Loss of function of Atrx recapitulates phenotypes 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 utilize a pathway known as alternative lengthening of telomeres (ALT). ALT is commonly associated with loss-of-function mutations in ATRX. Here, we developed a genetically engineered primary mouse model of sarcoma in CAST/EiJ mice to investigate the extent to which telomerase deficiency and Atrx-inactivation lead to ALT induction. We observed increases in multiple ALT-associated phenotypic indicators in tumors with loss of function mutations of <i>Atrx.</i> Furthermore, we found that loss of <i>Atrx</i> leads to an increase in telomeric instability and telomere sister chromatid exchange. However, Atrx-deficient tumors did not show productive telomere length maintenance in the absence of telomerase. This primary mouse model of sarcoma could facilitate future investigations into the molecular features of ALT <i>in vivo</i>.