K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas

Selin Jessa; Abdulshakour Mohammadnia; Ashot S Harutyunyan; Maud Hulswit; Srinidhi Varadharajan; Hussein Lakkis; Nisha Kabir; Zahedeh Bashardanesh; Steven Hébert; Damien Faury; Maria C Vladoiu; Samantha Worme; Marie Coutelier; Brian Krug; Augusto Faria Andrade; Manav Pathania; Andrea Bajic; Alexander G Weil; Benjamin Ellezam; Jeffrey Atkinson; Roy W R Dudley; Jean-Pierre Farmer; Sebastien Perreault; Benjamin A Garcia; Valérie Larouche; Mathieu Blanchette; Livia Garzia; Aparna Bhaduri; Keith L Ligon; Pratiti Bandopadhayay; Michael D Taylor; Stephen C Mack; Nada Jabado; Claudia L Kleinman

doi:10.1038/s41588-022-01205-w

K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas

Nat Genet. 2022 Dec;54(12):1865-1880. doi: 10.1038/s41588-022-01205-w. Epub 2022 Dec 5.

Authors

Selin Jessa^#^{1

2}, Abdulshakour Mohammadnia^#³, Ashot S Harutyunyan^#⁴, Maud Hulswit³, Srinidhi Varadharajan⁵, Hussein Lakkis^{2

3}, Nisha Kabir³, Zahedeh Bashardanesh², Steven Hébert^{2

3}, Damien Faury⁴, Maria C Vladoiu^{6

7

8}, Samantha Worme^{2

9}, Marie Coutelier^{2

3}, Brian Krug³, Augusto Faria Andrade³, Manav Pathania^{10

11}, Andrea Bajic³, Alexander G Weil¹², Benjamin Ellezam¹³, Jeffrey Atkinson¹⁴, Roy W R Dudley¹⁴, Jean-Pierre Farmer¹⁴, Sebastien Perreault¹⁵, Benjamin A Garcia^{16

17}, Valérie Larouche¹⁸, Mathieu Blanchette¹⁹, Livia Garzia^{20

21}, Aparna Bhaduri²², Keith L Ligon^{23

24

25}, Pratiti Bandopadhayay^{25

26

27}, Michael D Taylor^{7

8}, Stephen C Mack²⁸, Nada Jabado^{29

30

31}, Claudia L Kleinman^{32

33}

Affiliations

¹ Quantitative Life Sciences, McGill University, Montreal, Quebec, Canada.
² Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
³ Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
⁴ Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
⁵ Brain Tumour Program, Children's Cancer Centre and Department of Paediatrics, Baylor College of Medicine, Houston, TX, USA.
⁶ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
⁷ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁸ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁹ Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada.
¹⁰ Department of Oncology and The Milner Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.
¹¹ CRUK Children's Brain Tumour Centre of Excellence, University of Cambridge, Cambridge, UK.
¹² Department of Pediatric Neurosurgery, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Quebec, Canada.
¹³ Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Quebec, Canada.
¹⁴ Department of Pediatric Surgery, Division of Neurosurgery, Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada.
¹⁵ Division of Child Neurology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec, Canada.
¹⁶ Department of Biochemistry and Biophysics and Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
¹⁸ Department of Pediatrics, Centre mère-enfant Soleil du CHU de Québec-Université Laval, Quebec, Quebec City, Canada.
¹⁹ School of Computer Science, McGill University, Montreal, Quebec, Canada.
²⁰ Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
²¹ Division of Orthopedic Surgery, Faculty of Surgery, McGill University, Montreal, Quebec, Canada.
²² Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
²³ Department of Pathology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁴ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
²⁵ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
²⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
²⁷ Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
²⁸ Department of Developmental Neurobiology, Neural Brain Tumor Program, St Jude Children's Research Hospital, Memphis, TN, USA.
²⁹ Department of Human Genetics, McGill University, Montreal, Quebec, Canada. nada.jabado@mcgill.ca.
³⁰ Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. nada.jabado@mcgill.ca.
³¹ Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada. nada.jabado@mcgill.ca.
³² Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada. claudia.kleinman@mcgill.ca.
³³ Department of Human Genetics, McGill University, Montreal, Quebec, Canada. claudia.kleinman@mcgill.ca.

^# Contributed equally.

Abstract

Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations and molecular profiles. The contribution of the cell of origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte precursor cells (OPCs). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1⁺/SHH-dependent brainstem OPCs, whereas H3.3K27M gliomas frequently resemble dorsal PAX3⁺/BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, whereas other epigenetic changes are mainly contingent on the cell of origin chromatin state and cycling rate.

Publication types

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

MeSH terms

Brain
Cell Lineage / genetics
Chromatin*
Epigenomics*

Substances

Chromatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding