白血病相关巨噬细胞异质性机制研究

Cell heterogeneity is observed under both physiological and pathological conditions. In recent years, studies on cell heterogeneity in diseases are hot frontier aspects. The leukemic microenvironment play important roles in the development of leukemia. The development and mechanism of cell heterogeneity in leukemia need to be established. Macrophages, distinguished by their heterogeneity under physiological conditions, are important member in hematopoietic microenvironment. However, the mechanism of their heterogeneity and the association with the development of leukemia have not been established. During the study for the previous NSFC grants, we first proposed the criteria of leukemia-associated macrophage (LAM) in the literature and systematically studied the distribution and activation phenotypic characteristics of LAM during the development of leukemia. We observed that LAM exhibited heterogeneity in three aspects. In the present study, we will study the mechanisms of LAM heterogeneity in three aspects, i.e. heterogeneity in LAM origin, heterogeneity in tissue microenvironment-specific activation mechanisms and heterogeneity in LAM activation phenotypes. We will also study the roles of heterogenous LAM populations on the development of leukemia and explore anti-leukemia methods by intervention of LAM based on their heterogeneity. This study will not only enable us to further understand the role and significance of leukemic microenvironment on the development of leukemia, as well as the mechanism of microenvironmental factors on tumors and leukemia, but also provide clues for further study searching for new strategies and targets for the treatment of leukemia.

生理、病理条件下细胞均有异质性，疾病状态下细胞异质性研究是近年前沿热点领域。白血病微环境在白血病发展中发挥重要作用，其中细胞异质性的形成和作用机制急待阐明。巨噬细胞是造血微环境的重要成员，生理条件下有显著异质性，尚无白血病中异质性机制及与白血病进展关系相关研究。在国家自然科学基金资助下，我们在国际上首次提出了白血病相关巨噬细胞（LAM）的概念并系统研究了其数量变化和表型特点，发现LAM有三方面异质性。在此基础上，本课题利用小鼠急性白血病模型，从来源异质性、组织微环境特异性活化机制异质性以及活化表型异质性三方面阐明LAM异质性机制及与白血病发展的关系，并探索针对LAM异质性进行干预的抗白血病手段，更完整地阐明白血病微环境在白血病发展中的作用和意义，完善微环境因素对肿瘤、白血病作用机制，具有重要理论意义；同时，为进一步寻找白血病治疗的新策略和靶点提供线索，具有潜在应用前景。

巨噬细胞是造血微环境的重要成员，生理条件下有显著异质性，在白血病发展中发挥重要作用，其异质性机制及与白血病进展关系尚未阐明。在国家自然科学基金资助下，我们在国际上首次提出了白血病相关巨噬细胞（LAM）的概念并开展了系统研究，发现LAM有显著的异质性。本课题利用小鼠急性白血病模型，从来源异质性、组织微环境特异性活化机制异质性以及活化表型异质性三方面阐明LAM异质性机制及与白血病发展的关系，并探索针对LAM异质性进行干预的抗白血病手段。主要发现如下： T-ALL早、中期，髓外组织中单核细胞来源Ly6C+ LAM增多；Ly6C+ LAM表现出更显著的M1促炎表型；采用CCR2-/-小鼠证明去除单核细胞来源LAM显著减少白血病细胞髓外分布；阻断Ly6C+ LAM和T-ALL细胞间CCL8-CCR1/CCR2和CCL9/10-CCR1轴可减少白血病细胞髓外分布。不同组织LAM活化表型具有显著异质性，IRF7-JNK/SAPK通路差异造成骨髓和脾脏LAM异质性活化表型，活化该通路使LAM具有更多M1性质可延缓白血病进展。在完成原计划基础上，还阐明了LAM的miRNA表达谱，sM-CSF和mM-CSF异常活化LAM的作用机制，IL-34在巨噬细胞分化及白血病中的作用机制，白血病微环境中Tregs细胞的作用机制及NK细胞的特点，P2X7、Fbxw11、Legumain和DDIT4在白血病中的作用机制等。本研究顺利实施为深入阐明白血病微环境中LAM异质性的形成以及在白血病进展中的作用机制提供了重要的依据、线索，也为白血病免疫治疗提供了理论基础和潜在靶点，具有很强的理论意义和潜在应用前景。发表基金标注论著20篇（10篇发表在Cancer Res等SCI杂志上），国内外学术会议论文22篇，培养博士生7名、硕士生5名。