NFkB is a pleitropic family of transcription factors (TFs) known to play major roles in diverse cell processes such as proliferation, apoptosis and inflammation. It is comprised of two signaling arms: canonical (mediated by dimeric combinations of Rel-A, cRel, NFKB1/p50) and alternative (mediated by Rel-B and NFkB2/p52).
Despite considerable evidence supporting the role of the REL members in lymphomagenesis, it is not clear whether specific NFKB dimers control a particular set of target genes in distinct germinal center (GC) B-cell derived lymphomas. As a first approach to address this issue we performed ChIP-Seq for each REL member
in different cell lines mode of Non-Hodgkin Lymphoma (NHL) and HL. We included BJAB and HBL1, representing the two Diffuse Large B Cell Lymphoma (DLBCL) molecular subtypes GCB-and ABC respectively, UH01 a HL cell line, as well as primary centroblasts isolated from human tonsil. This analysis shaped two network architectures: a Rel-B hierarchical network in HL and a cREL hierarchy in NHL. Microarray analysis of these cell lines following knockdown of Rel-A, Rel-B, or cREL was merged with ChIP-Seq data. The overlap of Rel-A, cREL and Rel-B peaks and the corresponding shRNA downregulated targets suggested that these factors directly controlled regulators of the cell cycle and cell death, GC B-cell transcription factors and DNA repair pathways among other gene signatures. In summary, we found that HL is the only GC derived malignancy that depends on Rel-B for viability,
and thus differentiates HL from NHL These data argue that each Rel member has specific and unique functions and targets, as we predicted from the lack of similarities in their transactivation domains. The data reported herein contributes to the knowledge that different B-cell lymphomas are characterized by a preferential
activity of the canonical, the alternative or both NF-kB signaling arms simultaneously. This specificity should be taken into account for the development of therapies aimed at selectively inhibit the NF-kB signaling pathway or even interfere particular subunits of this TFs family involved in the pathogenesis of a GC-derived B-cell lymphoma subtype.