野生型核孔蛋白98(WTNup98)在Nup98融合基因阳性髓系肿瘤发生中的作用及机制探讨

项目名称： 野生型核孔蛋白98(WTNup98)在Nup98融合基因阳性髓系肿瘤发生中的作用及机制探讨

项目编号： No.81470327

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： 吴俣

作者单位： 四川大学

项目金额： 70万元

中文摘要： 核孔蛋白98（Nup98）是核孔复合物主要结构蛋白,参与跨核膜内外大分子的转运。迄今已有30余种Nup98相关融合基因在髓系肿瘤中被发现。Nup98融合基因异常转录可促进这类肿瘤发生。我们前期工作和国外最新研究提示野生型Nup98(WTNup98)可能具有抑癌基因和维持染色体稳定性作用。我们拟利用体外研究Nup98融合基因转染和WTNup98RNA干扰白血病细胞，体内研究Nup98-HOXA9/Nup98-JARID1A转基因小鼠,应用共聚焦显微镜，免疫共沉降等方法证实Nup98融合基因阳性细胞中存在WTNup98,WTNup通过组蛋白修饰促进Nup98融合基因转录，其自身抑癌基因功能受阻参与肿瘤发生。本研究实施有助于阐明WTNup在Nup98融合基因阳性髓系肿瘤发生中的作用及机制，为治疗提供理论依据。

中文关键词： 急性髓系白血病；核孔蛋白；Nup98；转录调控

英文摘要： Nucleoporin (Nup98) is the major structural component of Nuclear Pore Complex（NPC）， responsible for macromolecules transport across nuclear membrane. Up to now, more than 30 kinds of Nup98 fusion genes have been identified and were commonly seen among myeloid neoplasms with poor prognosis, such as acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia in blast crisis, et al. It is generally thought that the fused Nup98 genes prompted leukemogenesis through transcription dysregulation. Our preliminary date and the latest international research suggested the wide type Nup98(WTNup98) has potential roles in maintaining chromosome stability and tumor suppression . We are planning to in vitro transfect Nup98 fusion genes and WTNUp98 siRNA in acute leukemia cell lines ，study on Nup98-HOXA9 or Nup98-JARID1A transgenic mice in vivo to demonstrate the existence and functioning of WTNup98. Besides, WTNup98 enhanced Nup98 fusion gene transcription by histone modification and involved in leukemogenesis by impairment of tumor suppression. Our project will be good for investigate the role of WTNup98 in Nup98 fusion gene positive neoplasms and underlying mechanism, provideng theoretical foundation for future therapy.

英文关键词： acute myeloid leukemia;nucleoporins;Nup98;transcription regulation