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

Authors :
Marthe Minderman
Hildo C. Lantermans
Leonie J. Grüneberg
Saskia A. G. M. Cillessen
Richard J. Bende
Carel J. M. van Noesel
Marie José Kersten
Steven T. Pals
Marcel Spaargaren
Graduate School
Pathology
AII - Cancer immunology
CCA - Cancer biology and immunology
CCA - Imaging and biomarkers
AII - Inflammatory diseases
Clinical Haematology
CCA - Cancer Treatment and Quality of Life
09 Laboratory specialisms
Amsterdam Gastroenterology Endocrinology Metabolism
Source :
Minderman, M, Lantermans, H C, Grüneberg, L J, Cillessen, S A G M, Bende, R J, van Noesel, C J M, Kersten, M J, Pals, S T & Spaargaren, M 2023, ' MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas ', Blood cancer journal, vol. 13, no. 1, 37, pp. 37 . https://doi.org/10.1038/s41408-023-00809-7, Blood cancer journal, 13(1):37. Nature Publishing Group
Publication Year :
2023

Abstract

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.

Subjects

Subjects :
Oncology
Hematology

Details

Language :
English
ISSN :
20445385
Database :
OpenAIRE
Journal :
Minderman, M, Lantermans, H C, Grüneberg, L J, Cillessen, S A G M, Bende, R J, van Noesel, C J M, Kersten, M J, Pals, S T & Spaargaren, M 2023, ' MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas ', Blood cancer journal, vol. 13, no. 1, 37, pp. 37 . https://doi.org/10.1038/s41408-023-00809-7, Blood cancer journal, 13(1):37. Nature Publishing Group
Accession number :
edsair.doi.dedup.....8ea05d7940fbdd3124adb531fc9a6650