白血病重塑微环境及其对正常造血的影响机制

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.

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。

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。本项目围绕“白血病重塑微环境及其对正常造血的影响机制”这一核心科学问题，阐明了关键细胞因子、激素和细胞外小囊泡在白血病发生和正常造血中的作用；明确了生理及疾病状态下微环境成分的变化规律；探讨了正常造血干/祖细胞内源性调控因子及在病理状态下功能变化的分子机制；揭示了脾脏微环境在白血病发生中的作用；并在原有计划的基础上开发了新型技术和工具研究正常造血及疾病发生。在基金委重点项目资助下，取得了一系列重要研究成果，发表于Nat Cell Biol、Cell Stem Cell（3篇）、Dev Cell、Cell Res、J Clin Invest、J Exp Med、Nat Commun、Blood（5篇）、Leukemia等高水平SCI论文41篇，其中影响因子大于20分的10篇，10-20分共14篇；4篇文章被选为封面，6篇文章收到专文评述或F1000推荐，6篇文章入选中国血液学年度十大研究进展。获授权专利10项，出版专著1部，译著1部，组织出版我国干细胞转化研究和专家共识国际专刊（Stem Cells Transl Med 2021），创办中国首个血液学英文期刊《Blood Science》，牵头制定我国自体造血干细胞移植领域第一个团标，促进干细胞临床应用规范共识，获得了显著的社会和经济效益。