RARα嵌合癌蛋白是引起急性早幼粒白血病的关键致病蛋白，深入研究其分子动态调控机制可为抗白血病药物研发提供全新策略。我们前期研究发现RARα嵌合癌蛋白的共有RARα区域可发生棕榈酰化修饰，这一修饰对于维持其癌蛋白生物学功能至关重要。进一步研究显示zDHHC21可能是介导其发生棕榈酰化修饰的关键酶，抑制zDHHC21可导致嵌合癌蛋白发生核体聚集，最终诱导白血病细胞分化。本项目将在此基础上，深入阐明棕榈酰化修饰在动态维持RARα嵌合癌蛋白功能中的分子机制，明确zDHHC21调控该癌蛋白棕榈酰化修饰的作用及其方式，并以zDHHC21为靶点，构建药物筛选模型，发现zDHHC21选择性抑制剂。通过本项目的研究，不仅可阐明zDHHC21动态调控RARα嵌合癌蛋白发生棕榈酰化修饰的新分子机制，还有望通过抑制zDHHC21干预不同RARα嵌合癌蛋白引起的白血病的新途径，具有重要的理论意义和应用前景。

Acute promyelocytic leukemia (APL) is driven by RARα chimeric oncoproteins. It is important to study the molecular mechanisms of RARα chimeric oncoproteins, which may provide a new strategy for the development of anti-leukemic drugs. Our study has shown that palmitylation of RARα chimeric oncoproteins occurs in the RARα domain, which is essential for maintaining their biological function. Further studies have shown that zDHHC21 may be a key enzyme mediating the palmitylation of RARα chimeric oncoproteins. Inhibiting zDHHC21 can induce nuclear aggregation of chimeric oncoproteins, and ultimately induce leukemia cell differentiation. Therefore, we will further elucidate the molecular mechanism of palmitylation modification in maintaining the function of RARα chimeric oncoprotein. We will also clarify the function of zDHHC21 in regulating palmitylation of RARα chimeric oncoproteins. Moreover, we will screen for the pilot small molecular compounds that targeting zDHHC21. Our study will not only elucidate the new molecular mechanism of zDHHC21 regulating the palmitylation of RARα chimeric oncoproteins, but also explore a new way to interfere with different RARα chimeric oncoproteins induced leukemia by inhibiting zDHHC21. Thus, our studies have important theoretical significance and clinical application value.