USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma
Abstract The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC‐induced mitotic arrest. Here, we identify USP9X as the mitotic...
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Springer Nature
2016-06-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201506047 |
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| author | Katharina Engel Martina Rudelius Jolanta Slawska Laura Jacobs Behnaz Ahangarian Abhari Bettina Altmann Julia Kurutz Abirami Rathakrishnan Vanesa Fernández‐Sáiz Andrä Brunner Bianca‐Sabrina Targosz Felicia Loewecke Christian Johannes Gloeckner Marius Ueffing Simone Fulda Michael Pfreundschuh Lorenz Trümper Wolfram Klapper Ulrich Keller Philipp J Jost Andreas Rosenwald Christian Peschel Florian Bassermann |
| author_facet | Katharina Engel Martina Rudelius Jolanta Slawska Laura Jacobs Behnaz Ahangarian Abhari Bettina Altmann Julia Kurutz Abirami Rathakrishnan Vanesa Fernández‐Sáiz Andrä Brunner Bianca‐Sabrina Targosz Felicia Loewecke Christian Johannes Gloeckner Marius Ueffing Simone Fulda Michael Pfreundschuh Lorenz Trümper Wolfram Klapper Ulrich Keller Philipp J Jost Andreas Rosenwald Christian Peschel Florian Bassermann |
| author_sort | Katharina Engel |
| collection | DOAJ |
| description | Abstract The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC‐induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X‐linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B‐cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event‐free survival in patients treated with spindle poison‐containing chemotherapy. Accordingly, aggressive B‐cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Eμ‐Myc lymphoma model. Together, we specify the USP9X–XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B‐cell lymphoma. |
| format | Article |
| id | doaj-art-b5cf9b3c87fb41cfa1b6fcd1a47c21bb |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-b5cf9b3c87fb41cfa1b6fcd1a47c21bb2025-08-20T04:03:06ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-06-018885186210.15252/emmm.201506047USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphomaKatharina Engel0Martina Rudelius1Jolanta Slawska2Laura Jacobs3Behnaz Ahangarian Abhari4Bettina Altmann5Julia Kurutz6Abirami Rathakrishnan7Vanesa Fernández‐Sáiz8Andrä Brunner9Bianca‐Sabrina Targosz10Felicia Loewecke11Christian Johannes Gloeckner12Marius Ueffing13Simone Fulda14Michael Pfreundschuh15Lorenz Trümper16Wolfram Klapper17Ulrich Keller18Philipp J Jost19Andreas Rosenwald20Christian Peschel21Florian Bassermann22Department of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenInstitute of Pathology and Comprehensive Cancer Center Mainfranken, Universität WürzburgDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenInstitut für Experimentelle Tumorforschung in der Pädiatrie, Goethe‐Universität FrankfurtInstitute for Medical Informatics, Statistics and Epidemiology, Universität LeipzigDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenEberhard‐Karls‐Universität Tübingen, Institute for Ophthalmic Research, Medical Proteome CenterEberhard‐Karls‐Universität Tübingen, Institute for Ophthalmic Research, Medical Proteome CenterInstitut für Experimentelle Tumorforschung in der Pädiatrie, Goethe‐Universität FrankfurtDepartment of Medicine I, Saarland University Medical SchoolDepartment of Hematology and Oncology, Georg‐August‐Universität GöttingenInstitute of Pathology, Haematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig‐HolsteinDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenInstitute of Pathology and Comprehensive Cancer Center Mainfranken, Universität WürzburgDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenDepartment of Medicine III, Klinikum Rechts der Isar, Technische Universität MünchenAbstract The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC‐induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X‐linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B‐cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event‐free survival in patients treated with spindle poison‐containing chemotherapy. Accordingly, aggressive B‐cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Eμ‐Myc lymphoma model. Together, we specify the USP9X–XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B‐cell lymphoma.https://doi.org/10.15252/emmm.201506047B‐cell lymphomamitosisubiquitinUSP9XXIAP |
| spellingShingle | Katharina Engel Martina Rudelius Jolanta Slawska Laura Jacobs Behnaz Ahangarian Abhari Bettina Altmann Julia Kurutz Abirami Rathakrishnan Vanesa Fernández‐Sáiz Andrä Brunner Bianca‐Sabrina Targosz Felicia Loewecke Christian Johannes Gloeckner Marius Ueffing Simone Fulda Michael Pfreundschuh Lorenz Trümper Wolfram Klapper Ulrich Keller Philipp J Jost Andreas Rosenwald Christian Peschel Florian Bassermann USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma EMBO Molecular Medicine B‐cell lymphoma mitosis ubiquitin USP9X XIAP |
| title | USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma |
| title_full | USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma |
| title_fullStr | USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma |
| title_full_unstemmed | USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma |
| title_short | USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma |
| title_sort | usp9x stabilizes xiap to regulate mitotic cell death and chemoresistance in aggressive b cell lymphoma |
| topic | B‐cell lymphoma mitosis ubiquitin USP9X XIAP |
| url | https://doi.org/10.15252/emmm.201506047 |
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