申请人主要从事白血病细胞治疗相关研究：1）发现了Bcl11b的缺失会诱导小鼠T细胞重编程为类NK的新型肿瘤杀伤细胞（ITNK），揭示了Bcl11b在T细胞身份维持过程中的重要作用。在人T细胞中，阐明了KLF4直接负调控BCL11B等T细胞特异转录因子，从而阻断T细胞发育；2）发掘ANGPTL7通过激活WNT信号通路来促进人造血干细胞扩增与植入；3）构建了具有自主知识产权的无B、T、NK细胞的免疫缺陷小鼠NSI品系，并建立了免疫系统和白血病人源化小鼠模型。申请人共计发表论文14篇，作为第一作者在Science上发表1篇，通讯作者在Haematologica等期刊发表4篇论文。申请专利受理12项，授权4项。本项目计划研究：1）人T细胞重编程为ITNK的方法与分子机理，并评估人ITNK细胞杀伤肿瘤能力；2）ANGPTL7对白血病起始细胞的作用；3）ANGPTL7对ITNK细胞的调控作用。

The applicant obtained Ph.D. degree in Immunology from the University of Cambridge in 2010. After graduation, the applicant studied lymphocyte reprogramming and cancer immunotherapy at Sanger Institute as a postdoctoral research fellow. For the first time, the applicant demonstrated that T lymphocytes reprogrammed to a novel type of natural killer (NK)-like cells, ITNKs, upon loss of Bcl11b. ITNKs are capable of suppressing the growth and the metastasis of various tumors in vivo while keeping host cells intact, revealing the potential application of ITNKs in cancer immunotherapy. The research was published in Science in 2010 and was highlighted in top journals, including Science, Immunol Rev, and Nat Rev Clin Oncol. The applicant was invited to orally present this work in 2010 Cold Spring Harbor Lymphocytes Conference in New York. A PCT patent based on ITNK production and application has been granted. In 2011, the applicant joined Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences as a principal investigator. Leading a research lab focusing on developing novel cell-based therapies for leukemia treatment, the applicant have obtained following achievements: 1) revealed that KLF4 negatively regulates human T cell development by inducing SUMOylation and degradation of BCL11B, and directly binds to the promoters of NOTCH1 and suppresses its expression; 2) identified that ANGPTL7 is capable of stimulating human hematopoietic stem and progenitor cell expansion and increasing the repopulation activities of human hematopoietic progenitors in xenografts through Wnt signaling; 3) derived NSI mice, a mouse strain that lacks B, T, or NK cells and established several xenograft models with reconstitution of human immune system or patients-derived leukemia using NSI mice. The applicant has published 14 research articles, including a publication in Science as the first author and four publications in Haematologica, Mol Cancer, J Hematol Oncol, and Cell Regeneration as the corresponding author. The applicant has filed 12 patents, four of which have been granted. In addition, the applicant has been invited to peer-review research articles for several journals, including Oncotarget and J Hematol Oncol. In this application, the applicant proposes to work on three projects: 1) develop a novel method to reprogram human T cells into ITNKs by overexpressing KLF4 and NK specific transcription factors, investigate the molecular mechanisms involved in the reprogramming process, and validate whether human ITNKs are able to efficiently eliminate patient’s leukemia cells in vivo using humanized mouse models; 2) uncover effects of ANGPTL7 on leukemia initiating cells; 3) investigate whether ANGPTL7 activates human ITNK cells in vitro and in vivo.