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Loss of CYLD expression unleashes Wnt signaling in multiple myeloma and is associated with aggressive disease

Oncogene volume 36, pages 2105–2115 (2017)Cite this article

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Abstract

Deletion or mutation of the gene encoding the deubiquitinating enzyme CYLD is a common genomic aberration in multiple myeloma (MM). However, the functional consequence of CYLD loss and the mechanism underlying its putative role as a tumor suppressor gene in the pathogenesis of MM has not been established. Here, we show that CYLD expression is highly variable in myeloma cell lines and primary MMs and that low CYLD expression is associated with disease progression from monoclonal gammopathy of undetermined significance to MM, and with poor overall and progression free-survival of MM patients. Functional assays revealed that CYLD represses MM cell proliferation and survival. Furthermore, CYLD acts as a negative regulator of NF-κB and Wnt/β-catenin signaling and loss of CYLD sensitizes MM cells to NF-κB-stimuli and Wnt ligands. Interestingly, in primary MMs, low CYLD expression strongly correlated with a proliferative and Wnt signaling-gene expression signature, but not with an NFκB target gene signature. Altogether, our findings identify CYLD as a negative regulator of NF-κB and Wnt/β-catenin signaling in MM and indicate that loss of CYLD enhances MM aggressiveness through Wnt pathway activation. Thus, targeting the Wnt pathway could be a promising therapeutic strategy in MM with loss of CYLD activity.

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Acknowledgements

This study was supported by grants from the Dutch Cancer Society and EU-FP7 OVER-MYR.

Author contributions

HvA and KAK performed most in vitro experiments, analyzed the data, designed the figures and wrote the paper; AH-K provided technical assistance. CHM performed aCGH; AB, MvD and MP provided micro-array data and performed statistical analysis; PS supervised AB and MvD and reviewed the manuscript. MM provided CYLD reagents and expertize and reviewed the manuscript; MJK provided patient samples and reviewed the manuscript. MS and STP designed the research, supervised the study, analyzed the data. STP wrote the paper.

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Author notes

  1. H van Andel and K A Kocemba: These authors contributed equally to this work.

  2. M Spaargaren and S T Pals: These authors share last authorship.

Authors and Affiliations

  1. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    H van Andel, K A Kocemba, A de Haan-Kramer, M Spaargaren & S T Pals

  2. Lymphoma and Myeloma Center Amsterdam – LYMMCARE, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    H van Andel, K A Kocemba, A de Haan-Kramer, M J Kersten, M Spaargaren & S T Pals

  3. Department of Medical Biochemistry, Jagiellonian University Medical College, Krakow, Poland

    K A Kocemba

  4. Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    C H Mellink

  5. Department of Bioinformatics and Telemedicine, Jagiellonian University Medical College, Krakow, Poland

    M Piwowar

  6. Department of Hematology, Erasmus MC, Rotterdam, The Netherlands

    A Broijl, M van Duin & P Sonneveld

  7. Department of Cell Biology, University MC Utrecht, Utrecht, The Netherlands

    M M Maurice

  8. Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    M J Kersten

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  1. H van Andel
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Correspondence to S T Pals.

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van Andel, H., Kocemba, K., de Haan-Kramer, A. et al. Loss of CYLD expression unleashes Wnt signaling in multiple myeloma and is associated with aggressive disease. Oncogene 36, 2105–2115 (2017). https://doi.org/10.1038/onc.2016.368

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