骨髓niche功能缺陷对白血病的发生发展进程具有重要影响，但白血病环境中骨髓niche细胞发生怎样的缺陷及其机制目前尚不清楚。我们前期研究发现白血病环境中骨髓基质细胞功能缺陷，而且存在甲基化表观遗传学改变。因此，本课题以建立的MLL-AF9急性髓细胞白血病（MA9-AML）小鼠为模型，观察骨髓成骨细胞生物学功能改变；采用高通量ChIP-on-Chip检测方法和生物信息学对成骨细胞进行检测和分析，筛选特异表达的表观改变并采用分子生物学和细胞生物学手段对特异表观改变鉴定；构建干预特异表观改变的慢病毒载体，采用修饰的成骨细胞与白血病干细胞（LSCs）体外共培养和体内共移植实验明确其对LSCs生物学特性及对白血病发展和小鼠生存的影响。以期通过本课题的研究，明确白血病环境中骨髓niche成骨细胞表观遗传学改变及特异表观改变对LSCs生物学特性的影响，为从niche角度治疗AML提供新思路。

Bone marrow microenvironment (niche) plays a critical role in the pathogenesis of leukemia. Although abundant studies have demonstrated that niche has been closely associated with ontogenesis of leukemia, however, in luekemia stress the niche's dysfuction and its definite mechanisms are still unknown. In previous study, we have defined the dysfuction of bone marrow stromal cells from luekemic mice and acute myeloid luekemia (AML) patients. The epigenetic defects in the bone marrow stromal cells have also been demonstrated in our previous study. In present project, we would further investigate the biologic functions of osteoblasts, one of pivotal components in the bone marrow niche, with the well-established MLL-AF9 AML (MA9-AML) mouse model. The epigenetic alterations of osteoblasts in the leukemia host will be investigated through ChIP-on-Chip, and further analyzed with bioinformatics. The definitive epigenetic discrepancies will be verified with molecular and cellular biologic measures in vivo and in vitro. The impacts of definitive epigenetic alterations on the biological characteristics of leukemic stem cells (LSCs) and leukemia progression would be studied through co-cultured and co-transplanted with osteoblasts with modified with lentivirus vector along with LSCs. The available small molecular would be employed to modify the epigenetic changes in vivo. The project will specify the epigenetic alterations of osteoblats in the leukemia host, and its impacts on the biology characteristics of LSCs, and may provide evidences for the novel target of niche in leukemia therapy.