TOSO对NF-κB信号通路及慢性淋巴白血病细胞生存影响的研究

Toso, also known as FAIM3, is a gene newly identified to be selectively overexpressed in Chronic lymphocytic leukemia(CLL) as compared with other B cell malignancies and normal B cell, suggesting it might be involvement in the pathogenesis of CLL. In addition, recent studies have demonstrated that TOSO may involve in the activation of NF-κB pathway, which has been identified as the important abnormal pathway in the pathogenesis of CLL. But the detailed function of TOSO in CLL has not been well defined. Our previous works showed that TOSO was specifically overexpressed in Chinese patients with CLL and was an independent indicator for shorter treatment-free survival in CLL. By mass spectrometry, we then identified that TOSO might have direct interaction with TRAF2, which is the crucial activator of NF-κB pathway..In this project, we will further investigate ①the associations between TOSO and TRAF2 protein, ②whether TOSO will active NF-κB signaling pathway through TRAF2, ③the effect of TOSO on the proliferation and apoptosis of the primary cells of CLL and the B cell lymphoma's cell line, and ④the associations of the expression level of TOSO and the activation of NF-κB pathway in primary cells of CLL. The results may help us to define the exact mechanism of TOSO in the pathogenesis of CLL as the first time and provide the evidence to explore TOSO as a valuable therapeutic target for the treatment of CLL. So this project has great academic and applicative value.

TOSO是最近发现的慢性淋巴细胞白血病（CLL）特异性高表达基因，其具体功能尚不清楚。国外研究提示TOSO可能与NF-κB信号通路活化相关，而NF-κB信号通路异常活化在CLL发病中发挥关键作用。我们前期工作已证实TOSO在我国CLL患者中特异性异常高表达，是CLL独立的不良预后因素，TOSO与NF-κB信号通路活化的关键蛋白TRAF2存在相互作用。.本项目拟进一步开展如下工作：①鉴定TOSO与TRAF2间的相互作用；②TOSO是否通过TRAF2活化NF-κB信号通路；③TOSO对CLL原代细胞及B细胞淋巴瘤细胞系增殖、凋亡的影响；④结合临床分析CLL患者标本中TOSO表达水平与NF-κB活化水平的相关性。本项目的研究结果将揭示TOSO在CLL中的具体作用机制，为TOSO作为CLL治疗的新靶标提供理论依据，为进一步研究CLL的发病机制提供新途径，具有重要的理论意义和实用价值。

TOSO作为IgM的Fc端特异性受体，近年来发现在CLL中特异性高表达，我们的前期工作证实高表达TOSO是CLL的独立不良预后因素。但TOSO在CLL发生发展中如何发挥作用却无相关研究。通过本项基金支持，我们通过Co-IP方法筛选到TOSO直接作用的蛋白SYK，进一步证实TOSO可通过磷酸化SYK而活化BCR的下游信号通路，导致细胞凋亡受抑，BCR信号持续性通路活化是CLL的重要发病机制。我们在CLL患者原代细胞及NOD/SCID小鼠中对相应结果进行验证。本研究首次阐述了TOSO在CLL中的具体作用机制，为CLL发病机制研究提供新思路。