Mutations inhibiting KDM4B drive ALT activation in ATRX-mutated glioblastomas

M Udugama; L Hii; A Garvie; M Cervini; B Vinod; F-L Chan; P P Das; J R Mann; P Collas; H P J Voon; L H Wong

doi:10.1038/s41467-021-22543-z

Mutations inhibiting KDM4B drive ALT activation in ATRX-mutated glioblastomas

Nat Commun. 2021 May 10;12(1):2584. doi: 10.1038/s41467-021-22543-z.

Authors

M Udugama^#¹, L Hii^#¹, A Garvie¹, M Cervini¹, B Vinod¹, F-L Chan¹, P P Das², J R Mann², P Collas^{3

4}, H P J Voon⁵, L H Wong⁶

Affiliations

¹ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
² Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
³ Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁴ Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway.
⁵ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. joanna.voon@monash.edu.
⁶ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. lee.wong@monash.edu.

^# Contributed equally.

Abstract

Alternative Lengthening of Telomeres (ALT) is a telomere maintenance pathway utilised in 15% of cancers. ALT cancers are strongly associated with inactivating mutations in ATRX; yet loss of ATRX alone is insufficient to trigger ALT, suggesting that additional cooperating factors are involved. We identify H3.3^G34R and IDH1/2 mutations as two such factors in ATRX-mutated glioblastomas. Both mutations are capable of inactivating histone demethylases, and we identify KDM4B as the key demethylase inactivated in ALT. Mouse embryonic stem cells inactivated for ATRX, TP53, TERT and KDM4B (KDM4B knockout or H3.3^G34R) show characteristic features of ALT. Conversely, KDM4B over-expression in ALT cancer cells abrogates ALT-associated features. In this work, we demonstrate that inactivation of KDM4B, through H3.3^G34R or IDH1/2 mutations, acts in tandem with ATRX mutations to promote ALT in glioblastomas.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Chromatin / genetics
Chromatin / metabolism
Chromatin Immunoprecipitation
Chromatin Immunoprecipitation Sequencing
DNA Replication / genetics
Embryonic Stem Cells / metabolism*
Gene Knockout Techniques
Glioblastoma / genetics*
Glioblastoma / metabolism
Histone Demethylases / genetics
Histone Demethylases / metabolism
Histones / genetics*
Histones / metabolism
Humans
In Situ Hybridization, Fluorescence
Isocitrate Dehydrogenase / genetics
Jumonji Domain-Containing Histone Demethylases / genetics
Jumonji Domain-Containing Histone Demethylases / metabolism*
Mice
Mutation
Signal Transduction / genetics
Telomerase / genetics
Telomerase / metabolism
Telomere Homeostasis / genetics*
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Up-Regulation
X-linked Nuclear Protein / genetics*

Substances

Chromatin
Histones
Trp53 protein, mouse
Tumor Suppressor Protein p53
Isocitrate Dehydrogenase
isocitrate dehydrogenase 2, mouse
Idh1 protein, mouse
Histone Demethylases
Jumonji Domain-Containing Histone Demethylases
KDM4B protein, human
Kdm4b protein, mouse
Telomerase
Tert protein, mouse
Atrx protein, mouse
X-linked Nuclear Protein

Grants and funding

21-0146/AICR_/Worldwide Cancer Research/United Kingdom