诱导分化治疗是急性早幼粒细胞白血病（APL）临床治疗的重要策略，目前认为PML-RARα融合蛋白作为引起APL的关键致病蛋白，诱导其降解是分化治疗的前提，因此深入研究该蛋白降解的分子机制对进一步推动分化治疗意义重大。我们前期研究发现NEDD8可与PML-RARα相互作用，而抑制Neddylation不仅会影响该蛋白的稳定性，还具有显著的直接诱导分化作用（分化率>95%），相关研究未见报道。本项目将在此基础上，研究Neddylation调控PML-RARα的分子机制，探讨该修饰与SUMO化等修饰的关系，阐明NEDD8对其降解的影响，探索靶向PML-RARα的Neddylation作为分化治疗新策略的可能性。通过本研究，不仅将丰富PML-RARα蛋白水平调控的新分子机制，发现Neddylation的新底物蛋白和新生物学功能，还将为研究全新分化诱导剂提供新策略，具有重要的理论意义和临床应用价值。

The differentiation therapy is an important strategy for clinical treatment of acute promyelocytic leukemia (APL). The degradation of PML-RARα fusion protein that initates APL, is the premise of differentiation therapy; therefore, it is important to further study the molecular mechanisms of the protein degradation of PML-RARα. Our previous studies found that NEDD8 interacted with PML-RARα and the inhibition of Neddylation not only affects the stability of the PML-RARα protein, but also significantly induces differentiation of APL cells (differentiation rate was above 95%), which have not been reported previously. Thus, we will further investigate the molecular mechanisms involved in the Neddylation regulation of PML-RARα, evaluate the relationship between its SUMOylation and Neddylation, elucidate the effects of Neddylation on the degradation of PML-RARα, and explore the possibility of targeting Neddylation of PML-RARα as novel differentiation strategy. Taken together, these researches will not only enrich our understanding of the molecular mechanisms involved in PML-RARα protein degradation, reveal the novel substrate and biological function of Neddylation, but also provide novel strategy for developing differentiation inducing drugs. Therefore, our studies have important theoretical significance and clinical application value.