Abstract
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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Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (KFO 216), the IZKF Würzburg to KMK and SB, and by the Progetto professionalità from the Banca del Monte di Lombardia Foundation to MDV.
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Barrio, S., Stühmer, T., Da-Viá, M. et al. Spectrum and functional validation of PSMB5 mutations in multiple myeloma. Leukemia 33, 447–456 (2019). https://doi.org/10.1038/s41375-018-0216-8
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DOI: https://doi.org/10.1038/s41375-018-0216-8
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