Spectrum and functional validation of PSMB5 mutations in multiple myeloma

• Verfasst von: Barrio, Santiago [VerfasserIn]
• Verfasst von: Giesen, Nicola [VerfasserIn]
• Verfasst von: Raab, Marc-Steffen [VerfasserIn]
• Titel: Spectrum and functional validation of PSMB5 mutations in multiple myeloma
• Verf.angabe: 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
• Jahr: 2019
• Jahr des Originals: 2018
• Umfang: 10 S.
• Fussnoten: Published online: 19 July 2018 ; Gesehen am 19.11.2019
• Titel Quelle: Enthalten in: Leukemia
• Ort Quelle: London : Springer Nature, 1997
• Jahr Quelle: 2019
• Band/Heft Quelle: 33(2019), 2, Seite 447-456
• ISSN Quelle: 1476-5551
• DOI: doi:10.1038/s41375-018-0216-8
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1677982187

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.