整合多组学技术解析白血病分化阻滞调控网络

Transcriptional regulatory network (TRN) orchestrate lots of cellular process, such as proliferation 、 differentiation 、 apoptos is .The heterogeneity of leukemia makes it a great tendency of future research to decipher transcriptional regulatory process systematically in molecular network level. Acute promyelocytic leukemia (APL)，which can be specifically induced to differentiate from undifferentiated leukemia state by treatment of ATRA, is a good model for clarify the mechanism of leukemia cell differentiation and develop mole cular targeted therapy. Our study aimed to understand the transcriptional netw ork underlying differentiation using APL cells as a model system. Integrated with multilayer data, including large scale APL patient sample expression microarray data, genome-wide DNaseI hypersensitive sites data, histone modification profilin g data, transcript factor interaction data, we constructed a refine transcriptional regulatory network about APL differentiation. Moreover, we find out a set of key transcript factors and functional modules in the transcriptional regulatory network. Lastly, systematic siRNA knockdown of the selected key transcription factors confirmed the reliability of the regulatory network. Thus, the transcriptional regulatory network insight of APL induced differentiation make us understand in depth the mec hanism of differentiation block of leukemia cells, provide us a scientifi c Instruction to develop combinational targeted therapy for other kinds of leukemia.

转录调控网络精细调控细胞的增值、分化、凋亡等各个过程。白血病发生的异 质性使得在分子网络层面上系统地解析转录调控过程成为未来白血病研究的一大趋势。急性 早幼粒白血病（APL）可通过病理浓度全反式维甲酸（ATRA）的应用，靶向诱导未成熟细胞 分化，是研究白血病分化机制、开创分子靶向治疗的良好模型。本课题以APL诱导分化为模 型，通过整合多层次组学数据，如大规模病人样本表达谱、基因组DNaseI超敏感位点图谱、 组蛋白修饰图谱、转录因子调控数据，构建精细的APL诱导分化转录调控网络，筛选其中关 键的转录因子，解析其中重要的功能模块。更重要的是通过 RNAi 关键转录因子的表达谱数 据验证了调控网络的真实可靠。因此，从系统生物学的角度，以整合分析为手段，构建转录 调控网络来全面解析APL诱导分化对我们深入理解白血病分化阻滞的分子机制以及推动其他 类型白血病联合靶向治疗具有十分重要的指导意义。

急性早幼粒白血病（APL）可通过病理浓度全反式维甲酸（ATRA）的应用，靶向诱导未成熟细胞 分化，是研究白血病分化机制、开创分子靶向治疗的良好模型。基于本课题组前期的研究发现、以及此项目的支撑，本课题组系统、全面地分析了ATRA诱导APL分化模型转录调控分子网络，从而发现了一系列重要特征。而这些特征的意义不仅在APL分化机制本身，而且在于其它类型的白血病。例如，在前期的工作中，本课题组发现血液系特异的转录因子PU.1将致癌蛋白PML/RAR募集于附件染色质上的RAREh位点。而这次研究则进一步发现髓系特异的转录因子CEBP也参与PU.1募集PML/RAR的过程。综合而言，本课题组的先后发现说明了为何PML/RAR可以阻断髓系分化、同时也说明为何ATRA可以诱导APL向中性粒细胞分化。结果进一步提示PU.1与CEBP所形成的复合体也参与了其它AML的发病过程。进而，为拓展ATRA在其它白血病的应用提供了有力的依据（主体文章在整理、投递当中）。