白血病微环境通过Hes1信号通路对正常造血干细胞保护作用的机制研究

Leukemia is the competition failure between normal and abnormal hematopoiesis. But the mechanism of the function change of normal HSC under leukemia microenvironment has not studied systemicly. Previous work found that in Notch1-induced murine T-ALL, normal hematopoiesis is suppressed during the development of leukemia, but the impacts of leukemic environment on normal hematopoietic stem cell (HSC) and hematopoietic progenitor cells (HPC) were distinct in that normal HSCs were preserved in part because of increased mitotic quiescence of HSCs and resulted exhaustion of HPCs proliferation. To further elucidate the molecular mechanism, microarray analysis on normal HSCs in this model was conducted and verified by realtime PCR. The expression of Hes1 and its downstream target p21 were elevated in normal HSCs whereas their expression showed no significant alteration in HPCs. Interestingly, although over-expression of Hes1 by retroviral infection inhibited the in vitro colony formation of normal hematopoietic cells, in vivo results demonstrated that normal Lin- cells and HSPCs were better preserved when normal Lin- cells with Hes1 overexpression were co-transplanted with T-ALL leukemia cells. Our work confirmed that the differential expression of Hes1 between HSCs and HPCs resulted in the distinct responses of these cells to the leukemic condition and overexpression of Hes1 could enhance normal HSPCs in the leukemic environment. But the mechanism of how leukemic environment affect the expression of Hes1 in normal HSC is still unknown. To elucidate the mechanism, upstream factors of Hes1 especially the cell surface receptor will be found. Also, the ligand and its origin cells will be determined. The homing of normal HSC and HPC under leukemic environment will be determined. Study on the effect of leukemic environment on normal HSCs will provide new ideas for the pathogenesis of leukemia, and provide a theoretical basis for the treatment of leukemia.

白血病是正常造血与异常造血竞争失败的结果。但白血病微环境下正常HSC的功能改变及相关机理还没有系统研究。 我们前期工作发现，在Notch1过表达诱导的小鼠T-ALL发病过程，白血病微环境对正常HSC/HPC的影响不同：HSC更多进入静止期；HPC快速增殖直至衰竭。为阐明其机制，通过基因芯片结合RealtimePCR，发现Hes1在白血病来源HSC的表达高于对照，且高于白血病来源HPC。功能实验证实Hes1在白血病环境下对HSC有保护作用，维持其处于静止期，保持了数量和功能的稳定。但白血病微环境引起HSC中Hes1升高的机制尚不明确，本课题将进一步寻找Hes1的上游基因及细胞表面受体，并检测白血病微环境中相应配体的表达及其来源细胞，并确定正常HSC/HPC在白血病微环境中的归巢部位。 白血病微环境对正常HSC作用机理的深入研究，为白血病发病机制研究提供新的思路，为白血病治疗提供理论依据。

白血病是正常造血与异常造血之间的竞争失败的结果。我们的前期工作发现在T-ALL小鼠，正常HSCs因为进入静止期自我保护起来，而造血祖细胞却不停增殖，直至衰竭。造血干细胞和祖细胞之间Hes1的差异表达导致其不同结局。但白血病环境引起正常HSC中Hes1表达升高的机制仍是未知的。为了阐明机制，通过基因芯片比较了Hes1上游因子的表达差异并找到配体和它的来源细胞。结果发现Notch信号通路在正常造血干细胞激活，而在正常祖细胞沉默。基质细胞分泌配体Jagged-1。中和Jagged-1将破坏造血干细胞自我更新和增殖之间的平衡。本研究将为白血病的发病机制提供新的思路，为白血病的治疗提供理论依据。