核苷类似物是急性髓系白血病常用化学治疗药物，对肿瘤和正常细胞都具有抑制作用，故不具备肿瘤靶向性。肿瘤细胞内的核苷类似物易被高含量的脱氨酶分解，致使治疗效果明显下降，故寻找靶向肿瘤并避免脱氨反应失效的核苷类似物，对白血病治疗至关重要。本组前期发现表观修饰核苷5-羟甲基胞嘧啶（5hmC）的脱氨产物5-羟甲基尿嘧啶明显抑制细胞增殖，提示5hmC在肿瘤细胞内被脱氨后可影响细胞增殖，同期有效避免传统核苷类似物脱氨失效问题，遂5hmC有望成为恶性肿瘤治疗的新型靶向药物，但5hmC在恶性血液肿瘤内的代谢途径及作用机制尚不明确。项目通过质谱技术全面解析5hmC在急性髓系白血病细胞株HL60内的动态变化；明确5hmC对HL60在体外的抑制作用；建立人源化斑马鱼白血病模型，评价5hmC在体内抑瘤功效；寻找调节5hmC代谢关键因子，阐明其代谢途径及机制，为急性髓系白血病靶向治疗提供重要实验基础及理论依据。

Nucleoside analogs were used to treat acute myeloid leukemia as traditional chemotherapeutic drugs, but due to the inability to distinguish the cancer cells from normal cells, the nucleoside analogs usually do not show any targeting effects on tumor cells. In addition, due to the high levels of deaminase in cancer cells, the nucleoside analogs can be converted to their deamination products and further restrict their clinic applications. Our previous results showed that excessive amount of 5-hydroxymethyluracil, which is the deamination product of non-canonical epigenetic nucleobase 5-hydroxymethylcytosine, leads to the cell proliferation arrest, indicating that the non-canonical epigenetic nucleosides could be used as specific inhibitors for tumor cell proliferation, which would avoid the drug instability due to deamination. In this study, we will further investigate the dynamic kinetics and the metabolism pathway of non-canonical epigenetic nucleosides in HL60 cells using mass spectrometry. In addition, we will explore the effect of non-canonical nucleosides on the proliferation of acute myeloid leukemia cells and its mechanism in vivo using zebrafish as a model. The outcome of this study will help to develop new drugs for the treatment of acute myeloid leukemia.