缺乏RARA基因重排的急性早幼粒细胞白血病（APL）预后不良，临床缺乏有效的治疗方案，其发病的分子机制尚不明确。我们前期通过大样本基于下一代测序技术的APL患儿基因突变谱研究，在RARA基因重排阴性的样本中，首次发现了NPM1-CCDC28A融合基因，该样本中p53的RNA和蛋白水平均降低；Lin-细胞转染该融合基因，可以促进细胞增殖。由此我们推测NPM1-CCDC28A是缺乏RARA基因重排的APL的致病基因，可能通过抑制p53活性驱动APL的发生。本项目将通过小鼠模型，细胞水平以及分子水平全面研究NPM1-CCDC28A在APL发生发展中的作用及其分子机制。本项目将阐明非维甲酸信号途径导致APL的发生和发展的分子机制，进而为RARA阴性APL的的治疗研发提供理论基础。

The survival of acute promyelocytic leukemia（APL）without RARA rearrangement is much worse than with RARA rearrangement, and the pathogenesis and treatment for APL without RARA fusion are confused. In our previous study to explore the mechanisms involved in pathogenesis of APL, we performed comprehensive variant analysis in APL children based on next-generation sequencing. In APL without RARA fusion, we discovered NPM1-CCDC28A fusion for the first time with decreased level of p53. Lin- cells transfected with NPM1-CCDC28A fusion showed increased proliferation. On this basis we hypothesized that NPM1-CCDC28A contributes to leukemogenesis as driver alternations in APL and develops its oncogenic potential by inhibiting p53 activity. In this study, we will investigate the potential role and mechanisms of NPM1-CCDC28A fusion gene in the pathogenesis of APL in vitro and in vivo. Through this study, we will elucidate a novel mechanism involved in APL pathogenesis that the oncogenesis of APL can be driven by NPM1-CCDC28A fusion without the formation of aberrant retinoid receptors. This research will provide basic theory for treatment of APL without RARA fusion.