Alternative Lengthening of Telomeres (ALT) is a telomere maintenance pathway utilized in 15% of cancers. ALT cancers are strongly associated with inactivating mutations in ATRX; yet ATRX knockout (KO) 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 which is inactivated in ALT. Mouse ES cells inactivated for ATRX, TP53, TERT and KDM4B (KDM4B KO or H3.3G34R) show characteristic features of ALT. Conversely, KDM4B over-expression in ALT cancer cells abrogates ALT-associated features. Our data demonstrate that inactivation of KDM4B, either through H3.3G34R or IDH1/2 mutations, acts in tandem with ATRX mutations to promote ALT in cancers.
Citation Format: Lee H. Wong, Maheshi Udugama, Linda Hii, Andrew Garvie, Matthew Garvie, Benjamin Vinod, Lyn Chan, Jeffrey Mann, Philippe Collas, Joanna Voon. Mutations inhibiting KDM4B drive ALT telomere maintenance pathway in ATRX-mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2065.