Splenic marginal zone lymphoma (SMZL) is one of few B-cell lymphoma types that remain orphan of molecular lesions in cancer related genes. Detection of active NF-κB signaling in 14/24 (58%) SMZL prompted the investigation of NF-κB molecular alterations in 101 SMZL. Mutations and copy number abnormalities of NF-κB genes occurred in 36/101 (36%) SMZL, and targeted both canonical (TNFAIP3 and IKBKB) and non-canonical (BIRC3, TRAF3, MAP3K14) NF-κB pathways. Most alterations were mutually exclusive, documenting the existence of multiple independent mechanisms affecting NF-κB in SMZL. BIRC3 inactivation in SMZL was recurrently due to somatic mutations disrupting the same RING domain that in extranodal marginal zone lymphoma is removed by the t(11;18), pointing to BIRC3 disruption as a common mechanism across marginal zone B-cell lymphomagenesis. Genetic lesions of NF-κB provide a molecular basis for the pathogenesis of over 30% SMZL, and offer a suitable target for NF-κB therapeutic targeting in this lymphoma.
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