单细胞尺度解析白血病下造血干/祖细胞及其微环境的变化规律及机制

随着单细胞测序技术的迅猛发展，其在造血领域的运用也日趋常规化。造血干/祖细胞异质性和分化谱系问题也得到了相应的阐释。当发生病态造血如白血病时，造血系统受到严重抑制，同时微环境受白血病的影响演变成利于白血病生长的环境。但白血病是否会重塑造血干/祖细胞的异质性和分化模式，以及是否会改变微环境细胞如间充质干细胞、内皮细胞的异质性，目前仍未报道。申请者在前期的工作中，对白血病下正常造血受抑的规律和部分机制上进行了研究。在此基础上，本项目拟开展以下新的研究：1）解析白血病下骨髓和脾脏造血干/祖细胞和微环境细胞的异质性变化并构建分化图谱；2）探索微环境细胞分泌的潜在造血调控因子及其在白血病中的变化；3）阐明白血病下正常造血干/祖细胞及微环境细胞功能变化的分子机制。以期通过上述3个方面的研究，从单细胞尺度解析白血病下造血干/祖细胞及其微环境的变化规律及机制，最终为白血病的治疗提供新的思路和策略。

The heterogeneity and fate mapping of hematopoietic stem and progenitor cells (HSPCs) have been well refined in the recent years due to the rapid development of single cell RNA sequence technology. The normal hematopoietic system and its microenvironment can be severely disturbed in disease such as in leukemia. The expansion of leukemia cells leads to severe dysfunction of HSPCs. Meanwhile, leukemia cells create a self-reinforcing leukemic niche. However, whether leukemia can reshape the heterogeneity and hierarchy of HSPCs and niche cells is still unclear. This is an important and clinically relevant question that deserves a thorough investigation. We have conducted a series of research in the past several years and obtained some mechanisms on how leukemia suppresses normal hematopoiesis. Based on our previous studies, we plan to conduct further investigation with the following research goals: (1) to document the alterations of heterogeneity and differentiation hierarchy of HSPCs and niche cells in leukemic BM and spleen; (2) to explore new HSPC regulation factors and their changes in leukemia; (3) to study the mechanisms on how leukemia suppresses normal HSPCs and niche cells. Based on the unique interactions and mechanisms among normal HSPCs, leukemic niches and leukemia cells, this application is aimed to study the alterations of HSPCs and niche cells under leukemia condition at single cell resolution and develop new strategies to improve the current therapies for leukemia.