AML1-ETO融合蛋白调控BASP1的甲基化沉默促进t(8;21)急性髓系白血病发生的分子机制研究

t(8;21) acute myeloid leukemia (AML) is a common type of AML. The abnormal methylation patterns and silencing of tumor suppressor genes are important factors leading to the occurrence and development of this disease. In our previous study based on methylation chip screening and bioinformatics screening, we identified the hypermethylation and significant down-regulation of BASP1 in t(8;21) AML compared to the other subtype AML and normal people. The level of BASP1 expression was correlated with the clinical prognosis of patients. However, recent studies identified BASP1 as a transcriptional cosuppressor for WT1 and played as a tumor suppressor gene. In our previous study, we confirmed that the AML1-ETO fusion protein(AE) formed by the translocation of t(8;21) chromosome promoted the promoter methylation and silencing of BASP1, and over-expression of BASP1 inhibited the proliferation of leukemia cells. Based on this study, we will further explore the mechanism of epigenetic silencing of BASP1 promoted by AE, the biological function of BASP1 and the effect on WT1 involved signaling pathways. This will eventually figure out the function and mechanism of BASP1 in AE involved leukemogenesis, and provide a theoretical basis for the new target for prognosis and treatment of t(8;21) AML.

t(8;21)急性髓系白血病(AML)是AML中的常见类型，异常的甲基化模式和抑癌基因表达沉默是该疾病发生发展的重要因素。因此课题组在t(8;21)AML中进行了全基因组甲基化芯片筛查和生物信息学筛选，发现与其他亚型AML和正常人相比，BASP1在t(8;21)AML中特异性高甲基化和表达下调，并与患者预后相关。近年研究表明BASP1是WT1的转录共抑制因子起抑癌基因作用。课题组经前期实验证实t(8;21)染色体易位后形成的AML1-ETO融合蛋白(AE)可使BASP1启动子区甲基化而表达沉默，过表达BASP1能够抑制白血病细胞增殖。本课题拟在此基础上进一步揭示AE使BASP1发生甲基化沉默的分子机制、BASP1的生物学功能和对WT1等参与调控的信号通路的影响，最终明确BASP1在AE促白血病发生中的作用和分子机制，这将为t(8;21)AML的预后危险度分层和寻找新的治疗靶点提供理论依据。

t(8;21)急性髓系白血病(AML)是AML中的常见类型，异常的甲基化模式和抑癌基因表达沉默是该疾病发生发展的重要因素。因此课题组在t(8;21)AML中进行了全基因组甲基化芯片筛查和生物信息学筛选，发现与其他亚型AML和正常人相比，BASP1在t(8;21)AML中特异性高甲基化和表达下调，并与患者预后相关。近年研究表明BASP1是WT1的转录共抑制因子起抑癌基因作用。课题组经前期实验证实t(8;21)染色体易位后形成的AML1-ETO融合蛋白(AE)可使BASP1启动子区甲基化而表达沉默，过表达BASP1能够抑制白血病细胞增殖。本课题拟在此基础上进一步揭示AE可以通过直接结合到BASP1的启动子区域，发挥BASP1甲基化沉默的分子机制，并且我们通过构建BASP1质粒，研究了它的抗白血病作用，包括增殖抑制、克隆形成抑制，组织细胞周期、促进白血病细胞凋亡等细胞生物学功能，最终明确BASP1在AE促白血病发生中的作用和分子机制，这将为t(8;21)AML的预后危险度分层和寻找新的治疗靶点提供理论依据。