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

¹ Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Center Munich, German Research Center for Environment and Health, D-81377 Munich, Germany
² Immune Disease Institute, Harvard Medical School, Boston, MA 02115
³ The Department of Experimental Immunology, Helmholtz Center for Infectious Research, D-38124 Braunschweig, Germany
⁴ Institute of Pathology, Helmholtz Center Munich, German Research Center for Environment and Health, D-85764 Neuherberg, Germany
⁵ III Med. Department, Technical University of Munich, Klinikum rechts der Isar, D-81675 Munich, Germany

CORRESPONDENCE Ursula Zimber-Strobl: strobl{at}helmholtz-muenchen.de

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-B 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.

C. Hömig-Hölzel and C. Hojer contributed equally to this paper.

S. Casola's present address is IFOM-The Foundation for Cancer Research Institute of Molecular Oncology, 20139 Milan, Italy.

C. Hömig-Hölzel's present address is Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, Netherlands.

J. Rastelli's present address is Whitehead Institute for Biomedical Research, Cambridge, MA 02142.

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