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Multiple myeloma gammopathies

Spectrum and functional validation of PSMB5 mutations in multiple myeloma

Leukemia volume 33, pages 447–456 (2019)Cite this article

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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.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (KFO 216), the IZKF Würzburg to KMK and SB, and by the Progetto professionalità from the Banca del Monte di Lombardia Foundation to MDV.

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Author notes

  1. These authors contributed equally: Santiago Barrio, Thorsten Stühmer.

Authors and Affiliations

  1. Department of Hematology-Oncology, Internal Medicine II, University Hospital Würzburg, Würzburg, Germany

    Santiago Barrio, Thorsten Stühmer, Matteo Da-Viá, Andoni Garitano-Trojaola, Severin Fink, Manik Chatterjee, Ralf C. Bargou, Hermann Einsele & K. Martin Kortüm

  2. Gene Center, Ludwig-Maximilians University, Munich, Germany

    Clara Barrio-Garcia & Roland Beckmann

  3. Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany

    Nicola Lehners & Marc S. Raab

  4. Departement of Hematology, Kantonsspital St Gallen, St Gallen, Switzerland

    Andrej Besse & Christoph Driessen

  5. Department of Hematology, Hospital Universitario 12 de Octubre, CNIO, Complutense University, Madrid, Spain

    Isabel Cuenca & Joaquin Martinez-Lopez

  6. Institute of Pathology, University of Würzburg, Würzburg, Germany

    Ellen Leich & Andreas Rosenwald

  7. Comprehensive Cancer Center Mainfranken, Würzburg, Germany

    Andreas Rosenwald

  8. Division of Hematology-Oncology, Mayo Clinic, Scottsdale, AZ, USA

    Esteban Braggio & A. Keith Stewart

  9. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA

    A. Keith Stewart

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  1. Santiago Barrio
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Correspondence to K. Martin Kortüm.

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Barrio, S., Stühmer, T., Da-Viá, M. et al. Spectrum and functional validation of PSMB5 mutations in multiple myeloma. Leukemia 33, 447–456 (2019). https://doi.org/10.1038/s41375-018-0216-8

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