NANOG/RBPMS通路在急性髓系白血病细胞干性中的作用研究

Despite the remarkable efficacy of chemotherapy in eliminating acute myeloid leukemia (AML) cells, recent evidence suggests that leukemia cells with stem cell-like characteristics ("stemness") persist long-term, which may partially contribute to relapse. It is elusive which signal pathways promote the maintenance of leukemia cells stemness. In previous studies we have demonstrated that NANOG, which is a major transcription factor essential to the stem cell self-renewal, plays an important role in maintaining the stemness in acute leukemia cells. Furthermore, our results showed that NANOG protein can bind the promoter region of RNA-binding protein for multiple splicing (RBPMS) gene. RBPMS is a member of the RNA-binding protein family physically interacts with RNA and regulates post-transcription. It is indicated that RBPMS interacts with multiple genes which are important to keep the stemness of leukemia cells. The aim of this study is to characterize the effect of NANOG/RBPMS pathway on the stemness in AML cells and to explore the molecular mechanisms of NANOG/RBPMS pathways regulating the target genes at post-transcription. This study will provide an insights into the regulatory mechanisms of leukemia cells stemness, and broaden the knowledge about the regulation network of RNA binding proteins at post-transcription in leukemia.

具有类干细胞样特性（即"干性"）的白血病细胞的存在是疾病复发的主要原因之一。维持白血病细胞干性的核心分子机制尚不清楚。本项目组在前期研究中发现作为正常干细胞标记物之一的NANOG基因在急性白血病细胞的干性维持中起重要作用，且NANOG可通过结合RBPMS基因的启动子区域产生作用。RBPMS是一种RNA结合蛋白，该类蛋白在基因转录后水平调控中起重要作用，近期的研究显示RBPMS可能参与了白血病细胞干性的调控。在此基础上，本课题拟通过细胞、动物模型等层面阐明NANOG/RBPMS通路对急性髓细胞白血病细胞干性的影响，进而研究RBPMS与上游调控因子NANOG的精细作用方式，并探讨NANOG/RBPMS通路参与下游靶基因转录后调控的分子机制。本研究的如期完成，将有助于深入理解白血病细胞干性的调控机制，并拓宽白血病状态下RNA结合蛋白转录后调控网络的认识，为白血病治疗靶点的选择提供新的思路。

研究背景：急性髓系白血病（AML）是发病率最高的成人血液系统恶性肿瘤，虽然以化疗和造血干细胞移植为主的疗法取得了很大的成就，但部分患者出现疾病复发。具有类干细胞样特性（即“干性”）的白血病细胞的存在是疾病复发的主要原因之一。维持白血病细胞干性的核心分子机制尚不清楚。本项目组在前期研究中发现作为正常干细胞标记物之一的NANOG基因在急性白血病细胞的干性维持中起重要作用。研究内容：本课题拟通过细胞、动物模型等层面阐明NANOG/RBPMS通路对急性髓细胞白血病细胞干性的影响，进而研究RBPMS与上游调控因子NANOG的精细作用方式，并探讨NANOG/RBPMS通路参与下游靶基因转录后调控的分子机制。研究结果：研究证实在多种人AML细胞株NANOG及RBPMS的表达情况；下调NANOG或RBPMS的表达，可明显抑制AML细胞株的增殖、凋亡及克隆形成能力；通过拯救实验证实NANOG可通过RBPMS的作用影响白血病细胞的干性；NANOGP8可作用于RBPMS基因启动子区，从而激活RBPMS的转录；NANOG/RBPMS通路可通过影响P53通路影响白血病细胞的干性。科学意义：该研究的完成有助于深入理解白血病细胞干性的调控机制，为白血病治疗靶点的选择提供新的思路。