遗传变异、表观遗传和基因表达异常之间的协同作用是白血病发生的关键；ANP32A过表达在此过程中的作用和机制尚未见相关报道。前期研究发现ANP32A促进白血病细胞增殖、参与H3组蛋白修饰、协同MLL-AF9转化骨髓细胞；本项目将首先综合运用ChIP-Seq、基因芯片、免疫荧光和共沉淀、体外激酶试验等技术，系统揭示ANP32A全基因组的靶向位点和互作蛋白以及影响H3组蛋白修饰和相关酶复合物活性的分子机制。其次，利用MLL-AF9敲入和Anp32a敲除小鼠结合骨髓移植探讨ANP32A体内促进白血病发生的功能。最后，体外验证干预Anp32a功能抑制白血病细胞增殖的功能，并建立可诱导表达转基因小鼠体内验证干预内源Anp32a对MLL-AF9诱发白血病的治疗效果。本研究将系统阐明ANP32A与MLL-AF9、组蛋白修饰协同诱发白血病的机制，为白血病防治提供新靶点。

Synergestic interaction among genetic alterations and abnormal epigentics modifications and gene expression is essential for leukemogenesis. The role of ANP32A ovexpression in this process and its mechanism have not been reported. Our preliminary study found that ANP32A promoted leukemia cell proliferation, participated histone H3 modifications and synergized with MLL-AF9 to transform mouse bone marrow cells. First, this study will will integrate molecular biology techniques including ChIP-Seq, gene chip, immunofluorescence and immunoprecipitation, in vitro kinase assay etc to reveal the whole genome bingding sites , identify interacting proteins, verify its function on H3 histone modification and its effect on the activity of the related enzyme complex. Second, we will utilize MLL-AF9 knockin and Anp32a knockout mice and/or bone marrow transplantation technique to investigate the effect of Anp32a on leukemogensis in vivo. Finally, We will also explore the strategy to intefere ANP32A function that potentially impairs leukemia cell proliferation. We will also create transgenic mice to express interfering peptide in an inducible manner, by which we test if interfering endogenous Aanp32a function may have therapeutic effec on MLL-AF9-induced leukemogenesis. This study will systematically clarify the mechnism by which ANP32A synergize with MLL-AF9 and histone modifications to induce leukemia and provide novel target for leukemia therapy.