急性B淋巴细胞白血病致癌蛋白MEF2D-fusion的发病机制研究

急性淋巴细胞白血病是最常见的恶性肿瘤之一。目前，我国儿童和成人B-ALL的长期生存率分别是～70%和～20%。近期，上海血研所通过对B-ALL患者进行基因组全景式分析发现了一种新的MEF2D融合基因，在B-ALL中占～7%且预后较差。至今，关于该癌蛋白的结构信息和发病机制还知之甚少。目前，我们已解析出MEF2D结合DNA的复合物结构。初步功能实验证明该癌基因的异常表达在B细胞发育中起着重要的作用。靶向干扰其与靶基因的结合可以抑制该癌蛋白的转录激活和分化阻止功能。因此，在本项目中我们将有机结合之前在B-ALL领域中的研究基础（Leukemia, 2018； Leukemia, 2019），利用生物信息学、结构生物学、细胞和分子生物学、小鼠建模等多学科交叉融合，阐明MEF2D融合基因在白血病发病中的作用机制，优化和改进临床治疗方案，为提高病人的长期生存率提供理论基础。

Acute lymphoblastic leukemia (B-ALL) is one of the most common malignant tumors. Until today, the long-term survival rate of children with B-ALL in China is ～70%. The prognosis of adult B-ALL is much worse with a poor long-term survival rate of ～20%. Recently, using second-generation-sequencing and RNA-seq technologies, Shanghai Institute of Hematology has found a new class of oncogenic gene known as MEF2D-fusion in 203 B-ALL patients, accounting for ～7% B-ALL cases with poor prognosis. Despite the genomic discovery, the molecular mechanism concerning MEF2D-driven leukemogenesis remain poorly understood. Aimed by the recent determination of MEF2D-DNA structure (not published), we have demonstrated that interfering with the binding of MEF2D-fusion to its target genes can inhibit its transactivation activity, significantly impairing the inhibitory effects of DUX4/IGH upon B-cell differentiation in mouse progenitor cells. In this proposal, we will combine the previous success in B-ALL studies (Leukemia, 2018; Leukemia, 2019), to employ a multidisciplinary approach combining the technologies such as bioinformatics，structural biology, cellular and molecular biology, and the animal model to understand how MEF2D-fusion genes trigger a full-fledged leukemogenesis. Hopefully, these new findings will help to design novel therapeutic intervention specifically targeting MEF2D-type leukemia.