项目名称： MDSC差异性扩增在CML患者停药后复发中的作用及机制研究

项目编号： No.81670145

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 游泳

作者单位： 华中科技大学

项目金额： 25万元

中文摘要： 慢性髓系白血病(CML)患者能否安全的停止酪氨酸激酶抑制剂(tyrosine kinase inhibitor，TKI)治疗是该领域的研究焦点。通过分析文献并结合前期基础工作，我们认为髓源抑制细胞(MDSC)能够串联残留的肿瘤干细胞(LSC)和机体免疫组分这两大影响停药结局的核心元件，可能是决定患者停药后是否复发的关键要素。本课题拟从体外实验、动物模型以及临床病例等多个层次证明MDSC在CML患者停药后复发中发挥重要作用，在此基础上提出CML-LSC的分泌因素导致MDSC差异性扩增并初探其分子机制。本课题的完成，将首次证明MDSC是CML患者停药后复发的关键因素，MDSC的数目、亚型及功能有望成为评判是否能够安全停药的警戒线，其本身极有可能成为重要的免疫治疗干预靶点；同时提出LSC对MDSC的扩增效率不同是患者停药后差异结局的重要原因，为最终实现CML的临床治愈提供重要的研究切入点。

中文关键词： 髓源抑制细胞；停药；慢性髓系白血病；微泡；白血病干细胞

英文摘要： Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm characterized by the constitutive expression of the oncogenic tyrosine kinase BCR-ABL1. Clinical cure (drug cessation) has not yet been proven and life-long TKIs therapy is still the consensus recommendation. In the last ten years, constant clinical trials of discontinuing TKIs have reported that sustained treatment-free remission (TFR) could only be observed in about 40% of patients for two years. Retrospective survey indicated that lower number of CD4+ T cells and natural killer cells were associated with lower chance of successful treatment discontinuation. It is well known that although TKIs are largely ineffective in depleting quiescent leukemia stem cells (LSC). However, there appear to be no exact patients or disease characteristics that identify in advance those who can safely discontinue TKIs at present, as well as none connection between the two core elements (LSC and immune-agents) of post-cessation relapse. Myeloid-derived suppressor cells (MDSC) have been extensively studied in recent years owing to their role in suppressing immune responses of many pathological conditions, including cancer. MDSCs could suppress T-cells and natural killer cells, as well as antigen-presenting cells, abrogating the beneficial immune response. Besides, we discovered that total number of MDSC in relapse group was significantly higher than those maintain a stable remission after cessation. As a result, we assume that MDSC might play a pivotal role in the post-cessation relapse of CML patients..To confirm the hypothesis, MDSC would be sorted to improve its impact on T cell, NK cell and leukemia stem cells (LSC) in vitro. Besides, xenograft model of mice could be established to test the connection between the ability of tumorigenesis of LSC and the number, subtype of MDSC. Clinical samples would provide further evidences of the interrelationship of MDSC and T cells, NK cells and finally the endpoint of the patients. One aspect that merits further consideration is why MDSC was differential amplified in different patients. We speculated that CML derived microvesicles (MV) might sever as a novel factor. Horizontal transfer of BCR-ABL1 mRNA from MV into the recipient cells would be critical to amplify the MDSCs. Increased downstream signal STAT3, S100A8/9 could be considered the main mechanism in the recipient cells. Finally, this subject will act as the first report of the connection of MDSC and the post-cessation relapse. Whether the patient would relapse seems to depend on the MDSC and ultimately on the ability of LSC. MDSC would provide a novel and useful model to analyze the function of LSC and predict the relapse, by establishing a kind of new risk stratification system; MDSC itself could be act as a novel target of CML. These data probably improved the understanding of characteristic of LSC and provided important information about optimal molecular monitoring schedules in TKI discontinuation strategies.

英文关键词： Myeloid-derived suppressor cells;cessation;chronic myeloid leukemia;microvesicles;leukemia stem cells