白血病是造血干细胞异常增殖的血液恶性肿瘤，探索和发现白血病新的治疗靶点将有利于提高白血病的治愈率。在急性骨髓性白血病细胞中，AF10 蛋白是能与组蛋白甲基化酶Dot1L发生相互作用并调节Dot1L二甲基化酶活性的关键因子。但是迄今为止，关于AF10蛋白与组蛋白甲基化酶Dot1L相互作用的分子机理以及相关结构域的结构生物学研究却很少。本项目拟通过AF10-Dot1L复合物的结构与功能研究以及AF10-抑制性多肽分子复合物的结构与功能研究等工作的开展，来明确AF10蛋白分子结构特征、AF10蛋白与组蛋白甲基化酶Dot1L相互作用方式、特异性结合AF10蛋白的抑制性多肽分子的结构特征以及相关组蛋白识别结构域的分子特征，并通过基于复合物结构信息的多肽分子改造，获得具有体外高结合能力的抑制性多肽分子，以期望为白血病新的治疗靶点开发提供理论依据和借鉴，进一步促进基于结构信息的抗白血病靶向药物的开发。

Leukemia is cancer of the body's blood-forming tissues, including the bone marrow and the lymphatic system. Targeted therapy is a newer type of treatment for leukemia, which designed to attack a certain gene change in a cancer cell. In acute myeloid leukemia cell, AF10 regulates H3K79 di-methylation via interacting with histone methyltransferase Dot1L and histone H3K27, which provides therapeutic value for patients suffering from MLL fusion AMLs. So far, there is little structural knowledge about the AF10 protein with its interaction partner Dot1L. To understand the roles of AF10 in leukemogenesis, we have devised several specific aims to clarify the mechanism, including structural and functional studies of AF10-Dot1L complex, structural and functional studies of AF10-Inhibitory peptide, structural and functional studies of cancer related PZP domain containing protein. The overall scientific goals of these studies are to obtain the structure information of AF10-Dot1L interacting regions and complex of AF10-Inhibitory peptide and determine the general mechanism by which PZP motif recognizes the substrate as a single module. The success of this project will not only shed new light on our understanding of the targeted therapeutic role of AF10, but also may lead to the ultimate development of specific anti-leukemia drug based on the information of AF10-Dot1L and AF10-Inhibitory peptide structures.