双重靶标c-Mpl和STAT3/5拮抗多肽的筛选及其对白血病细胞的动态调控

白血病细胞增殖和分化依赖外源性细胞生长因子刺激作用，但人体白血病巨核系细胞有自发增殖的活性，这和血小板生成素受体（c-Mpl）异常表达导致的致病性密切相关。我们首次报道了c-Mpl胞外区域在白血病细胞Dami存在缺失的24个氨基酸的剪切形式，其对白血病增殖和分化中有重要的作用，本项目拟通过进一步发现，白血病Dami细胞株c-Mpl序列突变的分子特征，构建带有异常表达的c-Mpl和STAT3/5调控序列双靶标的共转染细胞模型。进而筛选噬菌体多肽展示文库，以获得高亲和、特异性的c-Mpl异常表达的拮抗多肽。同时，观察拮抗多肽对白血病细胞增殖、诱导分化和凋亡的影响，阐明在白血病细胞动态生长时，其对信号传导的关键调控作用。本项目的研究不但可深化对c-Mpl受体异常表达的选择机制认识，而且为寻找防治巨核细胞白血病新的药物作用靶标和分子标记提供科学依据。

The proliferation and differentiation of leukemia cells depend on the exogenous cell growth factor. However, the human leukemia megakaryocytes gain the ability of auto-proliferation, which is closely related to the pathogenicity entailed by the abnormal expression of thrombopoietin receptor(c-Mpl). We have first reported the presence of a misspliced form of c-Mpl with a 24 amino acids deletion in the extracellular domain of c-Mpl existed in leukemia Dami cells. The misspliced c-Mpl plays significant role in the proliferation and differentiation of leukemia cells. This project is to further investigate the molecular features of the mutations of c-Mpl in leukemia Dami cells. We constructed a co-transfected cell model carrying aberrant c-Mpl and STAT3/5 double-targets regulatory sequences. Then screen the Phage Peptides Display Library to harvest antagonistic peptides with high-affinity for specific aberrant c-Mpl. Meanwhile, investigate the contribution of antagonistic peptides to the proliferation, differentiation and apoptosis of leukemia cells as well as deciphering their regulatory effects on signal transduction during dynamic development tof leukemia cells. This project gives further insight into the alternative mechanism of the aberrant expressing c-Mpl. It can also aid in the exploration of new targets for drugs and offer theoretical basis for developing new pharmaceutical targets regarding the prevention and treatment of acute megakaryoblastic leukemia .