Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation

Eleonora Fonte, Andreas Agathangelidis, Daniele Reverberi, Stavroula Ntoufa, Lydia Scarfò, Pamela Ranghetti, Giovanna Cutrona, Alessandra Tedeschi, Aliki Xochelli, Federico Caligaris-Cappio, Maurilio Ponzoni, Chrysoula Belessi, Zadie Davis, Miguel A. Piris, David Oscier, Paolo Ghia, Kostas Stamatopoulos, Marta Muzio

Research output: Contribution to journalArticle

Abstract

Recent studies on splenic marginal zone lymphoma identified distinct mutations in genes belonging to the B-cell receptor and Toll-like receptor signaling pathways, thus pointing to their potential implication in the biology of the disease. However, limited data is available regarding the exact role of TLRs. We aimed at characterizing the expression pattern of TLRs in splenic marginal zone lymphoma cells and their functional impact on the activation, proliferation and viability of malignant cells in vitro. Cells expressed significant levels of TLR1, TLR6, TLR7, TLR8, TLR9 and TLR10 mRNA; TLR2 and TLR4 showed a low, variable pattern of expression among patients whereas TLR3 and TLR5 mRNAs were undetectable; mRNA specific for TLR signaling molecules and adapters was also expressed. At the protein level, TLR1, TLR6, TLR7, TLR9 and TLR10 were detected. Stimulation of TLR1/2, TLR2/6 and TLR9 with their respective ligands triggered the activation of IRAK kinases, MAPK and NF-κB signaling pathways, and the induction of CD86 and CD25 activation molecules, although in a heterogeneous manner among different patient samples. TLR-induced activation and cell viability were also inhibited by a specific IRAK1/4 inhibitor, thus strongly supporting the specific role of TLR signaling in these processes. Furthermore, TLR2/6 and TLR9 stimulation also significantly increased cell proliferation. In conclusion, we demonstrate that splenic marginal zone lymphoma cells are equipped with functional TLR and signaling molecules and that the stimulation of TLR1/2, TLR2/6 and TLR9 may play a role in regulating disease pathobiology, likely promoting the expansion of the neoplastic clone.

Original languageEnglish
Pages (from-to)1460-1468
Number of pages9
JournalHaematologica
Volume100
Issue number11
DOIs
Publication statusPublished - Oct 31 2015

ASJC Scopus subject areas

  • Hematology

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    Fonte, E., Agathangelidis, A., Reverberi, D., Ntoufa, S., Scarfò, L., Ranghetti, P., Cutrona, G., Tedeschi, A., Xochelli, A., Caligaris-Cappio, F., Ponzoni, M., Belessi, C., Davis, Z., Piris, M. A., Oscier, D., Ghia, P., Stamatopoulos, K., & Muzio, M. (2015). Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation. Haematologica, 100(11), 1460-1468. https://doi.org/10.3324/haematol.2014.119933