Role of the canonical NF-kappaB pathway in B-cell differentiation and oncogenic transformation

The proposed research is aimed at elucidating the biological role of nuclear factor-kappaB (NF-kappaB) signaling in the differentiation of antigen-activated B-cells in order to understand the disruption of this differentiation mechanism in the pathogenesis of B-cell lymphoma. A hallmark of adaptive immunity is the generation of plasma cells and long-lived memory B-cells in the germinal centers (GC) of lymph nodes. However, the beneficial role of the GC-reaction is countered by its detrimental role in lymphomagenesis, since most lymphomas originate from B-cells that have undergone the GC-reaction. Accumulating evidence points towards a causative role of a deregulated activation of the NF-kappaB transcription factor complex in GC B-cell lymphomagenesis, with several lymphoma subtypes showing constitutive activation specifically of the canonical NF-kappaB pathway. To understand how deregulated activation of this pathway promotes GC B-cell lymphomagenesis, it is critical to understand the role of NF-kappaB in normal B-cell differentiation. However, despite the extensive knowledge on NF-kappaB that has accumulated over the last decades, its function in the differentiation of GC B-cells is not understood. The aim of the present proposal is to elucidate the biological function of the canonical NF-kappaB pathway in GC B-cell differentiation and in the malignant transformation of B-cells by pursuing the following specific aims: (1) Determine the role of the individual subunits of the canonical NF-kappaB pathway in memory B-cell and plasma cell differentiation using conditional knockout mouse models. (2) Identify target genes of the canonical NF-kappaB pathway in differentiating GC B-cells. (3) Investigate the role of canonical NF-kappaB subunits in the transformation of B-cells. What is learned from the proposed studies is anticipated to provide the basis for the development of improved anti-lymphoma therapies.