The NF-κB Genomic Landscape in Lymphoblastoid B Cells

The nuclear factor kappa B (NF-kappa B) subunits RelA, RelB, cRel, p50, and p52 are each critical for B cell development and function. To systematically characterize their responses to canonical and noncanonical NF-kappa B pathway activity, we performed chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) analysis in lymphoblastoid B cell lines (LCLs). We found a complex NF-kappa B-binding landscape, which did not readily reflect the two NF-kappa B pathway paradigms. Instead, 10 subunit-binding patterns were observed at promoters and 11 at enhancers. Nearly one-third of NF-kappa B-binding sites lacked kB motifs and were instead enriched for alternative motifs. The oncogenic forkhead box protein FOXM1 co-occupied nearly half of NF-kappa B-binding sites and was identified in protein complexes with NF-kappa B on DNA. FOXM1 knockdown decreased NF-kappa B target gene expression and ultimately induced apoptosis, highlighting FOXM1 as a synthetic lethal target in B cell malignancy. These studies provide a resource for understanding mechanisms that underlie NF-kappa B nuclear activity and highlight opportunities for selective NF-kappa B blockade.