TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT
Alexandre de Nonneville,Sébastien Salas,François Bertucci,Alexander P. Sobinoff,José Adélaïde,Arnaud Guille,Pascal Finetti,Jane R. Noble,D. G. Churikov,Max Chaffanet,Elise Lavit,Hilda A. Pickett,Corinne Bouvier,Daniel Birnbaum,Roger R. Reddel,Vincent Géli +15 more
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TLDR
It is reported that most high‐grade pediatric osteosarcomas maintain their telomere length 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.Abstract:
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.read more
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TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT
Alexandre de Nonneville,Sébastien Salas,François Bertucci,Alexander P. Sobinoff,José Adélaïde,Arnaud Guille,Pascal Finetti,Jane R. Noble,D. G. Churikov,Max Chaffanet,Elise Lavit,Hilda A. Pickett,Corinne Bouvier,Daniel Birnbaum,Roger R. Reddel,Vincent Géli +15 more
TL;DR: It is reported that most high‐grade pediatric osteosarcomas maintain their telomere length 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.
Journal ArticleDOI
Cancer-associated<i>SMARCAL1</i>loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells
TL;DR: The role of SMARCAL1 in ALT-dependent de novo telomere synthesis, replication stress, and gliomagenesis in GBM and osteosarcoma cells was investigated in this paper .
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ATRX, a guardian of chromatin.
TL;DR: This article provided an overview of ATRX interactions and molecular functions and discussed the consequences of its impairment, including alternative lengthening of telomeres and therapeutic vulnerabilities that may be exploited in cancer cells.
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Self-Renewal and Pluripotency in Osteosarcoma Stem Cells’ Chemoresistance: Notch, Hedgehog, and Wnt/β-Catenin Interplay with Embryonic Markers
TL;DR: In this article , the role of Notch, Hedgehog, and Wnt/β-Catenin signaling in osteosarcoma self-renewal, pluripotency, and chemoresistance, and their potential as targets for anti-cancer therapies.
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GENIUS: GEnome traNsformatIon and spatial representation of mUltiomicS data
TL;DR: GenIUS as discussed by the authors is a framework for integrating multi-omics data using deep learning models developed for advanced image analysis, which is able to transform multomics data into images with genes displayed as spatially connected pixels.
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