Spectrum and functional validation of PSMB5 mutations in multiple myeloma

Barrio, Santiago; Stuehmer, Thorsten; Da-Via, Matteo; Barrio-Garcia, Clara; Lehners, Nicola; Besse, Andrej; Cuenca, Isabel; Garitano-Trojaola, Andoni; Fink, Severin; Leich, Ellen; Chatterjee, Manik; Driessen, Christoph; Martinez-Lopez, Joaquin; Rosenwald, Andreas; Beckmann, Roland; Bargou, Ralf C.; Braggio, Esteban; Stewart, A. Keith; Raab, Marc S.; Einsele, Hermann and Kortuem, K. Martin (2019): Spectrum and functional validation of PSMB5 mutations in multiple myeloma. In: Leukemia, Vol. 33, No. 2: pp. 447-456

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.

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Biochemistry
• Subjects: 500 Science > 540 Chemistry
• ISSN: 0887-6924
• Language: English