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B cell expansion and lymphomagenesis induced by chronic CD40 signaling is strictly dependent on CD19.

Cancer Res. 74, 4318-4328 (2014)
Verlagsversion DOI PMC
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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
CD40, a member of the Tumor necrosis factor 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. Since LMP1/CD40-expressing B-cells showed an upregulation of CD19, we investigated CD19 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 life span 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 is 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 provides 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Nf-kappa-b; Chronic Lymphocytic-leukemia; Tyrosine Kinase Activation; Cytoplasmic Tyrosines; Cd19-deficient Mice; Survival; Pathway; Amplification; Transduction; Responses
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 0008-5472
e-ISSN 1538-7445
Zeitschrift Cancer Research
Quellenangaben Band: 74, Heft: 16, Seiten: 4318-4328 Artikelnummer: , Supplement: ,
Verlag American Association for Cancer Research (AACR)
Verlagsort Philadelphia, Pa.
Begutachtungsstatus Peer reviewed
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501500-003
PubMed ID 24938766
Scopus ID 84905991448
Erfassungsdatum 2014-06-20