本课题针对我们发现WDR5在急性淋巴细胞白血病（ALL）中有促进肿瘤细胞增殖作用及其启动子区有IKAROS显著结合位点，提出以下科学假说：IKAROS通过组蛋白修饰和染色质重塑的表观遗传学机制，调控其靶基因WDR5，在B细胞ALL(B-ALL)的发生和疾病进展中发挥重要作用；IKAROS活性增强剂能重建IKAROS肿瘤抑制功能，与WDR5下调及抑制剂具有协同抗白血病细胞作用。本课题通过细胞模型[B-ALL细胞系和病人原代细胞]和动物模型[荧光素酶修饰人原代白血病细胞xenograft(PDX)小鼠]，采用CRISPR基因编辑技术、染色质免疫共沉淀、荧光素酶活性检测、慢病毒shRNA干扰、细胞增殖检测和协同作用分析、流式技术检测细胞凋亡和细胞周期等方法论证以上假说。对深入阐明B-ALL中新预后分子标记IKAROS对新靶点WDR5的表观遗传学调控机制有原创性意义，为探索新靶点治疗提供理论依据。

Our findings indicated that WDR5 can promote the cell proliferation in acute lymphoblastic leukemia (ALL) and the strong IKAROS binding peaks are detected in the promoter region of WDR5 in ALL by ChIP-seq. Thus our hypothesis for this study is: IKAROS regulates the expression of its target gene WDR5 through histone modification and chromatin remodeling, which plays an important role in oncogenesis /development of B-cell ALL and disease progression; IKAROS activator - CX4945 by restoring IKAROS tumor suppressor function may have synergistic anti-tumor effect with WDR5 shRNA or WDR5 inhibitor in ALL. We will use cell model (cell lines and primary cells), mouse model (PDX), living imaging, CRISPR gene editing technique, chromatin immunoprecipitation (ChIP), luciferase reporter assay, lentiviral shRNA interference, cell proliferation and synergy analysis, apoptosis assay and flow cytometry to demonstrate our hypothesis. This study has great significance to elucidate the underlying epigenetic mechanism of IKAROS regulation on the expression of its novel target WDR5 in B-ALL and to provide a theoretical basis for developing the novel target therapy on high-risk B-ALL.