SMARCAL1 is a targetable synthetic lethal therapeutic vulnerability in ATRX-deficient gliomas that use alternative lengthening of telomeres

作者：Alexandrea Brown, Laura M. Strickland, Elise N. Erman, Christopher J. Pirozzi, Justin T Low, Bill H. Diplas, Emiley Gibson, Mariah Shobande, Taher Khambati, Marharyta Krylova, Heng Liu, Roger E. McLendon, Zachary J. Reitman, S. Keir, Lee Zou, David. M Ashley, Matthew S. Waitkus · 发表于：Neuro-Oncology · 年份：2026 · DOI：10.1093/neuonc/noaf300 · 被引用次数：4 · 研究领域：Telomeres, Telomerase, and Senescence、Genetics and Neurodevelopmental Disorders、Chromatin Remodeling and Cancer

BACKGROUND: Approximately 10% of cancers achieve replicative immortality through a telomerase-independent mechanism of telomere maintenance, termed Alternative Lengthening of Telomeres (ALT). ALT is particularly prevalent in certain subtypes of malignant gliomas, such as IDH-mutant astrocytoma and pediatric glioblastoma, and frequently co-occurs with ATRX (ATRX chromatin remodeler) inactivating mutations. Although ALT is an adaptive mechanism through which cancer cells achieve proliferative immortality, the elevated levels of replication stress observed in ALT tumors constitute a potential therapeutic vulnerability. METHODS: Leveraging CRISPR/Cas9 screening data from the Cancer Dependency Mapping Project, coupled with patient-derived cell lines and xenografts, we identified SMARCAL1 as a novel synthetic lethal vulnerability in ATRX-deficient glioma models that engage ALT. Using complementary molecular assays for DNA damage, telomere maintenance, and telomeric replication stress, we define the mechanisms underlying cytotoxicity induced by SMARCAL1 depletion in ALT-positive glioma cells. RESULTS: Our data demonstrate the annealing helicase SMARCAL1 is a highly specific synthetical lethal vulnerability in cancers that use ALT. SMARCAL1 localizes to ALT-associated PML (Promyelocytic leukemia protein) bodies in ALT-positive glioma cell lines, including IDH-mutant astrocytomas. SMARCAL1 depletion, via doxycycline-induced RNAi, led to a hyperactivation of the ALT phenotype, high lev...