Alternative lengthening of telomeres: induction, maintenance and vulnerabilities

To maintain unlimited proliferative capacity, cancer cells must maintain their telomeres. ~85% of cancers achieve this by up-regulating telomerase, while the remaining ~15% of cancers employ the Alternative Lengthening of telomeres (ALT) pathway. Currently, there are no targeted treatments for ALT cancers, which have a poor prognosis and are universally aggressive. Insights into the mechanisms that promote/are essential for the ALT process may reveal vulnerabilities that could be exploited therapeutically. However, the lack of a cellular model that permits the induction of ALT has severely limited our ability to interrogate the underlying mechanisms. We have recently made a key discovery that Kaposi’s Sarcoma Herpes Virus (KSHV) infection triggers the stable acquisition of ALT. In this application, we will exploit KSHV to identify the host and virally encoded factors that are critical for ALT induction. Using PICh to interrogate the proteomic composition of telomeres, we have identified 703 proteins that are specifically enriched at ALT telomeres. We will perform a “703 ALT” CRISPR dropout screens to identify genes that modulate/are essential in ALT cancer cells but are dispensable in normal cells. Our proposal will expand our understanding of the ALT process and may identify critical vulnerabilities, which could be targeted therapeutically.