Mechanism of aberrant NF-κB activation through the canonical signaling pathway in human lymphomas. Aberrant activation of the canonical pathway. NF-κB can be aberrantly activated in HL by signals from CD30, CD40, and RANK, which induce the activation of the IKK complex via TRAF proteins. The latent membrane protein 1 (LMP1) of EBV engages the intracellular CD40 signaling machinery in HL. CARMA1, BCL10, and MALT1 are key upstream mediators of NF-κB activation in ABC-DLBCL. The viral oncoproteins TAX of HTLV-I and vFLIP of HHV-8 are able to bind IKKγ and induce constitutive IKK activation in ATL and PEL, respectively. The fusion protein IAP2-MALT1 or deregulated expression of the proteins MALT1 or BCL10 frequently activates the IKK complex in MALT lymphomas. Deregulated MALT1 expression is also found in selected cases of marginal zone lymphoma (MZL) and Burkitt lymphoma. Inactivating mutations of IκBα/ϵ, resulting in a decreased inhibitory function and a persistent NF-κB transcriptional activity, have been identified in HL. Amplifications of c-Rel have been recognized in HL, germinal center (GC)–DLBCL, and primary mediastinal B-cell lymphoma (PMBL). Illustration by Kenneth Probst.