Aberrant NF-kappaB signaling in lymphoma
NF-κB is widely involved in lymphoid malignancies such as Hodgkin’s lymphoma (HL), diffuse large B-cell lymphoma (DLBCL). However, functional roles of NF-κB dimers with distinct subunit composition and their specific transcriptomes remained unknown.
In HL cells, canonical as well as non-canonical IKK/NF-κB signaling is constitutively activated. Using combined ChIP-sequencing and microarray analyses we determined the cistromes and target gene signatures of both NF-κB signaling pathways. The various NF-κB subunits are recruited to regions with redundant κB motifs in a large number of genes. Yet, canonical and non-canonical NF-κB dimers up- and down-regulate distinct and overlapping gene sets that are associated with diverse tumor biological functions. p50 and p52, which are formed by NIK-dependent p105 and p100 precursor processing in HL cells, are the predominant DNA binding subunits. Logistic regression analyses of subunit binding pattern assigned to regulated genes reveal a cross-contribution of p52 and p50 to canonical and non-canonical transcriptomes. The pathway-specific signatures distinguish HL from other NF-κB-associated lymphoid malignancies and inversely correlate with gene expression pattern in normal germinal center B cells, the assumed precursors of HL cells. Our studies provide insights that are relevant for lymphomas with constitutive NF-κB activation and for the understanding of the mechanism of differential gene regulation by canonical and non-canonical NF-κB in general.
Linda von Hoff, Eva Kärgel, Kivia Pontes de Oliveira
Miguel Andrade (IMB Mainz), Norbert Hübner (MDC), Georg Lenz (Westfälische Wilhelms-Universität, Münster), Stephan Mathas (MDC)