Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-22543-z
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Funding
- Worldwide Cancer Research
- Brain Tumour Charity
- Cure Brain Cancer Foundation Australia
- American Brain Tumor Association
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The study reveals the functional role of histone demethylases KDM4B in regulating ALT activation, and identifies H3.3(G34R) and IDH1/2 mutations as cooperating factors with ATRX mutations to promote ALT in glioblastomas.
Alternative Lengthening of Telomeres (ALT) is a telomere maintenance pathway utilised in 15% of cancers that have been associated with mutations in ATRX. Here the authors reveal a functional role of histone demethylases KDM4B in regulating ALT activation. 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.
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