在稳态造血中，造血干/祖细胞受到胞内机制和外源微环境的精确调控。当发生病态造血如白血病时，造血严重失衡，造血干/祖细胞功能受抑；同时微环境受白血病细胞的影响，逐渐演变成有利于其自身生长增殖的环境。但对于白血病如何重塑微环境以及被重塑的微环境又如何进一步影响正常造血及其作用机制，仍知之甚少。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系列研究。在此基础上，本项目拟开展以下新的研究：（1）阐明关键造血细胞因子（SCF与CXCL12等）对白血病发病的影响；（2）明确白血病骨髓微环境成分的变化及其分子基础和对于造血抑制的作用；（3）探讨白血病下受抑的正常造血干/祖细胞的遗传与表观遗传调控的交互作用机制；（4）探明髓外微环境（脾脏）的激活机制及其对正常造血和白血病发展的特异性作用。本项目旨在针对白血病微环境对正常造血的影响机制，探索增强白血病治疗效果的新靶点和策略。

Under homeostatic conditions, the hematopoietic stem and progenitor cells (HSCs and HPCs) are precisely regulated by intrinsic and extrinsic factors. However, this steady state can be severely disturbed in disease such as in leukemia. The infiltration of the bone marrow by leukemic cells leads to profound dysfunction of HSCs and HPCs. Meanwhile, leukemia cells create a self-reinforcing leukemic niche, which promotes leukemic cell growth at the expense of normal hematopoiesis. However, the process how leukemia remodels the niche, which in turn interrupts the function of normal HSCs and HPCs is still an important and clinically relevant question that deserves a thorough investigation. We have conducted a series of research on this topic in the past several years and obtained some mechanisms on how leukemia suppresses normal HSCs and HPCs. Based on our previous studies, we plan to further investigate this question with the following research goals: (1) to characterize the effects of two key hematopoietic factors, SCF and CXCL12, on leukemogenesis; (2) to document the process of how leukemia remodel the niche components and their suppressive effects on normal hematopoiesis; (3) to explore the intrinsic mechanisms on how leukemia suppresses normal HSCs and HPCs, including genetic and epigenetic aspects; (4) to study how leukemic spleen niche components distinctly regulates both leukemic cells and HSPCs. Based on the unique interactions and mechanisms between leukemic niches and normal HSCs/HPCs, this study is aimed to discover novel molecular targets and develop new strategies to improve the current therapies for leukemia.