Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma

Abstract

Two groups report in this issue that A20 protein, a negative regulator of NF-κB signalling pathways, is frequently inactivated in patients with B-cell lymphoma. Kato et al. show that cells lacking the A20 gene generate tumours in immunodeficient mice, and that tumour formation is suppressed when the protein is re-expressed. Compagno et al. show that A20 is inactivated in around 30% of patients with B-cell lymphoma. Both groups show that A20 protein suppresses cell growth in vitro and prompts cells to commit suicide. Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adulthood. Here, mutations in multiple genes that regulate the NK-κB pathway are shown to be present in DLBCL, with the most commonly affected being the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NK-κB responses. Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL1. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-κB transcription complex2. However, except for a small fraction of cases3, it remains unclear whether NF-κB activation in these tumours represents an intrinsic program of the tumour cell of origin or a pathogenetic event. Here we show that >50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3, also called A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7 (TAK1) and TNFRSF11A (RANK)) regulators of NF-κB. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-κB responses, is most commonly affected, with ∼30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumour suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-κB. Thus, our results demonstrate that NF-κB activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-κB responses.