title: Loss of CYLD expression unleashes Wnt signaling in multiple myeloma and is associated with aggressive disease.
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.
authors: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam - LYMMCARE, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: H
authors: H
authors: van Andel
authors: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam - LYMMCARE, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Medical Biochemistry, Jagiellonian University Medical College, Krakow, Poland.
authors: K A
authors: KA
authors: Kocemba
authors: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam - LYMMCARE, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: A
authors: A
authors: de Haan-Kramer
authors: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: C H
authors: CH
authors: Mellink
authors: Department of Bioinformatics and Telemedicine, Jagiellonian University Medical College, Krakow, Poland.
authors: M
authors: M
authors: Piwowar
authors: Department of Hematology, Erasmus MC, Rotterdam, The Netherlands.
authors: A
authors: A
authors: Broijl
authors: Department of Hematology, Erasmus MC, Rotterdam, The Netherlands.
authors: M
authors: M
authors: van Duin
authors: Department of Hematology, Erasmus MC, Rotterdam, The Netherlands.
authors: P
authors: P
authors: Sonneveld
authors: Department of Cell Biology, University MC Utrecht, Utrecht, The Netherlands.
authors: M M
authors: MM
authors: Maurice
authors: Lymphoma and Myeloma Center Amsterdam - LYMMCARE, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: M J
authors: MJ
authors: Kersten
authors: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam - LYMMCARE, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: M
authors: M
authors: Spaargaren
authors: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam - LYMMCARE, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: S T
authors: ST
authors: Pals
mesh_terms: D016022:Case-Control Studies; D000074749:Deubiquitinating Enzyme CYLD; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD