IL-33/ST2L信号通路异常在骨髓增生异常综合征“二次打击”发病机制的探索性研究

Our previous published research has elucidated that EZH2, a histone methyltransferase that targets lysine 27 of histone H3 (H3K27), its loss-of-function mutation alone can only cause the ineffective hematopoiesis but prevents acute myeloid leukemia (AML) transformation. IL-33/ST2L signaling pathway dysfunction can be regulated by epigenetic regulator and alter the bone marrow microenvironment. Based on our unpublished preliminary data and literature review, we made a hypothesis that IL-33/ST2L signaling pathway dysregulation is a key ‘second-hit’ mechanism in the pathogenesis of MDS clonal evolution and/or AML transformation. In this ‘second-hit’ model, IL-33/ST2L signaling pathway is activated on the background of EZH2 loss-of-function mutation. This can cause excessive proinflammatory cytokines production, T cell dysfunction and abnormal molecular expression which regulate the bone marrow niche. The imbalanced bone marrow microenvironment finally leads to immune evade, MDS clonal evolution and/or AML transformation. We wish to prove our hypothesis using existed mouse models as well as a series of experiments in vitro and in vivo. IL-33/ST2L signaling pathway dysregulation was less documented previously in pathogenesis of MDS. The execution of this project can clarify the exact role of IL-33/ST2L-mediated bone marrow microenvironment dysregulation based on EZH2 loss-of-function mutation. Our findings may reveal a novel MDS pathogenesis and provide a solid theory foundation in MDS targeted therapy in the near future.

我们前期已发表的研究确定了EZH2突变在MDS发生中有重要作用，但尚不足以引起MDS的克隆演变及AML转化。IL-33/ST2L信号通路异常可以受到表观遗传学调控并导致造血微环境改变。根据文献及预实验结果，我们推测IL-33/ST2L信号通路异常是导致MDS发生克隆演变及/或AML转化的关键“二次打击”事件：在EZH2突变背景下IL-33/ST2L信号通路激活，导致相关促炎性因子表达，T细胞功能紊乱及造血细胞龛相关因子表达异常而使骨髓造血微环境失衡，恶性克隆免疫逃避并导致MDS向高危亚型或AML转化。本研究拟利用成熟的小鼠模型及系统的体内外实验证实我们的假说理论。IL-33/ST2L信号通路异常在MDS发病机制的研究很少，本课题的实施有希望系统阐明IL-33/ST2L通路介导的骨髓微环境异常在EZH2失功能背景下MDS克隆转化及免疫逃避的具体机制，为MDS的靶向治疗提供更坚实的理论基础。

骨髓增生异常综合征（MDS）发病机制复杂，其主要特征是无效造血和高危演变成急性髓系白血病。已发表的研究提示异常的造血微环境在其中有重要作用。本研究旨在阐明IL-33/ST2L通路介导的免疫微环境异常与MDS克隆转化及免疫逃避之间的关系。我们通过Elisa，luminex及流式细胞学，对MDS患者外周血中的包括可溶性ST2（sST2）在内的49种细胞因子，以及Tregs、MDSCs等免疫细胞进行检测，分析其与MDS进展的关系，并根据sST2、IL-2α水平建立了能够良好预测患者总体生存的危险因素评分预测模型。结果提示IL-33/ST2在内的炎性因子信号通路紊乱与MDS患者进展性事发生相关，且IL-2α/Tregs细胞可能通过sST2参与了该过程。我们进一步探讨了在MDS向高危亚型转化中Tregs，MDSCs，IL-1β的作用。揭示了高水平的IL-1β，nTregs/iTregs的亚型转换，高比例的MDSCs，以及NLRP3/IL-1β通路在MDS的疾病进展及向白血病转化中发挥的关键促进作用。我们研究的结果也为进一步寻找MDS的造血微环境中与疾病进展及向白血病转化的关键靶点的筛选及治疗提供了重要依据。本项目开展过程中发表Q1类期刊论文2篇，Q3类期刊论文1篇，另有2篇重要文章在审稿中。