急性髓系白血病(AML)的治疗仍存在很大挑战，发现AML发生发展中的关键调控分子并揭示其作用机理是该领域的关键科学问题。RNA结合蛋白(RBP)在多种生物学过程中的功能逐渐被认识，但在AML中的报道还甚少。申请人前期从寻找髓系分化和AML发生中关键RBP入手，发现QKI5在多种AML亚型中显著下调。初步的功能研究发现QKI5能够抑制AML细胞增殖并促进髓系分化，而该功能并不完全依赖其经典的RNA结合功能。机制研究发现QKI5能与染色质互作来调控一系列髓系分化相关基因的表达。因而提出以下假设：QKI5可转录调控基因表达抑制AML的发展。本项目将进一步通过体内、体外实验和临床调查明确QKI5在AML中的功能；通过多种DNA-蛋白或蛋白互作的组学技术系统分析QKI5调控的靶基因网络，在单分子水平明确其发挥转录调控功能的具体机制；并探索QKI5转录调控轴在AML预后或治疗中的意义。

Treatment of acute myeloid leukemia (AML), an aggressive and heterogeneous hematological malignancy, remains a challenge. Identification key genes in regulating differentiation arrest represent a powerful study for treatment. The role of RNA-binding proteins (RBPs) has been recognized in a wide variety of cellular processes, however, their function and working mechanism in AML is not fully understood. In our preliminary study to find key RBPs in AML occurrence, Quaking 5 (QKI5) was significantly down regulated in AML patients with several subtypes. Functional studies showed that overexpression of QKI5 could suppress cell proliferation while promote myeloid differentiation of AML cells, and more importantly, such regulation of QKI5 is not entirely dependent on its RNA binding function. In addition, we also found that QKI5 was co-localized and interact with chromatin in THP-1 cells, which is also independent of its RNA binding motif. Based on these findings, we proposed that QKI5 could inhibit the occurrence and maintenance of AML by transcriptional regulation. In this study, we will further confirm the function of QKI5 by both cell and animal studies, as well as investigate the mechanism underlying QKI5’s regulation in AML by systemically analyzing its DNA binding targets, influence on gene expression regulation and its interacting proteins. Through this study, we will understand the specific mechanisms underlying the transcriptional regulation of QKI5, and reveal new therapy target for AML.