Spectrum and functional validation of PSMB5 mutations in multiple myeloma
Despite an increasing number of approved therapies, multiple myeloma (MM) remains an incurable disease and only a small number of patients achieve prolonged disease control. Some genes have been linked with response to commonly used anti-MM compounds, including immunomodulators (IMiDs) and proteasom...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2019
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| In: |
Leukemia
Year: 2018, Volume: 33, Issue: 2, Pages: 447-456 |
| ISSN: | 1476-5551 |
| DOI: | 10.1038/s41375-018-0216-8 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1038/s41375-018-0216-8 Verlag: https://www.nature.com/articles/s41375-018-0216-8 
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| Author Notes: | Santiago Barrio, Thorsten Stühmer, Matteo Da-Viá, Clara Barrio-Garcia, Nicola Lehners, Andrej Besse, Isabel Cuenca, Andoni Garitano-Trojaola, Severin Fink, Ellen Leich, Manik Chatterjee, Christoph Driessen, Joaquin Martinez-Lopez, Andreas Rosenwald, Roland Beckmann, Ralf C. Bargou, Esteban Braggio, A. Keith Stewart, Marc S. Raab, Hermann Einsele, K. Martin Kortüm |
| Summary: | Despite an increasing number of approved therapies, multiple myeloma (MM) remains an incurable disease and only a small number of patients achieve prolonged disease control. Some genes have been linked with response to commonly used anti-MM compounds, including immunomodulators (IMiDs) and proteasome inhibitors (PIs). In this manuscript, we demonstrate an increased incidence of acquired proteasomal subunit mutations in relapsed MM compared to newly diagnosed disease, underpinning a potential role of point mutations in the clonal evolution of MM. Furthermore, we are first to present and functionally characterize four somatic PSMB5 mutations from primary MM cells identified in a patient under prolonged proteasome inhibition, with three of them affecting the PI-binding pocket S1. We confirm resistance induction through missense mutations not only to Bortezomib, but also, in variable extent, to the next-generation PIs Carfilzomib and Ixazomib. In addition, a negative impact on the proteasome activity is assessed, providing a potential explanation for later therapy-induced eradication of the affected tumor subclones in this patient. |
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| Item Description: | Published online: 19 July 2018 Gesehen am 19.11.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1476-5551 |
| DOI: | 10.1038/s41375-018-0216-8 |