This research proposal aims to elucidate the mechanisms by which constitutive activation of the nuclear factor-?B (NF-?B) transcription factor complex contributes to the oncogenic transformation of mature B lymphocytes. The majority of B-cell cancers originate from antigen-activated mature B cells that have undergone the germinal center (GC) reaction to generate memory B cells and plasma cells, and the development of several lymphoma subtypes has been linked to the oncogenic transformation of the precursors of memory B cells or plasma cells. Notably, these tumors frequently harbor genetic mutations in NF-?B pathway components that result in the constitutive activation of NF-?B signaling, thus identifying NF-?B as a critical player in GC- lymphomagenesis. These observations underscore the need to elucidate the molecular mechanisms by which NF-?B contributes to the transformation of the tumor precursor cells. NF-?B activation can occur via two different routes, the canonical and the alternative pathways, mediated by specific NF-?B subunits. We have obtained preliminary evidence suggesting that differential activation of the two NF-?B pathways is involved in memory B-cell versus plasma cell differentiation during the GC reaction. Despite extensive knowledge about the biology of NF-?B, its potential function in the differentiation of GC B cells is a novel concept that has not been explored. The objective of the proposed research is to determine the mechanisms by which the two NF-?B pathways and their respective subunits affect the cellular differentiation of memory B-cell and plasma cell precursors in order to understand the biological consequences of a constitutive activation of these pathways in B-cell cancers. Our Central hypothesis is that constitutive activation of NF-?B signaling contributes to the pathogenesis of B-cell tumors by disrupting the transcriptional mechanisms that regulate the differentiation of a GC B cell into a memory B cell or a plasma cell. To accomplish the objective of this application, we will define the roles of the separate NF-?B pathways in the differentiation of GC B cells in vivo using conditional mouse models. In addition, we will identify the biological programs controlled by the canonical and the alternative NF-?B pathways in differentiating native GC B cells and in GC-derived tumors of various developmental stages by performing a genome-wide identification of the transcriptional targets. We will also start to determine the extent to which NF-?B is involved in lymphoma pathogenesis in vivo. The rationale for the proposed research is that elucidating the role of the separate NF-?B pathways in GC B-cell differentiation and dissecting the contribution of each pathway to GC-lymphomagenesis will lead to the identification of new prognostic and/or diagnostic markers. Moreover, the results may provide the basis for developing innovative anti-cancer therapies that could reduce the adverse systemic side effects associated with the pharmacological inhibition of the entire NF-?B pathway by specifically targeting constitutive NF-?B signaling at the level of i.) the separate NF-?B pathways, ii.) the individual NF-?B subunits, or iii.) the specific transcriptional targets.