Role of the canonical NF-kappaB pathway in B-cell differentiation and oncogenic transformation
Final Report Abstract
Lymphoid malignancies, 80% of which originate from B-cells, represent a major public health concern. Despite recent advances, the treatment of B cell-derived tumors still represents a major challenge for medicine as most subtypes are associated with poor prognosis. These observations underscore the need to better understand the molecular mechanisms that underlie tumorigenesis and to develop highly specific anti-lymphoma drugs that could increase the efficacy of currently used treatment regimens. Elucidating the roles of the separate canonical NF-κB subunits in B-cell physiology and dissecting the contribution of each subunit to lymphomagenesis may provide the basis for developing innovative anti-cancer therapies. By specifically targeting constitutive NF-κB signaling at the level of the individual NF-κB subunits or their target genes, adverse systemic side effects associated with the pharmacological inhibition of the entire NF-κB pathway could be reduced. The findings achieved through Aim 1 demonstrate that deletion of a single NF-κB subunit can have drastic effects, and furthermore suggest that there is no general redundancy of the canonical NF-κB subunits c-REL and RELA during the GC reaction. Ablation of c-REL, but not RELA expression, in GC B-cells led to their numerical reduction, while the post-GC memory B-cell and plasma cell compartments were affected upon deletion of either subunit. Our results therefore suggest a model in which c-REL may be required either for the maintenance of GC B-cells or at the point of selection for affinity maturation, while RELA appears to be required at a later step in the GC reaction after affinity maturation has occurred, presumably at the differentiation of an antigen-selected GC B-cell into a post-GC B-cell. The GEP analysis per-formed under Aim 2 yielded very unique and interesting results, pointing towards a role of c-REL in GC B-cells beyond its known functions in cell survival and cell cycle regulation. Most notably, a group of genes involved in energy metabolism, and in particular lipid metabolism, was found to be differentially regulated in rel-deleted GC B-cells. This finding is of particular interest since fatty acid metabolism has been identified as an important contributor to cancer cell function in certain cancers. Further experiments are underway to solidify the observations made in Aims 1 and 2, in order to unequivocally identify the mechanisms underlying the loss of rel-deleted GC B-cells as well as relA-deleted post-GC B-cells. The described project is expected to be finalized within the next year.
Publications
- (2012). The diverse roles of IRF4 in late germinal center B-cell differentiation. Immunol Rev. 247:73-92
De Silva NS, Simonetti G, Heise N, Klein U
