DUX4作为转录因子，其异常表达会引起肌营养不良症的发生。而其参与的染色体易位产生的DUX4-IGH，会引起B急性淋巴细胞白血病的发生，这是新发现的一类融合基因。我们近期解析出DUX4的HD2结构域及其与DNA复合物的结构，并证明DUX4 N端的2个HD结构域在DUX4-IGH与靶基因的识别与转录激活中都发挥着重要的作用（Leukemia, 2018）。但DUX4的C端结构域（CTD）的结构和功能尚不清楚，需要进一步的研究。本项目旨在通过解析CTD结构域的晶体结构并结合分子、生化、细胞生物学方法，探究其在DUX4和DUX4-IGH对靶基因转录调控中的功能和作用，进一步阐明DUX4-IGH在白血病发病中的作用机制。以此为基础，借鉴我们近期在急性早幼粒细胞白血病中靶向癌蛋白结构治疗白血病的研究思路（Nature Communications，2018），促进转化医学的探索，改善白血病的治疗。

Abnormal overexpression of wild type DUX4 is often associated with human disease known as facioscapulohumeral muscular dystrophy (FSHD). In leukemia, it has been recently shown, by our lab and other research groups, that oncogenic fusion DUX4-IGH, derived from chromosomal translocation, can cause B-cell acute lymphoblastic leukemia (B-ALL). Very recently, we have determined the crystal structures of Apo- and DNA-bound DUX4-HD2 domain. Further supported by biophysical/molecular/cellular observations, we proposed an important role of DUX4-DNA recognition step in leukemogenesis（Leukemia, 2018). In this proposal, we will build on our previous success and continue to determine the bigger fragments of WT DUX4, DUX4/IGH, full length protein and their DNA-bound derivatives. After the structures of DUX4 and DUX4/IGH are obtained, we propose to verify its functions through molecular, biochemical and cellular characterization. The multidisciplinary approach will not only advance our understanding these oncogneic drivers, but also extend our knowledge towards translation application as attested by our recent success in acute promyelocytic leukemia（Nature Communications，2018).