Spectrum and functional validation of PSMB5 mutations in multiple myeloma
| Autor: | Andrej Besse, Andreas Rosenwald, Severin Fink, Matteo DaVia, Manik Chatterjee, Marc S. Raab, Isabel Cuenca, Clara Barrio-Garcia, Joaquin Martinez-Lopez, Andoni Garitano-Trojaola, A. Keith Stewart, Roland Beckmann, Nicola Lehners, Esteban Braggio, Thorsten Stühmer, Santiago Barrio, K. Martin Kortüm, Ellen Leich, Ralf C. Bargou, Christoph Driessen, Hermann Einsele |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Boron Compounds Male Cancer Research Proteasome Endopeptidase Complex Glycine medicine.disease_cause Somatic evolution in cancer Ixazomib Bortezomib Cohort Studies 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Antineoplastic Combined Chemotherapy Protocols medicine Biomarkers Tumor Humans Multiple myeloma Mutation business.industry Point mutation Hematology Middle Aged medicine.disease Prognosis Carfilzomib PSMB5 Gene Expression Regulation Neoplastic Survival Rate 030104 developmental biology Oncology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Female Neoplasm Recurrence Local business Multiple Myeloma Oligopeptides medicine.drug Follow-Up Studies |
| Zdroj: | Leukemia. 33(2) |
| ISSN: | 1476-5551 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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