异常骨髓微环境中基质细胞通过Hedgehog信号通路对急性T淋巴细胞白血病发生发展的作用机制研究

Leukemia is a malignant disease derived from leukemic stem cells (LSCs). Abnormal bone marrow microenvironment has been confirmed to play a significant role in the development of leukemia. Mesenchymal stromal cells are important components of the hematopoietic microenvironment. But the mechanism of the effect of abnormal stromal cells to the development of leukemia has not been studied systemicly..Our previous studies found that during the progression of T-ALL in mice, normal hematopoietic stem cells (HSCs) were urged into dormant state by abnormal bone marrow microenvironment through Hes1 signaling pathway and the function of HSCs was protected. Stromal cells in the microenvironment impeded the generation of normal hematopoietic progenitor cells (HPCs). However the effect and mechanism of stromal cells to leukemic cells especially LSCs is still unknown. We focus to elucidate the effect of stromal cells to the proliferation and apoptosis of leukemic cells especially LSCs and definite the interaction signalling pathways between stromal cells and leukemic cells. Previous results showed that Hedgehog signalling pathway is the key pathway participated in the bilateral interaction between leukemic cells and stromal cells. We will detect the changes of leukaemia progression by blocking this pathway..It will provide new ideas for the pathogenesis of leukemia by elucidating the effect of leukemic environment on leukemia progression, and it will provide a theoretical basis for the treatment of leukemia.

白血病是源于白血病干细胞的恶性克隆性疾病，异常骨髓微环境对白血病的发生发展起重要作用。基质细胞是微环境的重要组分，但异常骨髓微环境中基质细胞对白血病发生发展的影响及相关机理还没有系统研究。.前期工作发现，在T-ALL发病过程中，异常骨髓微环境通过Hes1信号通路使HSC进入静止期，保持了功能的稳定，而微环境中基质细胞却阻碍了HPC的正常扩增。但此微环境中基质细胞对白血病细胞尤其是白血病干细胞的影响及相关机制尚不明确，本课题旨在通过T-ALL患者原代细胞及T-ALL小鼠探讨异常微环境中基质细胞对白血病细胞尤其是白血病干细胞增殖凋亡的影响，并明确两者间相互作用的信号通路。预实验结果显示Hedgehog信号通路是基质细胞与白血病细胞相互作用的关键通路，通过阻断该通路，观察对白血病发生发展的影响。.白血病微环境对白血病作用机理的深入研究，为白血病发病机制提供新的思路，为白血病治疗提供理论依据。

急性淋巴细胞白血病（ALL）是一种侵袭性血液系统恶性肿瘤，多见于儿童，预后较成人好。众所周知，白血病的发生发展与骨髓微环境，尤其是骨髓基质细胞密切相关。骨髓基质细胞可能通过基因和蛋白质的调控影响白血病细胞的存活。在我们的研究中，我们使用NOTCH-1过表达的T-ALL小鼠模型来研究基质细胞对白血病细胞增殖、凋亡和存活的影响。结果表明，T-ALL来源的基质细胞对白血病细胞具有保护作用，并促进白血病细胞的增殖。在白血病的骨髓微环境中，间充质干细胞分化为基质细胞，而不是成骨细胞、破骨细胞、脂肪细胞和其他细胞。然后，基质细胞通过分泌细胞因子FGF2（fibroblast growth factor 2）激活白血病细胞中的PI3K信号通路，影响白血病的发生发展。总之，基质细胞介导的间接细胞间通讯可能参与白血病的发病机制，为今后以基质细胞为基础的抗白血病靶向治疗策略提供了可能的前景。