表观遗传调控影响造血系统肿瘤发生、发展和预后。TET2是造血系统肿瘤中最易突变的表观遗传基因之一。前期合作研究证实Tet2缺失引起髓系肿瘤的发生需要在造血干祖细胞阶段发生突变（Leukemia 2016）；阐明了Tet2与Tet1协同作用导致B细胞瘤发生(Cell Reports 2015）；初步证明Tet2敲除后WNT/β-catenin通路激活和miRNA表达谱改变可能是其参与髓系肿瘤发生的重要机制；发现DNA甲基转移酶抑制剂可有效延缓Tet2敲除小鼠肿瘤发生。本项目拟在前期基础上，结合小鼠模型和依托单位临床资源优势，开展下列研究：1）从调控信号通路及miRNA等方面阐明TET2参与血液肿瘤的机制；2）TET2协同其它分子参与血液肿瘤的作用机制；3）表观遗传调控药物对TET2突变血液肿瘤的作用及机制。通过本延续项目，阐明TET2对造血系统肿瘤的调控作用，寻找更好的TET2靶向治疗策略。

Recent studies have demonstrated that epigenetic regulation affects the generation, development and prognosis of hematological malignancies. Ten-Eleven-Translocation 2 (TET2) is the key regulator of DNA methylation and the most frequently mutated gene in hematological malignancies. In the past two years’ collaborative work, we verified that loss of Tet2 in hematopoietic stem/progenitor cells (HSPCs), but not more differentiated cells, resulted in myeloid malignancies (Leukemia, 2016). We also demonstrated that Tet2 in cooperation with Tet1, induced B cell malignancies (Cell Reports, 2015). Furthermore, we found that deletion of Tet2 in HSPCs led to increased WNT/β-catenin signaling pathway activation and significant changes of miRNA expression profile, indicating Tet2 may regulate myeloid malignancy through these pathways. Additionally, we found that methyltransferase inhibitors such as 5-Aza-dC could effectively prolong the leukemia development in Tet2 knockout mice. Based on the previous mice model work and the supporting institution’s clinical resources, we proposed in the current study that we will 1) Delineate mechanism how TET2 participates signaling pathway and miRNA regulation; 2) Understand how TET2 cooperates with TET1 in participation in hematological malignancies; 3) Identify the mechanism how DNA methyltransferase inhibitors could inhibit hematological malignancies with TET2 mutation via modifying epigenetic landscape. Through these proposed studies, we will have a better understanding of the mechanism how TET2 regulates hematological malignancies and to find better TET2 targeted therapeutic strategy.