Myosin 9-高三尖杉酯碱的直接靶蛋白对急性髓细胞白血病的作用与信号通路研究

高三尖杉酯碱（HHT）是治疗急性髓系白血病（AML）的重要药物，但其作用机制不详。我们曾发现HHT通过抑制JAK2/V617F与BCR/ABL肿瘤蛋白引起信号通路蛋白磷酸化而抑制急性白血病。但这不能回答HHT直接作用的靶蛋白是什么。新近，我们与美国华盛顿大学合作，制备了HTT亲和柱，寻找到HTT直接作用的靶蛋白为myosin 9。本课题将在此基础上，深入研究：（1）探讨myosin 9的mRNA表达与初发AML患者预后的关系。（2）将Myosin9过表达和沉默，阐明myosin 9在AML细胞株中的上下游通路及对HHT疗效变化。（3)构建不同myosin9表达水平的AML动物模型，予以HHT治疗，进一步阐明HHT及其靶蛋白myosin 9在AML中的作用机制，为寻找AML治疗的新的靶向药物与设计更优秀的白血病治疗策略，提供重要的科学依据，具有非常重要的意义。

Homoharringtonine(HHT) is one of the important drugs for management of acute myeloid leukemia in China, but little is known about the molecular mechanism of its action. Previously, we found that HHT could inhibit the phosphorylation of the signal proteins though oncogenic proteins such as JAK2/V617F and BCR/ABL.However, this could not answer the question that what is the direct target of HHT. Recently, in corporation with the University of Washington, we have discovered that myosin 9 is the direct target protein of HHT by preparing HHT affinity column, and the expression level of myosin 9 is associated with progression of chronic myeloid leukemia. Based on above research, we plan to explore: (1) what change will be caused by combination of HHT and myosin 9 on downstream molecules, and its relation with apoptosis and differentiation of leukemia cells? (2) What are the up and down-stream pathways of myosin 9 (3) What is the role and mechanism of myosin 9 signal complex in RUNX1/Myosine 9 pathway。We will clarify the effect of myosin 9 on proliferation, apoptosis and differentiation of leukemia cells, to provide foundation for searching new myeloid leukemia-specific drug- target and designing effective target drug.