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 Atrx. Furthermore, we found that loss of Atrx 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 in vivo.