Spectrum and functional validation of PSMB5 mutations in multiple myeloma

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 EinseleK. Martin Kortüm

Research output: Contribution to journalArticle

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)447-456
Number of pages10
JournalLeukemia
Volume33
Issue number2
DOIs
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Barrio, S., Stühmer, T., Da-Viá, M., Barrio-Garcia, C., Lehners, N., Besse, A., Cuenca, I., Garitano-Trojaola, A., Fink, S., Leich, E., Chatterjee, M., Driessen, C., Martinez-Lopez, J., Rosenwald, A., Beckmann, R., Bargou, R. C., Braggio, E., Stewart, A. K., Raab, M. S., ... Kortüm, K. M. (2019). Spectrum and functional validation of PSMB5 mutations in multiple myeloma. Leukemia, 33(2), 447-456. https://doi.org/10.1038/s41375-018-0216-8