ArticleEMBO molecular medicine2022
TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT.
Article in EMBO molecular medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 38 citations in OpenAlex.
- Twisting the End Game: How Telomere Chromatin Modifications Shape Telomere Maintenance.Aging cell · 2026Review
- SMARCAL1 is a candidate therapeutic target for ALT-positive tumors.Genes & development · 2026Article
- Murine osteosarcoma recapitulates the driver landscape and genomic complexity of osteosarcoma evolution in humans.bioRxiv : the preprint server for biology · 2026Article
- Telomeric DNA-Promyelocytic Leukemia (TEL-PML) Colocalization as an ALT Proxy in Relation to Metastatic Behavior in Osteosarcoma: A Retrospective Cohort Study.Current issues in molecular biology · 2026Article
- SMARCAL1 is a targetable synthetic lethal therapeutic vulnerability in ATRX-deficient gliomas that use alternative lengthening of telomeres.Neuro-oncology · 2026Article
- Functional analysis of telomere maintenance mechanisms is more informative than immunohistochemistry for ATRX mutation interpretation in Gliomas.Acta neuropathologica communications · 2025Article
- Leishmania mexicana telomeres at high resolution: Ku80, TERT, and alternative lengthening mechanisms.BMC genomics · 2025Article
- Alternative Lengthening of Telomeres: The Need forInternational journal of molecular sciences · 2025Article
- Loss of function ofiScience · 2025Article
- Locking the gates of immortality: targeting alternative lengthening of telomeres (ALT) pathways.Medical oncology (Northwood, London, England) · 2025Review
- The G-quadruplex experimental drug QN-302 impairs liposarcoma cell growth by inhibiting MDM2 expression and restoring p53 levels.Nucleic acids research · 2025Article
- The single-stranded DNA-binding factor SUB1/PC4 alleviates replication stress at telomeres and is a vulnerability of ALT cancer cells.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- TERRA and the alternative lengthening of telomeres: a dangerous affair.FEBS letters · 2025Review
- (B)On(e)-cohistones and the epigenetic alterations at the root of bone cancer.Cell death and differentiation · 2025Review
- Human PC4 supports telomere stability and viability in cells utilizing the alternative lengthening of telomeres mechanism.EMBO reports · 2024Article
- Endometrioid ovarian carcinoma landscape: pathological and molecular characterization.Molecular oncology · 2024Article
- Mechanisms of telomere maintenance and associated therapeutic vulnerabilities in malignant gliomas.Neuro-oncology · 2024Review
- Targeted PLK1 suppression through RNA interference mediated by high-fidelity Cas13d mitigates osteosarcoma progression via TGF-β/Smad3 signalling.Journal of cellular and molecular medicine · 2024Article
- Variation of Structure and Cellular Functions of Type IA Topoisomerases across the Tree of Life.Cells · 2024Review
- Mutant ATRX: pathogenesis of ATRX syndrome and cancer.Frontiers in molecular biosciences · 2024Review
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.