Zhang Xinxia, Shi Yaoyao, Weng Yuanyuan, Lai Qian, Luo Taobo, Zhao Jing, Ren Guoping, Li Wande, Pan Hongyang, Ke Yuehai, Zhang Wei, He Qiang, Wang Qingqing, Zhou Ren
Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
PLoS One. 2014 Oct 14;9(10):e108747. doi: 10.1371/journal.pone.0108747. eCollection 2014.
The Notch2 is a critical membrane receptor for B-cell functions, and also displays various biological roles in lymphoma pathogenesis. In this article, we reported that 3 of 69 (4.3%) diffuse large B-cell lymphomas (DLBCLs) exhibited a truncate NOTCH2 mutation at the nucleotide 7605 (G/A) in the cDNA sequence, which led to partial deletion of the C-terminal of PEST (proline-, glutamic acid-, serine- and threonine-rich) domain. The truncate Notch2 activated both the Notch2 and the NF-κB signals and promoted the proliferation of B-cell lymphoma cell lines, including DLBCL and Burkitt's lymphoma cell lines. Moreover, the ectopic proliferation was completely inhibited by ammonium pyrrolidinedithiocarbamate (PDTC), an NF-κB inhibitor. Simultaneously, PDTC also reduced the expression level of Notch2. Based on these results, we conclude that the Notch2 receptor with PEST domain truncation enhances cell proliferation which may be associated with the activation of the Notch2 and the NF-κB signaling. Our results are expected to provide a possible target for new DLBCL therapies by suppressing the Notch2 and the NF-κB signaling.
Notch2是B细胞功能的关键膜受体，在淋巴瘤发病机制中也发挥着多种生物学作用。在本文中，我们报告称，69例弥漫性大B细胞淋巴瘤（DLBCL）中有3例（4.3%）在cDNA序列的核苷酸7605（G/A）处出现NOTCH2截断突变，这导致富含脯氨酸、谷氨酸、丝氨酸和苏氨酸的PEST结构域C末端部分缺失。截断的Notch2激活了Notch2和NF-κB信号，并促进了B细胞淋巴瘤细胞系的增殖，包括DLBCL和伯基特淋巴瘤细胞系。此外，吡咯烷二硫代氨基甲酸铵（PDTC），一种NF-κB抑制剂，完全抑制了异位增殖。同时，PDTC也降低了Notch2的表达水平。基于这些结果，我们得出结论，具有PEST结构域截断的Notch2受体增强了细胞增殖，这可能与Notch2和NF-κB信号的激活有关。我们的结果有望通过抑制Notch2和NF-κB信号为新的DLBCL治疗提供一个可能的靶点。
