DHX15异常通过NF-κB/IκB-α、NKRF参与调控AML发生发展的机制研究

DHX15在不同类型肿瘤中，可与不同蛋白相互作用介导不同生物学过程及疾病转归，现尚无DHX15在AML中作用机制的报道。我们发现：AML患者DHX15异常（突变/高表达）与预后不良相关，DHX15可影响IκB-α磷酸化及下游分子p65的核易位，激活NF-κB通路，介导AML细胞的增殖及凋亡。结合现有报道，我们假说：DHX15异常可通过NF-κB/IκB-α、NKRF参与调控AML的发生发展。我们拟在临床、动物、细胞及分子水平，通过构建DHX15异常的细胞与动物模型，应用CRISPR/Cas9、RNA-seq、CO-IP质谱等系列分子技术，探究DHX15通过ETS-1-IKK-α-IκB-α核外通路以及DHX15与NKRF的核内相互作用，促进NF-κB/p65：p50介导的基因转录过程，参与AML发生发展的分子机制及其调控网络。为发现AML的新分子标志、开发靶向药物等奠定理论基础。

DHX15 interacts with proteins to direct different biological processes and disease developments in different types of tumors. But roles of DHX15 in AML remain unknown. Our studies showed abnormal DHX15 expression (mutation/upregulation) is associated with poor prognosis in AML patients. We found that DHX15 mediates the proliferation and apoptosis of AML cells by the NF-κB pathway. DHX15 interferes with phosphorylation of IκB-α and nuclear translocation of its downstream molecule p65, thus activating the NF-κB pathway. Based on current reports, we hypothesize that aberrant DHX15 participates in AML development by the regulation of NF-κB/IκB-α, NKRF. To verify our hypothesis, we will explore the role of DHX15 in regulatory networks of AML development by generating cells and animal models with aberrant DHX15 using CRISPR/Cas9, RNA-seq, and CO-IP technologies from the clinical, animal, and cellular aspects. We will reveal the role of DHX15 in ETS-1-IKK-α-IκB-α extranuclear pathway and DHX15-NKRF intranuclear pathway in promoting NF-κB/ p65: p50-mediated gene transcription. This study will establish a theoretical foundation for discovery of new biomarkers and developing target drugs in AML.