Somatic Mutation and Activation of the NF-κB Pathway in MCL. Activation of the classical and alternative NF-κB pathway in MCL may occur by chronic active BCR signaling and other mechanisms. Genomic sequencing studies have identified mutations in several elements of this regulatory pathway (denoted by red asterisks). Chronic active BCR (A) or Toll-like receptor (TLR) (B) signaling activate the classical NF-κB pathway. MCL that is dependent on BCR activation (A) may be blocked by BCR signaling inhibitors. Somatic mutations in the inhibitors of the alternative pathways (C) cIAP1 and cIAP2 (gene products of BIRC2 and BIRC3, respectively) and TRAF2/3 activate the alternative NF-κB pathway and confer resistance to inhibitors of the BCR signaling pathway. Somatic mutations in other elements of these pathways (CARD11, IKKβ, encoded by IKBKB, TLR2, and NIK, encoded by MAP3K14) also have been found in MCL by whole-exome or genome sequencing.Reprinted from Cancer Cell, Volume 25, Issue 1, Colomer D and Campo E, Unlocking New Therapeutic Targets and Resistance Mechanisms in Mantle Cell Lymphoma, Pages 7-9, Copyright 2014, with permission from Elsevier.