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.

替代端粒延长 (ALT) 是一种端粒维持途径，用于 15% 的癌症。ALT 癌症与ATRX中的失活突变密切相关；然而，仅丢失 ATRX 不足以触发 ALT，这表明还涉及其他合作因素。我们将 H3.3 ^G34R和 IDH1/2 突变确定为 ATRX 突变胶质母细胞瘤中的两个此类因素。这两种突变都能使组蛋白去甲基化酶失活，我们将 KDM4B 鉴定为 ALT 中失活的关键去甲基化酶。针对 ATRX、TP53、TERT 和 KDM4B（KDM4B 敲除或 H3.3 ^{G34R ）灭活的小鼠胚胎干细胞}) 显示 ALT 的特征。相反，ALT 癌细胞中的 KDM4B 过表达会消除 ALT 相关特征。在这项工作中，我们证明了通过 H3.3 ^G34R或 IDH1/2 突变使 KDM4B 失活与 ATRX 突变协同作用以促进胶质母细胞瘤中的 ALT。