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.
Highlights
CD40, a member of the TNF -receptor (TNF-R) family, is critically involved in germinal center formation and class switch recombination during T-cell dependent (TD)-immune responses [1]
FACS analysis revealed that IgMþ and IgDþ B cells in the spleen and inguinal lymph nodes (iLN) of latent membrane protein 1 (LMP1)/CD40//CD19À/À mice were strongly reduced in comparison with LMP1/ CD40//CD19þ/À mice (Fig. 2A)
Because CD19 was highly expressed on the surface of LMP1/CD40-expressing B cells, we investigated whether their improved survival depends on CD19
Summary
CD40, a member of the TNF -receptor (TNF-R) family, is critically involved in germinal center formation and class switch recombination during T-cell dependent (TD)-immune responses [1]. CD40 stimulation of B cells in vitro promotes Bcell activation, proliferation, and survival [2]. CD40 is widely expressed on B-cell lymphomas, frequently along with the CD40 ligand (CD40L), resulting in constitutive engagement of CD40 [3, 4]. Mutations leading to constitutive activation of CD40 have been observed in multiple myelomas [5]. We have shown recently that constitutively active CD40 signaling leads to B-cell activation and expansion and to B-cell lymphoma development in mice with high penetrance. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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