THPO-MPL介导的成骨细胞龛在维持白血病干细胞干性中的作用研究

白血病干细胞是白血病发病的根本机制，是白血病治疗复发及预后不良的重要根源。白血病干细胞受到微环境的调节，异常的骨髓微环境是维持白血病干细胞保持自我更新潜能、静息状态及免受药物清除等干性特征的庇护场所。本项目在前期研究发现白血病患者骨髓血浆中THPO水平异常升高以及白血病患者骨髓CD34+细胞的MPL表达显著升高的基础上，拟以THPO-MPL介导的骨髓微环境中成骨细胞龛的作用作为研究白血病干细胞干性特征的切入点，以急性髓系白血病患者来源的成骨细胞、白血病干细胞以及小鼠白血病模型为研究对象，通过确定白血病病态造血微环境下的成骨细胞龛是否存在THPO-MPL表达异常，THPO-MPL介导的成骨细胞龛与白血病干细胞相互作用在白血病干细胞的自我更新、休眠状态及抵抗化疗药物杀伤中的作用的体内及体外实验研究，阐明白血病成骨细胞龛在白血病干细胞干性中的作用及其分子机制，为白血病的治疗寻找新的线索和策略。

Leukemia is initiated and maintained by a rare population of leukemia stem cells (LSC), which is the key mechanism of relapsed or refractory leukemia. Abnormal hematopoietic microenvironment is critical for regulating LSC's fate. Importantly, bone marrow niche in leukemia state plays a key role in maintenance of LSC's stemness, including aberrant self-renewal,quiescence and drug resistant. Based on our previous finding that THPO levels were elevated in bone marrow and MPL was highly expressed in CD34+ leukemia cells from leukemia patients, in this project, we select THPO-MPL mediated osteoblastic niche as the breakthrough point of study on the role of abnormal micronenvironment in malignant stemness of LSC. Via study on osteoblastic cell and leukemia stem cell from leukemia patients, as well as on mouse leukemia model, we proposed to determine whether THPO-MPL is abnormal in leukemia state and the role of THPO-MPL mediated abnormal osteoblastic niche in maintaining self-renewal,dormant state and chemotherapy resistance.Finally, we will elucidate the contribution of osteoblastic niche in the stemness of LSC, and further define its molecular machanism. The objective of this research is to provide new clue and strategy for treatment of leukemia.