急性髓细胞白血病（AML）伴DNMT3A突变预后差，效应机制未明，缺乏高效靶向治疗方法。前期研究发现DNMT3A突变AML细胞存在重构的氨基酸代谢介导的凋亡抵抗现象。新近发现，重构的代谢对免疫微环境存在抑制效应。据此我们推测AML细胞重构代谢是DNMT3A突变效应机制的关键环节，且间接介导了白血病细胞的免疫抑制能力。本课题拟借助于构建的DNMT3A R882H突变AML克隆和野生克隆，筛选差异表达基因并靶向调控，证实DNMT3A R882H突变造成的重构氨基酸代谢有利于AML细胞抗凋亡和产生免疫抑制效应。构建携带突变克隆的小鼠模型，借助于色氨酸通路限速酶IDO1/TDO抑制剂735D的免疫干预，观察潜在的逆转效应；利用初诊AML病人标本证实上述现象。本课题的完成，将进一步阐明DNMT3A突变效应机制，从重构的代谢通路发现新的作用靶点，为突破DNMT3A突变治疗瓶颈提供新的策略和理论依据。

Patients with acute myeloid leukemia (AML) who had a DNMT3A mutation had poorer prognosis. The mechanism is not clear, which seriously restricts the effective targeted therapies. Previous studies showed that DNMT3A mutations caused a metabolic remodeling responsible for resisting daunorubicin-induced apoptosis. Recent studies found that the metabolic remodeling in AML cells lead to a suppressive effect on immune microenvironment. Thus, we speculate that the metabolic remodeling in AML cells is a key links of the effect mechanism of DNMT3A mutation, and it also indirectly mediates immunosuppressive effects of leukemia cells. In this study, several mutant AML cell lines with DNMT3A R882H are established. Differentially expressed genes are screened among mutant and wild clones. By targeted regulation of possible candidate genes, it will be confirmed that remodeling the amino acid metabolic passways is helpful for anti-apoptosis and immunosuppressive effects of AML cells with DNMT3A mutation. The mouse models carrying DNMT3A mutant clones are constructed and the reversal effect is observed by using the tryptophan pathway IDO1/TDO inhibitor 735D. The above phenomenon was further confirmed by using samples from patients with newly diagnosed AML. If successfully completed the research, it is very possible to uncover the effect mechanism of DNMT3A mutations in AML cells and find new potential therapeutic targets from the remodeling metabolic passways, which will provide theoretical basis and new strategies for breaking the treatment bottlenecks of AML with DNMT3A mutation.