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 D Braggio, Alexander Keith Stewart, Marc S. Raab, Hermann EinseleK. Martin Kortüm

Research output: Contribution to journalArticle

11 Citations (Scopus)

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)
JournalLeukemia
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Multiple Myeloma
Proteasome Inhibitors
Mutation
Proteasome Endopeptidase Complex
Clonal Evolution
Immunologic Factors
Missense Mutation
Point Mutation
Incidence
Therapeutics
Genes
Neoplasms

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Barrio, S., Stühmer, T., Da-Viá, M., Barrio-Garcia, C., Lehners, N., Besse, A., ... Kortüm, K. M. (Accepted/In press). Spectrum and functional validation of PSMB5 mutations in multiple myeloma. Leukemia. https://doi.org/10.1038/s41375-018-0216-8

Spectrum and functional validation of PSMB5 mutations in multiple myeloma. / Barrio, Santiago; Stühmer, Thorsten; Da-Viá, 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 D; Stewart, Alexander Keith; Raab, Marc S.; Einsele, Hermann; Kortüm, K. Martin.

In: Leukemia, 01.01.2018.

Research output: Contribution to journalArticle

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, RC, Braggio, ED, Stewart, AK, Raab, MS, Einsele, H & Kortüm, KM 2018, 'Spectrum and functional validation of PSMB5 mutations in multiple myeloma', Leukemia. https://doi.org/10.1038/s41375-018-0216-8
Barrio S, Stühmer T, Da-Viá M, Barrio-Garcia C, Lehners N, Besse A et al. Spectrum and functional validation of PSMB5 mutations in multiple myeloma. Leukemia. 2018 Jan 1. https://doi.org/10.1038/s41375-018-0216-8
Barrio, Santiago ; Stühmer, Thorsten ; Da-Viá, 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 D ; Stewart, Alexander Keith ; Raab, Marc S. ; Einsele, Hermann ; Kortüm, K. Martin. / Spectrum and functional validation of PSMB5 mutations in multiple myeloma. In: Leukemia. 2018.
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