Mutations inhibiting KDM4B drive ALT activation in ATRX-mutated glioblastomas.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33972520.
- Also identified by DOI 10.1038/s41467-021-22543-z and PMC identifier 8110556.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>G34R</sup> 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<sup>G34R</sup>) 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<sup>G34R</sup> or IDH1/2 mutations, acts in tandem with ATRX mutations to promote ALT in glioblastomas.
Medical subject headings
- Embryonic Stem Cells
- Glioblastoma
- Histones
- Jumonji Domain-Containing Histone Demethylases
- Telomere Homeostasis
- X-linked Nuclear Protein