组蛋白乙酰转移酶p300抑制剂在白血病治疗上的作用其机制研究

The acetylation of fusion protein AML1-ETO is required for the self renewal of leukemia stem cell in t(8;21) leukemia. It is a hot research area to study AML1-ETO acetylation mutation induced blockage of leukemia development and the therapeutic strategy for targeting the acetylation of AML1-ETO. In our recent study, we have found that p300 mediated acetylation of AML1-ETO is a novel protein modification in the primary cells from t(8;21) leukemia patients. Our study showed that this acetylation can enhance AML1-ETO's ability to active transcription of its downstream target genes. The results of the in vitro self renewal assays showed that the acetylation of AML1-ETO promote the self renewal of hematopoietic stem/progenitor cells. In the retrovirus mediated mouse transplantation assays, our results indicated that the acetylation of AML1-ETO is critical to the leuekmogenesis. To investigate the therapeutic strategy for targeting the acetylation of AML1-ETO and the underlying mechanism, our lab is examining the therapeutic efficacy of the novel p300 inhibitor that we got from the screening in the t(8;21) leukemia cell and mouse models. We are also going to use the thechnolgies of cell biology, molecular biology and ChIP/RNA-seq to understand the mechanism of AML1-ETO acetylation inhibitor, which will provide the important basis for the potential application of this inhibitor in the clinical aspect.

融合蛋白AML1-ETO（AE）的乙酰化在t(8;21)白血病干细胞自我更新调控过程中具有极为重要的作用，对于其乙酰化点突变体引起的白血病发病受阻以及针对该乙酰化的治疗策略是目前国际上的研究热点。组蛋白乙酰转移酶p300介导的AE乙酰化是我们在t(8;21)白血病患者细胞中发现的一种新型蛋白修饰。我们的研究显示此乙酰化能增强AE的转录活性，促进AE对下游基因的转录激活作用；体外干细胞自我更新实验表明AE乙酰化能促进造血干祖细胞自我更新的能力；逆病毒介导的小鼠骨髓移植实验表明AE乙酰化对白血病的形成致关重要。为了深入研究针对该乙酰化的治疗策略和作用机制，本课题组正在检测经筛选得到的新的p300抑制剂在t(8;21)白血病细胞和小鼠模型上的治疗作用，并将以此为研究对象，结合主要的细胞生物学、分子生物学和RNA/ChIP测序技术阐明药物作用机理，为其将来可能的临床应用提供重要依据。