDAC6 ARE ESSENTIAL FOR DRIVING GROWTH IN IDH1 MUTANT GLIOMA Article Open access 01 August 2023 ACCESSION CODES PRIMARY

ACCESSIONS ARRAYEXPRESS * E-MEXP-3239 DATA DEPOSITS Microarray data have been deposited with the ArrayExpress database under accession code E-MEXP-3239. Reprints and permissions information

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(1999) Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank members of the Thompson laboratory for technical help and critical reading of the manuscript. We thank T.

A. Gocke and the genomic core of University of Pennsylvania for their assistance with the microarray study; the molecular cytology core facility of Memorial Sloan-Kettering Cancer Center

(MSKCC) for technical help with the immunohistochemistry study; and O. Ouerfelli and M. K. Spassova at the organic synthesis core of MSKCC for the synthesis of octyl-2HG. This work was

supported by grants from the National Cancer Institute and National Institutes of Health. R.L.L. is an Early Career Award recipient of the Howard Hughes Medical Institute and the Geoffrey

Beene Junior Chair at MSKCC. D.M.O’R. is supported by the Betsy Cohen Fund of the Abramson Cancer Center at University of Pennsylvania. I.K.M. is supported by NCI-U54CA143798, the Doris Duke

Charitable Foundation, and an Advanced Clinical Research Award in Glioma from the American Society of Clinical Oncology. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Cancer Biology and

Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, 10065, New York, USA Chao Lu, Patrick S. Ward & Craig B. Thompson * Department of Cancer Biology, Perelman School of

Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA Chao Lu, Patrick S. Ward & Kathryn E. Wellen * Department of Neurosurgery, Perelman School of Medicine,

University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA Gurpreet S. Kapoor & Donald M. O’Rourke * Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer

Center, New York, 10065, New York, USA Dan Rohle, Sevin Turcan, Omar Abdel-Wahab, Timothy A. Chan, Ross L. Levine & Ingo K. Mellinghoff * Department of Pharmacology, Weill Cornell

Medical College, New York, 10065, New York, USA Dan Rohle & Ingo K. Mellinghoff * Department of Medicine, Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, 10065, New

York, USA Omar Abdel-Wahab & Ross L. Levine * Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania,

USA Christopher R. Edwards & Shelley L. Berger * Bioinformatics Core, Memorial Sloan-Kettering Cancer Center, New York, 10065, New York, USA Raya Khanin * Division of

Hematology/Oncology, Weill Cornell Medical College, New York, 10065, New York, USA Maria E. Figueroa & Ari Melnick * Department of Pathology & Laboratory Medicine, Perelman School of

Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA Donald M. O’Rourke * Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, 10065, New York,

USA Ingo K. Mellinghoff Authors * Chao Lu View author publications You can also search for this author inPubMed Google Scholar * Patrick S. Ward View author publications You can also search

for this author inPubMed Google Scholar * Gurpreet S. Kapoor View author publications You can also search for this author inPubMed Google Scholar * Dan Rohle View author publications You

can also search for this author inPubMed Google Scholar * Sevin Turcan View author publications You can also search for this author inPubMed Google Scholar * Omar Abdel-Wahab View author

publications You can also search for this author inPubMed Google Scholar * Christopher R. Edwards View author publications You can also search for this author inPubMed Google Scholar * Raya

Khanin View author publications You can also search for this author inPubMed Google Scholar * Maria E. Figueroa View author publications You can also search for this author inPubMed Google

Scholar * Ari Melnick View author publications You can also search for this author inPubMed Google Scholar * Kathryn E. Wellen View author publications You can also search for this author

inPubMed Google Scholar * Donald M. O’Rourke View author publications You can also search for this author inPubMed Google Scholar * Shelley L. Berger View author publications You can also

search for this author inPubMed Google Scholar * Timothy A. Chan View author publications You can also search for this author inPubMed Google Scholar * Ross L. Levine View author

publications You can also search for this author inPubMed Google Scholar * Ingo K. Mellinghoff View author publications You can also search for this author inPubMed Google Scholar * Craig B.

Thompson View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS C.L., P.S.W. and C.B.T. designed the study. C.L., P.S.W., G.S.K., D.R. and M.E.F.

performed research; S.T., D.R., T.A.C. and I.K.M. contributed research material; C.L., P.S.W., G.S.K., O.A.-W., C.R.E., R.K., M.E.F., A.M., K.E.W., D.M.O’R., S.L.B., R.L.L. and C.B.T.

contributed to data analysis and interpretation; C.L., P.S.W. and C.B.T. wrote the manuscript. CORRESPONDING AUTHOR Correspondence to Craig B. Thompson. ETHICS DECLARATIONS COMPETING

INTERESTS C.B.T. is a consultant of Agios Pharmaceuticals and has a financial interest in Agios. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This file contains a Supplementary

Discussion, Supplementary Figures 1-8 with legends and Supplementary Tables 1-2. (PDF 729 kb) POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR

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demethylation and results in a block to cell differentiation. _Nature_ 483, 474–478 (2012). https://doi.org/10.1038/nature10860 Download citation * Received: 03 June 2011 * Accepted: 16

January 2012 * Published: 15 February 2012 * Issue Date: 22 March 2012 * DOI: https://doi.org/10.1038/nature10860 SHARE THIS ARTICLE Anyone you share the following link with will be able to

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