The NF-κB signaling pathway and its activation in HRS cells. In the classical NF-κB signaling pathway, activation of diverse receptors leads via TRAFs (TNF receptor associated factors), often in association with the receptor interacting protein (RIP), to activation of the IKK complex, which consists of IKKα, IKKβ and NEMO. The IKK complex phosphorylates the NF-κB inhibitors IκBα and IκBε. This marks them for proteasomal degradation, thereby releasing the NF-κB factors (p50/p65 or p50/Rel heterodimers) and allowing their nuclear translocation. The signal transduction can also be inhibited by A20, which removes activating ubiquitins from RIP and TRAFs and adds Lys-48–linked ubiquitins to these molecules to mark them for proteasomal degradation. In the alternative NF-κB pathway, receptor activation leads to stimulation of the kinase NIK, which then activates an IKKα complex. Activated IKKα processes p100 precursors to p52 molecules, which then translocate as p52/RelB NF-κB heterodimers into the nucleus. HRS cells show constitutive activity of both the classical and alternative NF-κB signaling pathway, which is a central mechanism in HL pathogenesis. The NF-κB activity in HRS cells is mediated by diverse mechanisms, eg, receptor signaling through CD40, RANK, BCMA, and TACI, and signaling through the EBV-encoded latent membrane protein 1 in EBV-positive cases. Genetic lesions contributing to NF-κB activity involve genomic REL amplifications, destructive mutations in the genes of the NF-κB inhibitors IκBα and IκBε, gains or translocations of Bcl-3, and inactivating mutations in the NF-κB inhibitor A20, the latter mainly in EBV-negative cases. The frequency of genetic lesions and viral infections in classical HL cases is indicated. Adapted from Küppers.³