CST7在t（8；21）急性髓系白血病发生中的功能和调控机制研究

The AML1-ETO fusion protein generated by the t(8;21) translocation plays a critical and initiating role in the pathogenesis of acute myeloid leukemia (AML) with t(8;21). As an oncogenic fusion protein, AML1/ETO influences crucial biological processes during the leukemogenesis, such as differentiation, proliferation and apoptosis, through regulating the expression of its target genes. Recently, we have identified genome-wide AML1/ETO targets using high throughput ChIP-seq technology. Intriguingly, hematopoietic specific cystatin F (CST7) that is a member of the type II cystatin family, is among the list of AML1/ETO targets. Numerous studies suggest that the other members of the type II cystatin family act as tumor suppressors and influence the development of progression of many solid tumors through suppressing the pathways involved in proliferation, migration and invasion. However, it is still unknown how CST7 is regulated and what function it plays in the development of leukemia. In this study, we will investigate the precise transcription regulatory mechanism by which AML1/ETO suppresses CST7 expression at both transcription factor binding level and epigenetic level. Furthermore, we will use t(8;21) positive cell lines to verify the impact of CST7 on proliferation, cell cycle and differentiation. Our study will be of help to uncover the tumor suppressor function of CST7 in leukemia and provide a potential target for the treatment of t(8;21) AML.

由t(8；21)易位形成的AML1/ETO融合基因是急性髓系白血病M2b亚型发病的主要原因。AML1/ETO作为一个致癌的异常转录因子，通过调控其靶基因干扰了分化、增殖、凋亡等与白血病发生密切相关的生物学过程。申请人前期应用高通量ChIP-seq技术揭示了AML1/ETO的全基因组靶基因谱及结合规律。造血细胞特异性表达的半胱氨酸蛋白酶抑制剂家族成员CST7为AML1/ETO的靶基因之一。大量研究提示该家族的其他成员具有抑癌基因的作用，通过影响细胞增殖、转移和侵袭等过程在多种实体瘤的发生发展中发挥重要功能。然而CST7在白血病发生和发展中的调控及功能仍不清楚。本项目拟在前期基础上研究AML1/ETO在转录因子及表观遗传学水平上调控CST7表达的分子机制，并探索CST7对M2b型白血病细胞增殖、周期与分化的影响，阐明其在白血病发生中的功能，为白血病治疗提供潜在靶点。