通过重启程序性坏死（Necroptosis）阻抑慢性淋巴细胞白血病细胞炎症因子表达的机制研究

Chronic lymphocytic leukemia (CLL) is a clonal B-cell malignancy. Necroptosis is known as a well regulated cellular death program; chronic inflammation plays an important role in the initiation and progression of CLL. We have provided the first evidence that CLL cells have defects in necroptotic signaling and have explored the mechanisms (52th ASH meeting, oral presentation). We will further perform investigations listed below: ①confirm that CLL cells have both defective necroptotic signaling and up-regulation of pro-inflammatory factors; ②show that re-activate necroptotic pathway by LEF1 down-regulation may inhibit the expression of multiple pro-inflammatory factors; ③indentify LEF11 as a positive transcript regulator of multiple pro-inflammatory factors in CLL cells; ④explore the effect of other components in necroptotic pathway on pro-inflammatory factor expression; ⑤investigate the in vivo influence of re-activated necroptotic signaling on pro-inflammatory factors level. This study will improve our scientific hypothesis on the pathogenesis of CLL. LEF1 will be identified as an ideal “dual functional” treatment target. Our project will reveal more detailed molecular basis of CLL and provide novel treatment strategy for this disease.

慢性淋巴细胞白血病（CLL）是一种B淋巴细胞克隆性疾病。程序性坏死（Necroptosis）是新发现的细胞死亡机制；慢性炎症在CLL发生发展中的重要作用日益引人注目。申请人首次揭示了CLL细胞内程序性坏死途径存在缺陷并初步探讨了其机制（52届美国血液学年会口头报告）。现拟开展如下工作：①证实CLL细胞同时存在程序性坏死缺陷及多种炎症因子高表达；②阐明下调LEF1重启程序性坏死可以抑制CLL细胞多种炎症因子的表达；③探讨LEF1对多种炎症因子的转录激活作用；④研究程序性坏死途径中其它关键组分对炎症因子表达的影响；⑤体内证实重启程序性坏死途径对CLL细胞多种炎症因子表达的抑制作用。项目将完善申请人关于LEF1在CLL发病机制中重要作用的科学假说；LEF1将成为兼具调节CLL细胞程序性坏死和炎症反应“双重作用”的理想治疗靶点。该项目会进一步揭示CLL的分子机制并为其综合治疗提供新的策略与模式。

我们按照项目计划书完成了本研究。我们的结果显示慢性淋巴细胞白血病（CLL）细胞同时存在程序性坏死缺陷及多种炎症因子高表达，重启程序性坏死可以抑制B淋巴细胞炎症因子的表达，LEF1及炎症因子（如LTβ）在NF-κB等信号转导通路中具有重要调节作用。同时，多种炎症因子水平对细胞程序性坏死的具有调节功能。所以，程序性坏死途径和多种炎症因子在CLL细胞中存在交互调节作用。项目完善了我们关于LEF1在CLL发病机制中重要作用的科学假说，进一步揭示了CLL的分子机制。本项目发表15篇论文，其中SCI论文8篇。项目培养4名博士研究生。

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