Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies

Hsiao P J Voon; Linda Hii; Andrew Garvie; Maheshi Udugama; Brian Krug; Caterina Russo; Anderly C Chüeh; Roger J Daly; Alison Morey; Toby D M Bell; Stephen J Turner; Joseph Rosenbluh; Paul Daniel; Ron Firestein; Jeffrey R Mann; Philippe Collas; Nada Jabado; Lee H Wong

doi:10.1186/s13059-023-03122-5

Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies

Genome Biol. 2023 Dec 8;24(1):284. doi: 10.1186/s13059-023-03122-5.

Authors

Hsiao P J Voon¹, Linda Hii¹, Andrew Garvie¹, Maheshi Udugama¹, Brian Krug², Caterina Russo², Anderly C Chüeh¹, Roger J Daly¹, Alison Morey³, Toby D M Bell⁴, Stephen J Turner³, Joseph Rosenbluh¹, Paul Daniel^{5

6}, Ron Firestein^{5

6}, Jeffrey R Mann⁷, Philippe Collas^{8

9}, Nada Jabado^{2

10

11}, Lee H Wong¹²

Affiliations

¹ Cancer Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
² Department of Human Genetics, McGill University, Montreal, QC, Canada.
³ Department of Microbiology, Monash University, Clayton, VIC, Australia.
⁴ School of Chemistry, Monash University, Clayton, VIC, Australia.
⁵ Hudson Institute of Medical Research, Clayton, VIC, Australia.
⁶ Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
⁷ Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
⁸ Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0317, Oslo, Norway.
⁹ Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424, Oslo, Norway.
¹⁰ Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
¹¹ Department of Paediatrics, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
¹² Cancer Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia. lee.wong@monash.edu.

Abstract

Background: Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia.

Results: We find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2-which are common events in adult gliomas and myeloid leukemias-also disrupt the formation of PML bodies.

Conclusions: We identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.

Keywords: Arsenic trioxide; Histone variant H3.3; PML bodies; Pediatric glioma.

MeSH terms

Adult
Brain Neoplasms* / genetics
Child
Glioma* / genetics
Histones* / genetics
Humans
Mutation
Promyelocytic Leukemia Nuclear Bodies / genetics
Promyelocytic Leukemia Nuclear Bodies / pathology

Substances

Histones
H3-3A protein, human
H3f3a protein, mouse