Publikation

Spectrum and functional validation of PSMB5 mutations in multiple myeloma

Wissenschaftlicher Artikel/Review - 19.07.2018

Bereiche
PubMed
DOI

Zitation
Barrio S, Martinez-Lopez J, Rosenwald A, Beckmann R, Bargou R, Braggio E, Stewart A, Raab M, Einsele H, Driessen C, Chatterjee M, Leich E, Stühmer T, Da-Viá M, Barrio-Garcia C, Lehners N, Besse A, Cuenca I, Garitano-Trojaola A, Fink S, Kortüm K. Spectrum and functional validation of PSMB5 mutations in multiple myeloma. Leukemia 2018
Art
Wissenschaftlicher Artikel/Review (Englisch)
Zeitschrift
Leukemia 2018
Veröffentlichungsdatum
19.07.2018
eISSN (Online)
1476-5551
Kurzbeschreibung/Zielsetzung

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.