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.
The proposed research is relevant to public health because Hodgkin and Non-Hodgkin lymphomas as well as multiple myeloma, the majority of which shows constitutive NF-?B activation, often have an unfavorable prognosis and their treatment represents a major challenge for medicine. The rationale for the proposed research is that once the biology of NF-?B in the pathogenesis of B-cell malignancies is known, there will be a basis for developing innovative therapies against lymphoid cancer that are aimed at inhibiting NF-?B. Thus, the proposed research is relevant to the mission of the NIH pertaining to the understanding of the causes of cancer and the subsequent development of effective treatments.
|Milanovic, Maja; Heise, Nicole; De Silva, Nilushi S et al. (2017) Differential requirements for the canonical NF-?B transcription factors c-REL and RELA during the generation and activation of mature B cells. Immunol Cell Biol 95:261-271|
|De Silva, Nilushi S; Anderson, Michael M; Carette, Amanda et al. (2016) Transcription factors of the alternative NF-?B pathway are required for germinal center B-cell development. Proc Natl Acad Sci U S A 113:9063-8|
|De Silva, Nilushi S; Silva, Kathryn; Anderson, Michael M et al. (2016) Impairment of Mature B Cell Maintenance upon Combined Deletion of the Alternative NF-?B Transcription Factors RELB and NF-?B2 in B Cells. J Immunol 196:2591-601|
|De Silva, Nilushi S; Klein, Ulf (2015) Dynamics of B cells in germinal centres. Nat Rev Immunol 15:137-48|
|Klein, Ulf; Heise, Nicole (2015) Unexpected functions of nuclear factor-?B during germinal center B-cell development: implications for lymphomagenesis. Curr Opin Hematol 22:379-87|
|Heise, Nicole; De Silva, Nilushi S; Silva, Kathryn et al. (2014) Germinal center B cell maintenance and differentiation are controlled by distinct NF-?B transcription factor subunits. J Exp Med 211:2103-18|