TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT
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 repo...
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-08-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202215859 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Alexandre de Nonneville |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-948680b27447452fa822018d83b4b8e5 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-948680b27447452fa822018d83b4b8e52025-08-20T04:03:02ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-08-01141012210.15252/emmm.202215859TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALTAlexandre de Nonneville0Sébastien Salas1François Bertucci2Alexander P Sobinoff3José Adélaïde4Arnaud Guille5Pascal Finetti6Jane R Noble7Dimitri Churikov8Max Chaffanet9Elise Lavit10Hilda A Pickett11Corinne Bouvier12Daniel Birnbaum13Roger R Reddel14Vincent Géli15Marseille Cancer Research Centre (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli‐Calmettes, Team « Telomere and Chromatin ». Equipe labellisée Ligue Nationale Contre Le Cancer, Aix‐Marseille UnivDepartment of Medical Oncology, Assistance Publique Hôpitaux de Marseille ‐ Timone HospitalPredictive Oncology Laboratory, Marseille Cancer Research Centre (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli‐Calmettes, Aix‐Marseille UniversityTelomere Length Regulation Unit, Faculty of Medicine and Health, Children's Medical Research Institute, University of SydneyPredictive Oncology Laboratory, Marseille Cancer Research Centre (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli‐Calmettes, Aix‐Marseille UniversityPredictive Oncology Laboratory, Marseille Cancer Research Centre (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli‐Calmettes, Aix‐Marseille UniversityPredictive Oncology Laboratory, Marseille Cancer Research Centre (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli‐Calmettes, Aix‐Marseille UniversityCancer Research Unit, Faculty of Medicine and Health, Children's Medical Research Institute, University of SydneyMarseille Cancer Research Centre (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli‐Calmettes, Team « Telomere and Chromatin ». Equipe labellisée Ligue Nationale Contre Le Cancer, Aix‐Marseille UnivPredictive Oncology Laboratory, Marseille Cancer Research Centre (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli‐Calmettes, Aix‐Marseille UniversityDepartment of Medical Oncology, Assistance Publique Hôpitaux de Marseille ‐ Timone HospitalTelomere Length Regulation Unit, Faculty of Medicine and Health, Children's Medical Research Institute, University of SydneyDepartment of Pathology, Assistance Publique Hôpitaux de Marseille ‐ Timone HospitalPredictive Oncology Laboratory, Marseille Cancer Research Centre (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli‐Calmettes, Aix‐Marseille UniversityCancer Research Unit, Faculty of Medicine and Health, Children's Medical Research Institute, University of SydneyMarseille Cancer Research Centre (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli‐Calmettes, Team « Telomere and Chromatin ». Equipe labellisée Ligue Nationale Contre Le Cancer, Aix‐Marseille UnivAbstract 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.https://doi.org/10.15252/emmm.202215859alternative lengthening of telomeresATRXosteosarcomastelomeresTOP3A |
| spellingShingle | 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 TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT EMBO Molecular Medicine alternative lengthening of telomeres ATRX osteosarcomas telomeres TOP3A |
| title | TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT |
| title_full | TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT |
| title_fullStr | TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT |
| title_full_unstemmed | TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT |
| title_short | TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT |
| title_sort | top3a amplification and atrx inactivation are mutually exclusive events in pediatric osteosarcomas using alt |
| topic | alternative lengthening of telomeres ATRX osteosarcomas telomeres TOP3A |
| url | https://doi.org/10.15252/emmm.202215859 |
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