title: B-cell expansion and lymphomagenesis induced by chronic CD40 signaling is strictly dependent on CD19.
abstract: CD40, a member of the TNF receptor family, is expressed on all mature B cells and on most B-cell lymphomas. Recently, we have shown that constitutive activation of CD40 signaling in B cells induced by a fusion protein consisting of the transmembrane part of the Epstein-Barr viral latent membrane protein 1 (LMP1) and the cytoplasmic part of CD40 (LMP1/CD40) drives B-cell lymphoma development in transgenic mice. Because LMP1/CD40-expressing B cells showed an upregulation of CD19, we investigated CD19's function in CD40-driven B-cell expansion and lymphomagenesis. Here, we demonstrate that ablation of CD19 in LMP1/CD40 transgenic mice resulted in a severe loss and reduced lifespan of mature B cells and completely abrogated development of B-cell lymphoma. CD19 is localized to lipid rafts and constitutively activated by the LMP1/CD40 fusion protein in B cells. We provide evidence that the improved survival and malignant transformation of LMP1/CD40-expressing B cells are dependent on activation of the MAPK Erk that is mediated through CD19 in a PI3K-dependent manner. Our data suggest that constitutively active CD40 is dependent on CD19 to transmit survival and proliferation signals. Moreover, we detected a similarly functioning prosurvival pathway involving phosphorylated CD19 and PI3K-dependent Erk phosphorylation in human diffuse large B-cell lymphoma cell lines. Our data provide evidence that CD19 plays an important role in transmitting survival and proliferation signals downstream of CD40 and therefore might be an interesting therapeutic target for the treatment of lymphoma undergoing chronic CD40 signaling.
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Munich, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hojer
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Munich, Germany.
authors.forename: Samantha
authors.initials: S
authors.lastname: Frankenberger
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Munich, Germany.
authors.forename: Lothar J
authors.initials: LJ
authors.lastname: Strobl
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Munich, Germany.
authors.forename: Samantha
authors.initials: S
authors.lastname: Feicht
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Munich, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Djermanovic
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Munich, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Jagdhuber
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Munich, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hömig-Hölzel
authors.affiliation: Institute for Clinical Chemistry and Pathobiochemistry, Technical University of Munich, Munich, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Ferch
authors.affiliation: Institute for Clinical Chemistry and Pathobiochemistry, Technical University of Munich, Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Munich, Germany. strobl@helmholtz-muenchen.de.
authors.forename: Ursula
authors.initials: U
authors.lastname: Zimber-Strobl
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019013:CD40 Antigens / Q000276:immunology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008223:Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation
chemical_list: D018941:Antigens, CD19; D019013:CD40 Antigens