PADI4靶向调控sox4在白血病细胞定向分化中的作用及关键机制研究

Inducing differentiation of leukemic cells is an effective way to treat leukemia. The key issue to reverse the abnormal differentiation is to select appropriate therapeutic targets or signaling pathway. On the basis of screening leukemia differentiation related gene, we first discovered peptidylarginine deiminase 4 (PADI4) is closely associated with the differentiation of leukemia cells. Furthermore, we also confirmed that PADI4 could regulate the expression of sox4, and modify it as well through citrullination. Based on the reports that SOX4 is an important regulator of the differentiation of leukemia cells, we hypothesized that the regulatory effects of PADI4 exerted on sox4 may be the key mechanism which accounted for the function that PADI4 regulating differentiation of leukemia cell. In this project, we plan to study the function of PADI4 in the differentiation of leukemia cell lines. Further study regarding the molecular mechanism of PADI4 would also be lauched in leukemia cells as following: (1) how does PADI4 regulate sox4 expression;(2)the effects of PADI4 on the function of sox4;(3)whether or not PADI4 coordinate sox4 during differentiation process. Above all, our progect aim to elucidate the function and the key mechanism of PADI4 during the differentiation of leukemia cell lines, which also make PADI4 as interference target feasible and applicabe.

诱导细胞分化是治疗白血病的有效途径，而治疗靶点或信号通路的确定是逆转异常分化的关键。本课题组在筛选白血病分化关联基因的基础上，首次发现肽基精氨酸脱亚胺酶4（PADI4）与白血病细胞分化密切相关，同时证实PADI4可以调控sox4表达，并能通过相互作用介导sox4瓜氨酸化。而文献报道sox4是一个重要的白血病细胞分化调节因子。因此，我们推测PADI4对sox4的靶向调控及瓜氨酸化修饰可能是PADI4调控白血病细胞定向分化的关键机制。本项目拟在前期研究基础上，深入分析PADI4在白血病细胞分化过程的功能，并进一步从PADI4对sox4表达调控、功能调控及二者是否协同调控白血病细胞分化三个方面展开相关机制研究。旨在阐明PADI4在白血病细胞分化过程中的功能及关键机制，为将PADI4作为白血病治疗靶点提供理论依据和实验线索。

诱导细胞分化是治疗白血病的有效途径，而治疗靶点或信号通路的确定是逆转异常分化的关键。本课题组前期研究发现肽基精氨酸脱亚胺酶4（PADI4）与白血病细胞分化密切相关，同时证实PADI4可以调控sox4表达，并能通过相互作用介导sox4瓜氨酸化。本项目进一步研究发现白血病细胞分化过程PADI4表达升高主要受甲基化水平调控;升高表达的PADI4从细胞浆进入细胞核,负调白血病分化重要调控因子PU.1的表达,而转录因子SOX4通过结合PU.1的启动子负调其表达。因此，PADI4通过SOX4依赖途径调控PU.1的表达，参与调控白血病细胞分化过程。研究过程中我们发现PADI4的过表达可能在白血病治疗过程发生的白血病细胞分化综合征中发挥重要作用。下一步将围绕此发现展开炎性因子调控白血病细胞分化综合征的分子机制研究，为深入全面了解PADI4在白血病发生发展过程的分子功能提供理论依据，以期为寻找白血病新的治疗靶点提供理论和实验依据。

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