This study investigates the genetic basis of constitutive NF-kB activation in diffuse large B-cell lymphoma (DLBCL), a common form of adult lymphoma. The authors found that over 50% of activated B-cell-like (ABC) DLBCL and a smaller fraction of germinal center B-cell-like (GCB) DLBCL cases harbor somatic mutations in multiple genes regulating the NF-kB pathway, including negative regulators (TNFAIP3/A20) and positive regulators (CARD11, TRAF2, TRAF5, MAP3K7/TAK1, and TNFRSF11A/RANK). The A20 gene, which encodes a ubiquitin-modifying enzyme involved in terminating NF-kB responses, was the most frequently affected, with ~30% of patients showing biallelic inactivation. Functional assays demonstrated that A20 loss led to apoptosis and cell growth arrest, suggesting a tumor suppressor role. Additionally, missense mutations in TRAF2 and CARD11 enhanced NF-kB activation. These findings indicate that NF-kB activation in DLBCL is caused by genetic lesions affecting multiple genes, potentially promoting lymphomagenesis by prolonging NF-kB responses.This study investigates the genetic basis of constitutive NF-kB activation in diffuse large B-cell lymphoma (DLBCL), a common form of adult lymphoma. The authors found that over 50% of activated B-cell-like (ABC) DLBCL and a smaller fraction of germinal center B-cell-like (GCB) DLBCL cases harbor somatic mutations in multiple genes regulating the NF-kB pathway, including negative regulators (TNFAIP3/A20) and positive regulators (CARD11, TRAF2, TRAF5, MAP3K7/TAK1, and TNFRSF11A/RANK). The A20 gene, which encodes a ubiquitin-modifying enzyme involved in terminating NF-kB responses, was the most frequently affected, with ~30% of patients showing biallelic inactivation. Functional assays demonstrated that A20 loss led to apoptosis and cell growth arrest, suggesting a tumor suppressor role. Additionally, missense mutations in TRAF2 and CARD11 enhanced NF-kB activation. These findings indicate that NF-kB activation in DLBCL is caused by genetic lesions affecting multiple genes, potentially promoting lymphomagenesis by prolonging NF-kB responses.