急性髓系白血病表观基因组重组与地西他滨作用机制研究

Acute myeloid leukemia (AML) is a form of cancer that derives from abnormal proliferation and differentiation of cells of the hematopoietic system. Other than one subtype, the acute promyelocytic leukemia (APL), more than 60% of adult patients of AML are not curable. Decitabine is a hypomethylation agent widely used in the treatment of AML, yet its clinical efficacy and specificity remain unclear due to a lack of understanding of the relationship between abnormal DNA methylation patterns and gene regulatory mechanisms. Here we aim to investigate the cis-regulatory elements (CRE) targeted by decitabine in AML cell lines and clinical samples. In parallel, we will map the CREs downstream of epigenetic regulator mutations. By comparing CREs regulated by decitabine and DNA methylation regulator mutations, we will determine the epignenomic changes responding to decitabine in AML, thus providing mechanistic understanding of its clinical efficacy. Finally, we will optimize the protocols in processing blood samples for epigenomic profiling of AML in clinical settings.

急性髓细胞白血病是造血系统细胞分化失常引起的恶性疾病。早期急髓细胞里常见的致癌基因DNMT3A, TET2，IDH1/2均为表观基因组重组因子，它们通过影响染色质DNA甲基化水平来引发白血病。地西他滨是在白血病治疗中具有显著疗效的去甲基化表观遗传学药物，然而由于DNA甲基化调控机制广泛作用于染色质的各个区域，并呈细胞类型特异的动态变化，因此至今为止地西他滨的作用靶点和特异性还不清楚。本研究将在急髓细胞里定位地西他滨和多种DNA甲基化调控因子突变下游的基因调控位点， 并在此基础上阐明与去甲基化药物和甲基化调控因子相对应的表观基因组重组的分子机理。本研究还将优化利用少量血液细胞解析肿瘤基因组调控序列的方法，从而探索表观基因组学研究技术在急髓临床检测中的应用。

急性髓细胞白血病是造血系统细胞分化失常引起的恶性疾病，表观遗传学药物通过影响基因调控位点活跃程度来改变下游基因网络来诱导白血病细胞分化或者死亡，从而达到缓解和治疗效果。本研究整合多种表观基因组学研究手段，从染色质开发程度、组蛋白修饰模式、基因表达水平等多组学层面揭示急性髓系白血病细胞对药物作用的响应机制。在项目执行期间，完成开发和应用ATAC-seq, ChIP-seq, RNA-seq(包括单细胞RNA-seq)等实验和整合分析流程，在基因组水平上定义M2型急性髓系白血病细胞在地西他滨、西达苯胺、全反式维甲酸等药物作用下的基因调控位点，发现部分急性髓系白血病亚型细胞在药物作用下呈现分化紊乱现象。这些研究不仅揭示了急性髓系白血病细胞对抗肿瘤药物的异质性的分子机制，而且为进一步探索筛选靶向表观基因组调控因子的药物奠定了基础。