ADAT1介导tRNA次黄嘌呤修饰促进HOX翻译抑制AML细胞分化的作用机制

分化阻滞是急性髓系白血病（Acute Myeloid Leukemia，AML）的重要发病原因，但是具体调控机制尚未完全阐明。研究表明，tRNA表达谱的改变可通过影响蛋白质翻译参与细胞发育状态调控，在AML分化调控中的作用尚待明确。申请者新近研究发现，AML病人中tRNA-Ala及I修饰水平显著升高，介导I37修饰的酶ADAT1高表达与病人预后不良密切相关。据此我们提出了ADAT1介导tRNA-Ala-I37修饰，改变细胞内tRNA-Ala表达，影响HOX基因在核翻译，抑制细胞分化，推进AML进程的科学新假设。本课题应用生物信息学整合多组学以及人源化AML/条件性敲除小鼠模型等技术手段开展研究，试图阐明ADAT1介导tRNA-Ala-I37修饰途径调控AML细胞分化的作用机制，深入解析AML发病分子机制，为诱导分化治疗模式在AML中的创新应用奠定理论基础。

Cell differentiation block is an important cause in the pathogenesis of AML, but the specific regulatory mechanism has not been fully elucidated. In the previous study, the applicants found that up-regulated ADAT1 leads to an increase in tRNA-Ala-I37 modification, and further enhances the expression and stability of tRNA-Ala. Therefore, we speculated that high-level I37 modified status on tRNA-Ala mediated by ADAT1 in AML patients improves the stability and abundance of tRNA-Ala, which can have broad regulatory consequences across the proteome of cells, especially those transcripts enriched for Alanine cognate codons and inhibits AML cell differentiation. In this study, we applied high throughput sequencing and conditional knockout mouse model, to clarify the mechanism of I37 modification mediated by ADAT1 on tRNA-Ala in regulating the differentiation of AML cells, which provides a theoretical foundation for the innovative application of induced differentiation therapy mode in AML.