Loss of function of Atrx leads to activation of alternative lengthening of telomeres in a primary mouse model of sarcoma.

The development of a telomere maintenance mechanism is essential for immortalization in human cancer. While most cancers elongate their telomeres by expression of telomerase, 10-15% of human cancers use a pathway known as alternative lengthening of telomeres (ALT). In this work, we developed a genetically engineered primary mouse model of sarcoma in CAST/EiJ mice which displays multiple molecular features of ALT activation after CRISPR/Cas9 introduction of oncogenic Kras ^G12D and loss of function mutations of Trp53 and Atrx . In this model, we demonstrate that the loss of Atrx contributes to the development of ALT in an autochthonous tumor, and this process occurs independently of telomerase function by variation of mTR alleles. Furthermore, we find that telomere shortening from the loss of telomerase leads to higher chromosomal instability while loss of Atrx and activation of ALT lead to an increase in telomeric instability, telomere sister chromatid exchange, c-circle production, and formation of ALT-associated promyelocytic leukemia bodies (APBs). The development of this primary mouse model of ALT could enable future investigations into therapeutic vulnerabilities of ALT activation and its mechanism of action.
Competing Interests: DGK is a cofounder of Xrad Therapeutics, which is developing radiosensitizers, and serves on the Scientific Advisory Board of Lumicell, which is commercializing intraoperative imaging technology. DGK is a coinventor on patents for radiosensitizers and an intraoperative imaging device. DGK also receives funding for a clinical trial from a Stand Up To Cancer (SU2C) Catalyst Research Grant with support from Merck. Amgen provided the mouse variant TVEC used in this study. The laboratory of DGK currently receives funding or reagents from Xrad Therapeutics, Merck, Bristol-Myers Squibb, Varian Medical Systems, and Calithera, but these did not support the research described in this manuscript.