Loss of CYLD promotes splenic marginal zone lymphoma
Splenic marginal zone lymphoma (SMZL) is a distinct clinical and pathological entity among marginal zone lymphomas. Genetic and microenvironmental factors leading to aberrant activation of the NF-κB pathway have been implicated in SMZL pathogenesis. CYLD is a negative regulator of NF-κB and other signaling pathways acting as a deubiquitinase of regulatory molecules and has been reported as a tumor suppressor in different types of cancer, including B-cell malignancies. To assess whether CYLD is implicated in the natural history of SMZL, we profiled primary cells from patients with SMZL and SMZL cell lines for CYLD expression and functionality. We report that CYLD is downregulated in patients with SMZL and that <i>CYLD</i> ablation in vitro leads to NF-κB pathway hyperactivation, promoting the proliferation of SMZL cells. In addition, we found that CYLD deficiency was associated with increased migration of SMZL cells in vitro, through CCR7 receptor signaling, and with increased dissemination in vivo. <i>CYLD</i> loss was sufficient to induce BcR signaling, conferring increased resistance to ibrutinib treatment in vitro. In summary, our work uncovers a novel role of CYLD as a key regulator in SMZL pathogenesis, dissemination, and resistance to targeted agents. On these grounds, CYLD could be proposed as a novel target for patient stratification and personalized interventions.
Authors
- Uday Aditya Sarkar (ORCID: https://orcid.org/0000-0002-7401-7193)
- Ferdinando Bonfiglio (ORCID: https://orcid.org/0000-0003-2488-3867)
- Davide Rossi (ORCID: https://orcid.org/0000-0002-2837-1597)
- Emanuela Sant’Antonio (ORCID: https://orcid.org/0000-0001-5393-0381)
- George Mosialos (ORCID: https://orcid.org/0000-0002-5342-4873)
- Daniela Belloni (ORCID: https://orcid.org/0000-0002-3487-4203)
- Fabrizio Mavilia
- Joan Climent (ORCID: https://orcid.org/0000-0002-8927-6614)
- Vasileios Vasileiou (ORCID: https://orcid.org/0000-0003-0145-033X)
- Lydia Scarfò (ORCID: https://orcid.org/0000-0002-0844-0989)
- Alessandro Campanella (ORCID: https://orcid.org/0000-0002-3463-1199)
- Michela Frenquelli (ORCID: https://orcid.org/0000-0003-4166-0438)
- Κώστας Σταματόπουλος (ORCID: https://orcid.org/0000-0001-8529-640X)
- Masanori Daibata (ORCID: https://orcid.org/0000-0001-8714-2068)
- Eleonora Perotta (ORCID: https://orcid.org/0000-0002-5939-0619)
- Sofoklis Keisaris
- Jessica Bordini (ORCID: https://orcid.org/0000-0002-2669-6953)
- Silvia Heltai
- Elisabetta Albi (ORCID: https://orcid.org/0000-0002-5745-5343)
- Fotis Psomopoulos (ORCID: https://orcid.org/0000-0002-0222-4273)
- Athanasios Pseftogas (ORCID: https://orcid.org/0000-0002-6165-8119)
- Paolo Ghia (ORCID: https://orcid.org/0000-0003-3750-7342)
- Pamela Ranghetti
- Konstantinos Xanthopoulos (ORCID: https://orcid.org/0000-0001-8759-8962)
- Georgios Gavriilidis
- Caterina Taccetti
- Francesca Martini (ORCID: https://orcid.org/0000-0002-1168-6568)
Institutions
- Democritus University of Thrace (GR)
- Vita-Salute San Raffaele University (IT)
- Aristotle University of Thessaloniki (GR)
- Kochi Medical School Hospital (JP)
- Institute of Oncology Research (CH)
- IFOM (IT)
- Dana-Farber Cancer Institute (US)
- CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) (IT)
- IRCCS Ospedale San Raffaele (IT)
- Centre for Research and Technology Hellas (GR)
- Istituto Oncologico della Svizzera Italiana
- University of Naples Federico II (IT)
Publication Details
- Journal
- HemaSphere
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1002/hem3.70098
- Citations
- 2
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 2.94
Funders
- Associazione Italiana per la Ricerca sul Cancro
- Hellenic Foundation for Research and Innovation