急性T淋巴细胞白血病IKZF2-WDR5-HIF1A新调控通路的表观遗传学机制和治疗新靶标研究

本课题针对我们前期新发现：WDR5抑制剂能阻止急性T淋巴细胞白血病（T-ALL）细胞增殖，并通过高通量多组学研究筛选出IKZF2-WDR5-HIF1A新调控通路，提出以下科学假说：IKZF2-WDR5在T-ALL中相互结合，通过调控下游靶基因HIF1A增强子活性和Loop形成、以及染色质可及性的表观遗传学新机制，重塑染色质空间结构，从而上调HIF1A表达，促进白血病细胞异常增殖和化疗耐药；联合新靶点药物WDR5抑制剂与HIF1A抑制剂通过阻断IKZF2-WDR5-HIF1A调控通路，协同发挥抗白血病作用。本课题从分子-细胞-动物（荧光素酶修饰PDX小鼠模型等）三个层面，采用ATAC-seq、HiChIP和3C等最前沿组学技术论证以上假说。本课题源于我们新发现，旨在从现象到本质揭示迄今没有答案的原创性科学问题，并通过转化应用于临床新靶点治疗和联合治疗，探索临床新治疗策略。

We previously found that WDR5 inhibitors could suppress the cell proliferation in T-cell acute lymphoblastic leukemia (T-ALL) and IKZF2-WDR5-HIF1A is a novel regulatory pathway in T-ALL oncogenesis by high-throughput multi-omics screening. Based on our findings, we proposed the following scientific hypothesis: IKZF2-WDR5 interacts with each other to regulate HIF1A expression through novel epigenomic mechanisms, including modulating the enhancer activity, Loop formation, as well as chromatin accessibility to remodel the chromatin space structure, and further promotes leukemia cell abnormal proliferation and chemotherapy resistance. Novel combination of targeted drugs WDR5 inhibitor with HIF1A inhibitor has synergistic anti-leukemia effect by blocking the IKZF2-WDR5-HIF1A signaling pathway. This study will demonstrate our hypothesis by using the molecular-cell-mouse models, as well as by utilizing the cutting-edge new technologies such as chromatin accessibility assay (ATAC-seq), HiChIP and chromosome conformation capture (3C). This project will answer the innovation scientific questions from our novel discoveries, aiming to produce the original research achievement and to develop the novel anti-leukemia drugs and combination therapies.