Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas

Brian Krug; Nicolas De Jay; Ashot S Harutyunyan; Shriya Deshmukh; Dylan M Marchione; Paul Guilhamon; Kelsey C Bertrand; Leonie G Mikael; Melissa K McConechy; Carol C L Chen; Sima Khazaei; Robert F Koncar; Sameer Agnihotri; Damien Faury; Benjamin Ellezam; Alexander G Weil; Josie Ursini-Siegel; Daniel D De Carvalho; Peter B Dirks; Peter W Lewis; Paolo Salomoni; Mathieu Lupien; Cheryl Arrowsmith; Paul F Lasko; Benjamin A Garcia; Claudia L Kleinman; Nada Jabado; Stephen C Mack

doi:10.1016/j.ccell.2019.04.004

Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas

Cancer Cell. 2019 May 13;35(5):782-797.e8. doi: 10.1016/j.ccell.2019.04.004.

Authors

Brian Krug¹, Nicolas De Jay², Ashot S Harutyunyan¹, Shriya Deshmukh¹, Dylan M Marchione³, Paul Guilhamon⁴, Kelsey C Bertrand⁵, Leonie G Mikael⁶, Melissa K McConechy¹, Carol C L Chen¹, Sima Khazaei¹, Robert F Koncar⁷, Sameer Agnihotri⁷, Damien Faury⁶, Benjamin Ellezam⁸, Alexander G Weil⁹, Josie Ursini-Siegel¹⁰, Daniel D De Carvalho¹¹, Peter B Dirks¹², Peter W Lewis¹³, Paolo Salomoni¹⁴, Mathieu Lupien⁴, Cheryl Arrowsmith¹⁵, Paul F Lasko¹⁶, Benjamin A Garcia³, Claudia L Kleinman¹⁷, Nada Jabado¹⁸, Stephen C Mack¹⁹

Affiliations

¹ Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
² Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
³ Department of Biochemistry and Biophysics, and Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
⁵ Department of Pediatrics, Division of Hematology and Oncology, Texas Children's Cancer and Hematology Centers, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Department of Pediatrics, McGill University, The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.
⁷ Department of Neurological Surgery, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.
⁸ Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC H3T 1C5, Canada.
⁹ Department of Pediatric Neurosurgery, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC H3T 1C5, Canada.
¹⁰ Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
¹¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
¹² Department of Surgery and Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹³ Department of Biomolecular Chemistry, School of Medicine and Public Health and Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA.
¹⁴ Nuclear Function in CNS Pathophysiology, German Center for Neurodegenerative Diseases, 53127 Bonn, Germany.
¹⁵ Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁶ Department of Biology, McGill University, Montreal, QC H3A 1B1, Canada.
¹⁷ Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada. Electronic address: claudia.kleinman@mcgill.ca.
¹⁸ Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Pediatrics, McGill University, The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada. Electronic address: nada.jabado@mcgill.ca.
¹⁹ Department of Pediatrics, Division of Hematology and Oncology, Texas Children's Cancer and Hematology Centers, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: scmack@bcm.edu.

Abstract

High-grade gliomas defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes. We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.

Keywords: H3K27M; H3K27ac; enhancer; epigenetic therapy; pediatric high-grade glioma; repetitive element; viral mimicry.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acetylation
Brain Neoplasms / drug therapy
Brain Neoplasms / genetics
Brain Neoplasms / metabolism*
Cell Line, Tumor
Chromatin / metabolism
Enhancer Elements, Genetic / drug effects
Epigenomics / methods
Gene Expression Regulation, Neoplastic / drug effects
Glioma / drug therapy
Glioma / genetics
Glioma / metabolism*
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylase Inhibitors / therapeutic use
Histones / genetics*
Histones / metabolism*
Humans
Mutation

Substances

Chromatin
Histone Deacetylase Inhibitors
Histones

Abstract

Publication types

MeSH terms

Substances

Grants and funding