研究发现表观遗传学异常与急性髓系白血病的发生及发展有密切联系，但目前可供选择的药物较少，且存在耐药问题。本课题组前期通过生物信息学分析发现小檗碱（BBR）具有表观遗传学调控的作用，BBR可抑制AML细胞株EZH2蛋白表达，从而降低组蛋白甲基化水平，抑制耐药白血病细胞增殖诱导凋亡。目前已有文献研究显示抑制EZH2可上调p53通路，引起肿瘤细胞凋亡及细胞周期停滞。基于上述研究我们提出小檗碱通过抑制EZH2蛋白，诱导p53通路激活，诱导白血病细胞凋亡及细胞周期停滞的假说。本项目拟在细胞株、原代AML细胞、人源化AML移植鼠模型中，采用ChIP、流式细胞分析等方法从体内、外研究小檗碱治疗AML的作用及机理，为难治复发AML治疗策略提供新的理论依据及药物选择。

In recent years, combination chemotherapy and stem cell transplantation greatly increased the rate of complete remission in AML. However, improvements were less pronounced in relapsed patients. The unmet need in this population may be addressed using optimal chemotherapy combination and novel agents. Abnormity in DNA methylation and histone methylation/ acetylation played important role in drug-resistant of acute myelocytic leukemia (AML) . Berberine, an isoquinoline plant alkaloid, has a wide range of biochemical and pharmacological effects. However, the exact mechanism of these bio-activities remains poorly understood. We previously demonstrated significant similarity between berberine and epigenetic modulators. These findings suggested a possible role of berberine in epigenetic modulation. We recently found berberine induces AML cells apoptosis and inhibits growth via suppression of EZH2. Targeting EZH2 regulates the ATM/p53 pathway in hepatocellular carcinoma. So we speculate that berberine might modulate expression of EZH2 then inhibit p53 pathways, leading to overcome drug resistance and improve therapeutic. We further investigate this hypothesis in AML cell lines, primary AMLcells and in patient-derived xenograft (PDX) humanized mouse models.