表观遗传学基因突变和图谱异常在白血病中十分常见，但它们在白血病的发生发展中的作用还不清楚。申请人前期工作阐明这些表观遗传学突变，包括甲基转移酶MLL3（Cancer cell, 2014）、代谢/表观遗传学IDH突变(Genes Dev, 2013)等为白血病的驱动基因。共发表SCI论文20篇，他引1047次。其中第一作者/通讯作者在Cancer Cell、Genes Dev、JEM、JCI等发表论文8篇，总影响因子89.9。申请人因此获得了包括白血病与淋巴癌协会“职业发展奖”等多个学术奖项，受邀在国际会议Acute Leukemia XV上做大会报告。在此基础上，申请人将进一步通过自我构建的可诱导、逆转和荧光示踪的shRNA系统及CRISPR/dCas9基因技术，研究表观遗传学基因在白血病维持中的作用及其分子机制。该研究将为针对表观遗传学异常的肿瘤靶向治疗提供理论基础。

The mutations of epigenetic regulators and epigenetic abnormalities are common in acute myeloid leukemia (AML). My previous work has identified these epigenetic mutations, such as the deficiency of MLL3, a H3K4 mono- and di-methytransferase (Chen C., et al., Cancer cell, 2014, IF=23.9）,and IDH mutants, a unique link between cancer metabolism and epigenetics (Chen C., et al., Genes & Development, 2013, IF=12.6), as driver mutations in AML.AML comes from self-renewal dysregulation of hematopoietic stem cells (HSC). I also systematically studied the role of mTOR pathway in HSC self-renewal (Chen, et al., Journal of Clinical Investigation, 2010, IF=15.4; Chen, et al., Science Signaling, 2009, IF=7.6; Chen, et al., Journal of Experimental Medicine, 2008, IF=15.2). These work have been highly appreciated by the peer investigators in the field, with total citations of 1047, and H index=14.Therefore I received multiple academic rewards, including the Leukemia & Lymphoma Society Career Development Program Award (2011-2014）and Keystone Symposia Future of Science Fund Scholarship (2014). I was invited to give a Main Symposium presentation on the international conference Acute Leukemia XV (Munich, Germany, Feb. 22-25).Based on my previous work on the functional roles of epigenetic factors in leukemia genesis, in this proposed study, I will apply inducible, reverable and traceable shRNA and CRISPR/dCa9 gene regulation systems to identify the role and molecular mechanism of epigenetic genes in tumor maintenance. I will test whether these epigenetic abnormalities in AML can be reversed, which will shed light on the epigenetic target therapy for this dismal disease.