DUX4-IGH融合蛋白诱导急性B淋巴细胞白血病的发病机制研究

急性淋巴细胞白血病是最常见的儿童白血病，其中急性B淋巴细胞白血病的比例占80%。最近发现一种新融合基因，DUX4-IGH，在B-ALL中约占7%。迄今为止，DUX家族的分子、结构信息知之甚少，DUX4-IGH如何结合DNA、调控下游靶基因进而引发B-ALL的发生机制亦尚不清楚。在前期研究中，我们解析出DUX4的HD2结构域的晶体结构。初步功能研究表明，干扰DUX4-IGH与DNA的结合可以抑制DUX4-IGH下游靶基因ERGalt的转录激活和高表达。与此同时，我们通过对B-ALL病人RNA-seq数据的分析，找到了一些可能受DUX4-IGH调控而异常高表达的基因，提示它们在B-ALL发病中也起着重要的作用。本项目研究目标是，利用结构生物学手段，结合细胞和分子生物学、小鼠建模等技术，阐明DUX4-IGH在白血病发病中的作用机制，寻找、设计和优化可以应用在临床上的小分子靶向药和化疗方案。

Acute lymphoblastic leukemia (ALL) is the most common childhood leukemia, of which B acute lymphoblastic leukemia (B-ALL) is most prevalent form (~80%). Very recently, a novel DUX4-IGH oncogenic fusion has been reported in 7% in B-ALL patients. However, until now, very little structural and molecular information is available for DUX family, and it is not clear how DUX4-IGHs bind DNA to regulate downstream target genes to trigger B-ALL leukemgenesis. In our preliminary research, we have determined the crystal structure of HD2 domain of DUX4. Point mutations can abolish or significantly impair the DNA binding activity of DUX4-HD2. More importantly, the perturbations in the binding interfaces of DUX4-IGH preclude the transactivating activities of DUX4-IGH on transcription/expression of ERGalt, a leukemogenic ERG isofrom in B-ALL. Using RNA-seq technology, we have identified some direct DUX4-IGH target genes abnormally overexpressed in DUX4-driven B-ALL, and thought to play important role in the transformation of B lymphoid precursors. In this proposal, we propose to employ a multidisciplinary approach combining the technologies such as structural biology, cellular and molecular biology, and the animal model to 1）clarify the transactivational basis of DUX4-IGH-driven B-ALL leukemogenisis; 2) search/design/improve the novel therapeutic intervention specifically targeting the interaction DUX4:DNA in B-precursor acute lymphoblastic leukemia.