分化诱导是急性髓系白血病（AML）的经典疗法，目前尚无广谱的分化诱导剂。申请者构建MCSFR-GFP的白血病细胞分化筛选模型，从课题组海洋化合物库中发现海洋苔虫内酯bryostatin-4和bryostatin-21具有诱导AML分化的活性，能促使NB4和HL-60细胞上调细胞表面分化抗原CD11c与CD11b，其可能通过MCSFR启动子的激活，调节分化相关信号分子P21、P27、HDAC、DNMT和THAP10，启动广谱白血病细胞分化信号通路。本研究旨在利用SPR、ITC、质谱等方法鉴定靶蛋白，采用高含量细胞分析、RNA干扰技术和AML1-ETO9a与PML-RAR alpha转基因和PDX小鼠模型，明确苔虫内酯诱导白血病分化的MCSFR启动子依赖机制，为AML诱导分化疗法提供先导化合物。

Differentiation induction is a traditional therapy in acute myeloid leukemia (AML). However, there is no broad-spectrum differentiation inducer. The differentiation induction abilities of the marine-derived compound library were evaluated through AML leukemia cells with ectopic expression of MCSFR and GFP, revealing that bryostatin-4 and bryostatin-21 induced differentiation in NB4 and HL-60 cells and up-regulate the expressions of cell surface markers CD11c and CD11b in AML cells. Bryostatins may initiate the differentiation signaling pathway in subsets of AML cell lines by produced the activation of the MCSFR promoter and regulated the differentiation-related signaling molecules such as P21, P27, HDAC, DNMT, and THAP10. This project will use SPR, ITC, and mass spectrometry to elucidate the target protein of bryostatins in AML. Moreover, to investigate the impact of bryostatins on AML differentiation induction, cell cycle arrest, and cell differentiation using high-content cell analysis, RNA interference technology, and AML1-ETO9a and PML-RAR alpha transgenic mice and PDX model for understanding the MCSFR promoter-dependent mechanisms of bryostatins-induced leukemia differentiation. Eventually, we provide lead compounds for the differentiation therapy of AML.