端粒维护机制是恶性肿瘤细胞允许复制性不衰老的必需品。尽管大多数癌症是通过激活酶端粒酶来实现的，但少数癌症则使用名为另类端粒长度调节（ALT）的端粒酶独立机制。ALT是通过同源指导修复机制来进行的，并且通常与ATRX突变相关。我们以前表明，一部分具有ATRX表达ALT阳性肿瘤的成人GBM患者携带SMARCAL1基因丧失功能突变，该基因编码参与重复分叉重建和重复应激解决的退火解旋酶。然而，SMARCAL1缺乏、肿瘤发生和新生端粒合成之间的因果关系尚不清楚。 我们使用患者源性ALT阳性的GBM细胞系来调查SMARCAL1在ALT介导的新生端粒合成、重复应激和体内胶质瘤形成中的作用。SMARCAL1表达的诱导性复苏抑制了ALT指标并抑制了GBM和骨肉瘤细胞中的新生端粒合成，这表明SMARCAL1缺乏在本身缺乏SMARCAL1功能的癌症中扮演了ALT诱导的功能性角色。SMARCAL1缺乏的ALT阳性细胞在无法检测到端粒酶活性的情况下可以连续在体内传播，表明SMARCAL1缺乏的ALT表型以一种促进肿瘤生成的方式维持端粒。因此，SMARCAL1缺乏是ALT的许可因素，促进了胶质瘤生成。在ALT阳性细胞系中诱导复苏SMARCAL1可以动态调节ALT活性，这对未来旨在理解ALT机制并确定靶向ALT表型的新型抗癌治疗非常有价值。 ©作者（S）2023。由牛津大学出版社代表神经肿瘤学会出版。保留所有权利。有关许可，请发送电子邮件至：journals.permissions@oup.com。

Telomere maintenance mechanisms are required to enable the replicative immortality of malignant cells. While most cancers activate the enzyme telomerase, a subset of cancers use telomerase-independent mechanisms termed alternative lengthening of telomeres (ALT). ALT occurs via homology directed-repair mechanisms and is frequently associated with ATRX mutations. We previously showed that a subset of adult GBM patients with ATRX-expressing ALT-positive tumors harbored loss-of-function mutations in the SMARCAL1 gene, which encodes an annealing helicase involved in replication fork remodeling and the resolution of replication stress. However, the causative relationship between SMARCAL1 deficiency, tumorigenesis, and de novo telomere synthesis is not understood.We used a patient-derived ALT-positive GBM cell line with native SMARCAL1 deficiency to investigate the role of SMARCAL1 in ALT-mediated de novo telomere synthesis, replication stress, and gliomagenesis in vivo.Inducible rescue of SMARCAL1 expression suppresses ALT indicators and inhibits de novo telomere synthesis in GBM and osteosarcoma cells, suggesting that SMARCAL1 deficiency plays a functional role in ALT induction in cancers that natively lack SMARCAL1 function. SMARCAL1-deficient ALT-positive cells can be serially propagated in vivo in the absence of detectable telomerase activity, demonstrating that the SMARCAL1-deficient ALT phenotype maintains telomeres in a manner that promotes tumorigenesis.SMARCAL1 deficiency is permissive to ALT and promote gliomagenesis. Inducible rescue of SMARCAL1 in ALT-positive cell lines permits the dynamic modulation of ALT activity, which will be valuable for future studies aimed at understanding the mechanisms of ALT and identifying novel anti-cancer therapeutics that target the ALT phenotype.© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.