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

Research output: Contribution to journalArticleResearchpeer-review

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 H3.3G34R 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 H3.3G34R) 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 H3.3G34R or IDH1/2 mutations, acts in tandem with ATRX mutations to promote ALT in glioblastomas.

Original languageEnglish
Article number2584
Number of pages11
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 10 May 2021

Cite this