MYD88突变通过调控可变剪接事件影响慢性淋巴细胞白血病BCR通路的机制研究

MYD88 mutation status is related to the differential mRNA expression landscapes in CLL and they contribute to the progression of CLL through multiple pathways. In our previous study, we found that MYD88 mutations predict unfavorable prognosis in CLL patients with mutated IGHV gene. However, the molecular and pathological mechanisms of a MYD88 hotspot mutation in CLL is yet to be discovered. This study is to investigate the mutation and clinical significance of MYD88 gene in CLL patients, the differential expression of MYD88 L265P-related genes and signaling pathways, and the regulation of alternative splicing events. Inhibiting spliceosome function may be a potential therapeutic target for CLL patients with mutant MYD88 gene. In summary, our project is to provide novel insights for further understanding of the molecular and pathological mechanisms of MYD88 mutation in CLL.

慢性淋巴细胞白血病（CLL）中MYD88基因突变与转录水平的多种差异表达及其调控mRNA的差异剪接密切相关，共同作用并通过多种途径影响CLL细胞的生物学功能。我们研究发现，伴MYD88突变的患者在伴IGHV突变的CLL患者群体中预后较差，疾病进展迅速。目前CLL中MYD88基因突变的作用机制尚不清楚。本研究拟探讨：CLL患者中MYD88基因突变情况及临床意义；CLL中MYD88基因突变对BCR通路活化状态及下游信号通路的影响；MYD88突变相关的BCR通路基因的差异剪接事件，并阐明MYD88突变是否参与调控BCR通路上述基因的可变剪接事件；剪接抑制剂对伴MYD88突变的CLL细胞的影响，探究伴此突变的CLL患者是否能从中获益，从而改善预后。

慢性淋巴细胞白血病(chronic lymphocytic leukemia, CLL)是西方国家发病率最高的成人白血病，CLL具有高度异质性，随着近年来生物和基因技术的迅速发展，研究发现了越来越多新的分子学预后指标。在前期研究中，我们发现CLL中MYD88基因突变有其独特的预后价值，通过系统且完整的实验，本研究阐明了CLL中MYD88 L265P通过参与调控BCR通路及凋亡通路相关基因的可变剪接事件，引起相关基因及信号通路的差异表达；剪接抑制剂可以逆转CLL中MYD88突变对BCR通路抑制剂伊布替尼敏感性的影响，其诱导细胞死亡与GSDME切割和MCL1的下调相关。MYD88突变CLL患者有其独特的免疫微环境，细胞焦亡通路受到抑制，其焦亡相关基因如PLCG1存在差异剪接事件。细胞焦亡在CLL中具有预后意义，焦亡高风险组CLL患者MYD88下游信号通路显著下调，肿瘤免疫失调，疾病预后差。