新的逆转录病毒致癌基因Np9调控白血病干细胞自我更新信号通路分子机制的研究

项目名称： 新的逆转录病毒致癌基因Np9调控白血病干细胞自我更新信号通路分子机制的研究

项目编号： No.81470306

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 徐荣臻

作者单位： 浙江大学

项目金额： 70万元

中文摘要： 已知白血病干细胞(LSC)在白血病起始,耐药和复发中起着十分重要的作用,但调控LSC存活和自我更新的关键因子及相应分子机制尚未阐明。新近,我们在国际上率先证实逆转录病毒调节基因Np9是一种新的病毒致癌基因,其编码的Np9蛋白在56%的白血病人群中高表达,但在正常造血干细胞样本中未见表达,且其表达量与LSC呈显著正相关。进一步发现Np9是一种能同时上调β-catenin等多个与LSC存活和自我更新相关信号分子的关键分子之一,能强有力促进白血病细胞生长,但其作用机制不详。本项目拟应用全基因表达芯片,免疫共沉淀,蛋白质质谱,Western blot,shRNA等技术分离和鉴定Np9蛋白上下游信号分子及相应信号通路,重点关注与LSC存活和自我更新相关的信号通路,以期阐明Np9调控LSC自我更新信号通路的分子机制,为下一步以Np9作为新的白血病治疗性靶标奠定基础,具有重要科学理论意义和潜在应用价值。

中文关键词： 白血病干细胞；靶向治疗；发病机制；信号通路；分子生物学

英文摘要： It is well known that leukemia stem cell (LSC) plays a critical role in the initiation, drug resistance and relapse of leukemia, but it is unknown what factors determine the survival and self-renewal of LSC and how they regulate corresponding actions. Recently, we demonstrated that the regulatory gene Np9 of retrovirus is a novel viral oncogene. The viral protein Np9 encoded by this viral gene was detected in 56% of leukemia patients, but rare in normal hematopoietic stem cell samples. Moreover, the abundance of viral Np9 protein was positively correlated with the level of LSC in leukemia patients. Further studies showed that the viral Np9 was a critical molecule that simultaneously up-regulated multi-signaling molecules, such as β-catenin, involved in the survival and self-renewal of leukemia stem cells. However, its mechanism remains unclear. In this proposal, we will try to identify up-stream and down-stream partners interacting with the viral Np9 protein and corresponding pathways using human genome array,CoIP, Protein MS, Western blot, shRNA, etc. We will focus on the identification of signaling pathways essential for the survival and self-renewal of LSC and expect to reveal the molecular mechanism by which the viral Np9 regulates the self-renewal of LSC. These data will lay a foundation for the viral Np9 as therapeutic target of leukemia stem cells, and will be of scientific significance and potential application for clinic.

英文关键词： leukemia stem cell;targeted therapy;mechanism;signaling pathway;molecular biology