Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
Blood. 2011 Nov 3;118(18):4930-4. doi: 10.1182/blood-2011-06-359166. Epub 2011 Aug 31.
Splenic marginal zone lymphoma (SMZL) is one of the few B-cell lymphoma types that remain orphan of molecular lesions in cancer-related genes. Detection of active NF-κB signaling in 14 (58%) of 24 SMZLs prompted the investigation of NF-κB molecular alterations in 101 SMZLs. Mutations and copy number abnormalities of NF-κB genes occurred in 36 (36%) of 101 SMZLs and targeted both canonical (TNFAIP3 and IKBKB) and noncanonical (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 recurred because of somatic mutations that disrupted the same RING domain that in extranodal marginal zone lymphoma is removed by the t(11;18) translocation, which points 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 more than 30% of SMZLs and offer a suitable target for NF-κB therapeutic approaches in this lymphoma.
脾边缘区淋巴瘤 (SMZL) 是少数几种缺乏癌症相关基因分子病变的 B 细胞淋巴瘤之一。在 24 例 SMZL 中，有 14 例 (58%) 检测到活跃的 NF-κB 信号，这促使我们对 101 例 SMZL 进行了 NF-κB 分子改变的研究。在 101 例 SMZL 中，有 36 例 (36%) 出现了 NF-κB 基因的突变和拷贝数异常，涉及经典 (TNFAIP3 和 IKBKB) 和非经典 (BIRC3、TRAF3、MAP3K14) NF-κB 途径。大多数改变是相互排斥的，证明了存在多种影响 SMZL 中 NF-κB 的独立机制。SMZL 中的 BIRC3 失活是由于体细胞突变所致，这些突变破坏了与结外边缘区淋巴瘤中相同的 RING 结构域，而结外边缘区淋巴瘤中的 t(11;18)易位则会切除该结构域，这表明 BIRC3 失活是边缘区 B 细胞淋巴瘤发生的共同机制。NF-κB 的遗传病变为超过 30%的 SMZL 提供了发病机制的分子基础，并为该淋巴瘤的 NF-κB 治疗方法提供了合适的靶点。
