A20 deficiency and deregulated Notch2 signaling in lymphomagenesis and autoimmunity

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The immune system protects us from pathogens but deregulated immune signals can cause severe immunopathologies, such as cancer and autoimmunity. Many genes that encode components of signaling pathways regulating the differentiation, proliferation and apoptosis of immune cells are mutated in these diseases. Our application is focused on the investigation of deregulated NF-kB and Notch2 signaling in B cell differentiation and immune diseases. Both signaling pathways regulate the differentiation of Marginal Zone (MZ) B cells and are frequently hyperactivated in lymphomas, the most common cancer of immune cells. NF-kB transcription factors regulate genes involved in inflammation, proliferation and survival. Polymorphisms in and near the TNFAIP3/A20 gene locus, which encodes the A20 negative feedback inhibitor of NF-kB activation, are linked to human autoimmune diseases. Importantly, of all genomic aberrations causing elevated NF-kB activity in human lymphomas, functional loss of A20 is the most common, underscoring the critical role of A20 in human disease. Recently, we showed that ablation of A20 specifically in B cells impairs their differentiation and causes an autoimmune syndrome in aged mice. Notch 1-4 are members of a transmembrane receptor family that is involved in manifold cell fate decisions. We showed that B cell specific expression of constitutively active Notch 2 (Notch2IC) drives nearly all B cells into the MZ B cell compartment. Mutations in the NOTCH2 gene resulting in increased stability of NOTCH2 have been recurrently found in human splenic MZ B cell lymphoma (SMZL) and Diffuse Large B cell lymphomas (DLBCL). Our current data indicate that Notch2IC is not acting as a strong oncogene in B cells. The reason might be that Notch2IC induces proliferation as well as apoptosis in mature B cells. Fittingly, simultaneously with Notch2 recurrent mutations in genes leading to the activation of canonical and non-canonical NF-kB signaling have been detected in human SMZL. Therefore, we postulate that deregulated Notch2 signaling causes B cell lymphomas only in combination with antiapoptotic signals, such as NF-kB activation. The goals of our application are to study pathogenic functions of A20 deficiency and enhanced Notch2 signaling alone and in combination in B-cell mediated diseases: (i) We aim to characterize how signaling pathways downstream of IL17R and TLRs cause immunopathology in A20-deficient B cells. Furthermore, we propose to test the hypothesis that enhanced levels of BAFF synergize with loss of A20 in autoimmunity. (ii) By studying the consequences of deregulated Notch2 signaling in activated MZ B and germinal center B cells, we aim to explore the influence of deregulated Notch signaling in activated B lymphocytes. (iii) Our common goal is to investigate the cooperation between enhanced Notch2 signaling and deregulated NF-kB (A20-deficiency, LMP1/CD40 expression) signaling in B cell lymphoma development and autoimmunity.