Although the requirement of the NF-kB pathway in B-cell lymphomas is clear, the role of the individual REL (c-rel, relA, and relB) proteins is not understood. This is particularly interesting for several reasons. The first is the observation that c-rel is often amplified in several lymphomas: 50% of Hodgkin's (HL) and 20-30% of diffuse large B-cell lymphomas (DLBCL). However, the specific role of c-rel amplification, as opposed to relA and rel B is not known. Secondly, the lack of similarities in the primary sequences of the three RELs is considerable. This disparity does not lie within the DNA binding and dimerization Rel Homology Domain (RHD), but rather in the C-terminal transcriptional transactivation domains (TAD) of the three. There is only 10% similarity between c-rel and relA, for example. We have therefore constructed the hypothesis that the three REL proteins are functionally distinct and unique. The differences in the TADs suggest that each REL protein has different promoter targets and unique transcriptional biochemistry. Furthermore, the specificity of the c-rel amplification implies that the REL proteins each will have distinct, nonoverlapping functions in lymphoma tumorigenesis. We are therefore addressing the functions of the REL family in B-cell lymphomas in vivo and in vitro. We are addressing REL family functions in several ways. We have begun an in vitro analysis of the protein factors that are necessary for the transcriptional activity of each REL family member. As stated above, we expect these factors to be different for each REL protein. Secondly, we have embarked on an extensive analysis of the genomic distribution of the REL proteins and the promoters they regulate. We are analyzing several different human B-cell lines that represent both Hodgkin's and non-Hodgkin's lymphomas. Finally, we are using cell viability assays and shRNAs that target each REL member to assess their relative importance in the maintenance of lymphoma cell viability.
