PuSH - Publikationsserver des Helmholtz Zentrums München: Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis.

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Hömig-Hölzel, C. ; Hojer, C. ; Rastelli, J. ; Casola, S.* ; Strobl, L.J. ; Müller, W.* ; Quintanilla-Martinez, L. ; Gewies, A.* ; Ruland, J.* ; Rajewsky, K.* ; Zimber-Strobl, U.

Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis.

J. Exp. Med. 205, 1317-1329 (2008)

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CD40, a member of the tumor necrosis factor (TNF) receptor family, plays an essential role in T cell-dependent immune responses. Because CD40 is widely expressed on the surface of tumor cells in various B cell malignancies, deregulated CD40 signaling has been suggested to contribute to lymphomagenesis. In this study, we show that B cell-specific expression of a constitutively active CD40 receptor, in the form of a latent membrane protein 1 (LMP1)/CD40 chimeric protein, promoted an increase in the number of follicular and marginal zone B cells in secondary lymphoid organs in transgenic mice. The B cells displayed an activated phenotype, prolonged survival and increased proliferation, but were significantly impaired in T cell-dependent immune responses. Constitutive CD40 signaling in B cells induced selective and constitutive activation of the noncanonical NF-kappaB pathway and the mitogen-activated protein kinases Jnk and extracellular signal-regulated kinase. LMP1/CD40-expressing mice older than 12 mo developed B cell lymphomas of mono- or oligoclonal origin at high incidence, thus showing that the interplay of the signaling pathways induced by constitutive CD40 signaling is sufficient to initiate a tumorigenic process, ultimately leading to the development of B cell lymphomas.

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