Alternative Lengthening of Telomeres: The Need for ATRX Mutations Is Lineage-Dependent

During carcinogenesis, cells must acquire a telomere maintenance mechanism in order to avoid telomere shortening-induced replicative senescence. While most tumors activate telomerase, a minority of them employ a recombinational mechanism called Alternative Lengthening of Telomeres (ALT). One of the most investigated features is the association between ALT and ATRX mutations, since this has been shown to be the gene with the highest rate of mutations among ALT tumors. However, most of these studies, and in particular, mechanistic studies in vitro, have been carried out on mesenchymal tumors (sarcomas). In the present study, using genomic and expression data from the DepMap portal, we identified several non-mesenchymal ALT cell lines, and we compared the incidence of ATRX and other gene mutations between ALT cell lines of different origins (mesenchymal, neural, epithelial, hematopoietic). We confirmed that ATRX is frequently mutated in mesenchymal and neural ALT cell lines but not in epithelial ones. Our results showed that mutations of ATRX or other proteins involved in the maintenance of telomere integrity are needed for ALT activation in all cell types, and ATRX is preferentially mutated in mesenchymal ALT cells. Besides a more precise interpretation of the role of ATRX loss in ALT establishment, we proposed a model in which mutation of this gene impairs differentiation in mesenchymal and neural cells (but not in epithelial ones). Therefore, we explained the high incidence of ATRX mutations in mesenchymal and neural tumors with the fact that they both trigger ALT and impair differentiation, thus promoting two steps at once in the process of carcinogenesis.