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Article Dans Une Revue EMBO Molecular Medicine Année : 2022

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

Sébastien Salas
Hilda A Pickett
Roger R Reddel

Résumé

In some types of cancer, telomere length is maintained by the alternative lengthening of telomeres (ALT) mechanism. In many ALT cancers, the a-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 ALTpositive 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 ATRXmediated 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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hal-03877721 , version 1 (29-11-2022)

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Alexandre de Nonneville, Sébastien Salas, François Bertucci, Alexander P Sobinoff, José Adélaïde, et al.. TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT. EMBO Molecular Medicine, 2022, 14, ⟨10.15252/emmm.202215859⟩. ⟨hal-03877721⟩

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