Normal B cells require a low level (tonic) signal from the B-cell receptor to activate the NF-κB pathway and maintain survival, and in specific subsets of B cells this requires CARD11. Thus, it is possible that ABC DLBCL cells are a mutated form of one of these specific CARD11-dependent subsets. Alternatively, ABC DLBCL cells might have acquired mutations within this pathway that make them dependent on CARD11. Staudt and colleagues investigated these possibilities by sequencing all coding exons of CARD11 in 20 ABC DLBCL biopsy samples and cell lines. Three biopsy samples and one cell line had missense base substitutions in the coiled-coil domain that enables CARD11 oligomerization and activation of the NF-κB pathway. Sequencing the exons encoding the coiled-coil domain in an additional 136 DLBCL biopsy samples indicated that 9.6% of the ABC subtype had mutations near to or within this domain compared with 3.8% of germinal centre B-cell-like subtypes.
How do mutations within the coiled-coil region affect CARD11? Six of eleven CARD11 mutants showed constitutive high-level activation of NF-κB in non-antigen-stimulated cells, and all mutants had increased levels of NF-κB activation compared with wild-type CARD11 in stimulated cells. CARD11 is normally diffusely localized in the cytoplasm in the absence of antigen stimulation, but the CARD11 mutants were aggregated in the cytoplasm, and co-localized with the NF-κB activator IκB kinase (IKK) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1), a signalling protein required for activation of IKK. IKK within these complexes was active, indicating that mutations within the coiled-coil domain induce constitutive activation of CARD11 and suggest that the coiled-coil domain might regulate the activity of CARD11.
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