CRISPR-based interrogation of alternative lengthening of telomeres: mapping dependencies, stress-buffering pathways, and therapeutic vulnerabilities.

Authors

Ruth Lannoo, Oliver Bechter, Dirk Daelemans

Published in

Cancer letters. Pages 218888. Oct 15, 2026. Epub Oct 15, 2026.

Abstract

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that supports the growth of approximately 5-10% of human tumors and represents an attractive but insufficiently explored therapeutic target. CRISPR-based functional genomics has emerged as a powerful approach to systematically interrogate ALT biology and identify genetic dependencies associated with the ALT state. In this Review, we discuss the CRISPR-based strategies applied to ALT, including hypothesis-driven targeted loss-of-function screens, phenotype-driven optical screens, in silico mining of large-scale dependency datasets, and genome-wide screens in ALT-adjacent states. Across these approaches, recurrent dependencies converge on pathways mediating replication stress buffering, DNA repair, and telomere maintenance, including FANCM, SMARCAL1, and SUB1. Collectively, these findings support a model in which ALT-positive cells rely not on a unique ALT-specific factor, but rather on stress-buffering mechanisms that prevent chronic telomeric dysfunction from triggering replication catastrophe and cell death, highlighting these pathways as promising candidates for further therapeutic investigation.

PMID:
42880484
Bibliographic data and abstract were imported from PubMed on 16 Oct 2026.

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