早期胸腺细胞（ETPs）的急性淋巴细胞白血病（ETP-ALL）是一种新的T细胞急性淋巴性白血病（T-ALL）的独特生物次类型。但T-ALL和ETP-ALL的基因突变特性不同，在后者中常见细胞因子信号通路活化性基因突变和含有表观调节因子EzH2的Polycomb Repressor Complex 2具有高度突变现象。为了研究Ezh2在体内如何促进ETP-ALL发病的分子机制，我们用Ezh2与P53条件性双重基因敲除方法成功建立了ETP-ALL小鼠模型。本课题采用RNA测序法对ETP-ALL发病前后基因表达进行分析，筛选出EZH2下游的直接靶基因；利用甲基化测序法对ETP-ALL动物模型小鼠发病前后的甲基化水平进行系统分析。了解T细胞分化相关基因的DNA异常甲基化修饰情况。在此基础上，根据EZH2诱导ETP-ALL发生发展过程中的表观遗传信息形成、维持和作用的规律和特点，筛选相应的治疗模式。

Early T cell precursor (ETP) acute lymphoblastic leukemia (ALL) has been identified as a new pathologic entity with poor outcome in patients with T-ALL. In contrast to cortical T-ALL, ETP-ALL has been characterized by the activating mutations in genes regulating cytokine signaling and the alterations in the polycomb repressor complex 2 (PRC2) components, including EZH2. To investigate how EZH2 alterations promote the development of ETP-ALL, we generated a novel mouse model of ETP-ALL by utilizing Ezh2 and Trp53 conditional knockout mice. The Ezh2/p53-dificient mice developed lethal ETP-ALL in mice following the accumulation of cytoplasmic CD3+c-Kit+CD44+CD25- DN leukemic cells, while p53-dificient mice developed CD8+ cortical T-ALL in this setting as previously reported. We are going to identify the Ezh2 target genes using RNA sequencing analysis in healthy CD3+c-Kit+CD44+CD25- DN cell and cytoplasmic CD3+c-Kit+CD44+CD25- DN ETP-ALL leukemic cell. . Since DNA methylation is critical for the precise activation of genes during normal T-cell differentiation, we are going to investigate whether altered DNA hypermethylation contributed to silencing the expression of T-cell differentiation regulators in Ezh2/p53-dificient cells. .In addition, we also to test tdecitabine, a demethylating agent, in the treatment of ETP-ALL mouse model.. Thus, we demonstrate that Ezh2 play a tumor suppressor role in the pathogenesis of ETP-ALL in vivo in the absence of p53. We illustrate how combined deletion of Ezh2 and p53 altered the epigenetic regulation to an extent not seen in either deletion alone, and induced highly penetrant ETP-ALL characterized by the molecular profile similar to that in patients with ETP-ALL harboring mutations in the PRC2 components.