MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas.

Autor: Minderman M; Department of Pathology, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands.; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.; Cancer Center Amsterdam (CCA), Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands., Lantermans HC; Department of Pathology, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands.; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.; Cancer Center Amsterdam (CCA), Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands., Grüneberg LJ; Department of Pathology, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands.; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.; Cancer Center Amsterdam (CCA), Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands., Cillessen SAGM; Department of Pathology, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands.; Department of Pathology, Amsterdam UMC, location VU University, Amsterdam, Netherlands., Bende RJ; Department of Pathology, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands.; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.; Cancer Center Amsterdam (CCA), Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands., van Noesel CJM; Department of Pathology, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands.; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.; Cancer Center Amsterdam (CCA), Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands., Kersten MJ; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.; Department of Hematology, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands., Pals ST; Department of Pathology, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands.; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.; Cancer Center Amsterdam (CCA), Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands., Spaargaren M; Department of Pathology, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.; Cancer Center Amsterdam (CCA), Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.
Jazyk: angličtina
Zdroj: Blood cancer journal [Blood Cancer J] 2023 Mar 15; Vol. 13 (1), pp. 37. Date of Electronic Publication: 2023 Mar 15.
DOI: 10.1038/s41408-023-00809-7
Abstrakt: The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is a protease and scaffold protein essential in propagating B-cell receptor (BCR) signaling to NF-κB. The deubiquitinating enzyme cylindromatosis (CYLD) is a recently discovered MALT1 target that can negatively regulate NF-κB activation. Here, we show that low expression of CYLD is associated with inferior prognosis of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) patients, and that chronic BCR signaling propagates MALT1-mediated cleavage and, consequently, inactivation and rapid proteasomal degradation of CYLD. Ectopic overexpression of WT CYLD or a MALT1-cleavage resistant mutant of CYLD reduced phosphorylation of IκBα, repressed transcription of canonical NF-κB target genes and impaired growth of BCR-dependent lymphoma cell lines. Furthermore, silencing of CYLD expression rendered BCR-dependent lymphoma cell lines less sensitive to inhibition of NF-κΒ signaling and cell proliferation by BCR pathway inhibitors, e.g., the BTK inhibitor ibrutinib, indicating that these effects are partially mediated by CYLD. Taken together, our findings identify an important role for MALT1-mediated CYLD cleavage in BCR signaling, NF-κB activation and cell proliferation, which provides novel insights into the underlying molecular mechanisms and clinical potential of inhibitors of MALT1 and ubiquitination enzymes as promising therapeutics for DLBCL, MCL and potentially other B-cell malignancies.
(© 2023. The Author(s).)
Databáze: MEDLINE
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