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  • TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT.

TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT.

EMBO molecular medicine (2022-08-04)
Alexandre de Nonneville, Sébastien Salas, François Bertucci, Alexander P Sobinoff, José Adélaïde, Arnaud Guille, Pascal Finetti, Jane R Noble, Dimitri Churikov, Max Chaffanet, Elise Lavit, Hilda A Pickett, Corinne Bouvier, Daniel Birnbaum, Roger R Reddel, Vincent Géli
RESUMO

In some types of cancer, telomere length is maintained by the alternative lengthening of telomeres (ALT) mechanism. In many ALT cancers, the α-thalassemia/mental retardation syndrome X-linked (ATRX) gene is mutated leading to the conclusion that the ATRX complex represses ALT. Here, we report that most high-grade pediatric osteosarcomas maintain their telomeres by ALT, and that the majority of these ALT tumors are ATRX wild-type (wt) and instead carry an amplified 17p11.2 chromosomal region containing TOP3A. We found that TOP3A was overexpressed in the ALT-positive ATRX-wt tumors consistent with its amplification. We demonstrated the functional significance of these results by showing that TOP3A overexpression in ALT cancer cells countered ATRX-mediated ALT inhibition and that TOP3A knockdown disrupted the ALT phenotype in ATRX-wt cells. Moreover, we report that TOP3A is required for proper BLM localization and promotes ALT DNA synthesis in ALT cell lines. Collectively, our results identify TOP3A as a major ALT player and potential therapeutic target.

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Sigma-Aldrich
Anti-γ-Tubulin antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-DAXX antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Anti-ATRX antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody