促红细胞生成素介导儿童急性淋巴细胞白血病骨质破坏的作用及其机制研究

The incidence of acute lymphoblastic leukemia (ALL) ranks first in malignant tumors of children. In nowadays, bone destruction is not only one of the main symptoms of ALL, but also the great difficulty during the treatment of ALL. Furthermore, there is no effective therapy for the bone destruction because its mechanism is unclear. Our preliminary data shows that it was the critical reason of bone destruction that the differentiation of bone marrow derived cells was inhibited by high dose EPO. It was shown that the expression of EPO and EPOR was increased in children with ALL. Interestingly, the high dose EPO contributed to destruction of the dynamic balance between bone formation and resorption through decreasing the osteogenic differentiation potential of mesenchymal stem cells, activating the mature of osteoclasts, and reducing the synthesis of osteoprotegerin. Taken together, based on our previous study, we will take the differentiation of bone marrow derived cells as a point, establish mouse model with B type ALL, and inject EPO and Jak2 blocker (AG490) to confirm that EPO/EPOR signaling pathway regulates the OPG/RANKL/RANK signaling pathway through the phosphorylation of JAK2-STAT3 signaling. This project will employ a variety of biological technologies to study the effect of EPO on bone formation and resorption. Once this hypothesis is confirmed, it will enrich the knowledge of mechanisms of bone destruction in children with ALL, and provide a new therapeutic target for prevention and treatment of the bone destruction in clinic.

急性淋巴细胞白血病居儿童恶性肿瘤之首，骨质破坏是其主要症状之一，至今对骨质破坏机制尚不清楚，且无针对骨质破坏的有效干预手段。本项目的前期研究发现超高剂量的EPO对骨髓基质细胞分化的影响是导致骨破坏的重要原因。EPO、EPOR不仅在白血病细胞高表达，且EPO抑制成骨细胞分化的同时促进破骨细胞的活化,并通过减少骨保护素的合成来破坏成骨细胞和破骨细胞的动态平衡。项目组在前期工作基础上，拟进一步以白血病细胞自分泌超高剂量的EPO影响骨髓基质细胞的分化为切入点，建立动物模型，分别阻断EPO和JAK2，通过系统研究阐明EPO/EPOR信号通过JAK2-STAT3信号的活化调节OPG/RANKL/RANK信号途径，以及运用上述信号途径的抑制剂EPOR和AG490来干预骨破坏的发展，从基因和蛋白质水平详细阐述超高剂量的EPO在骨质破坏中的作用，为儿童急性淋巴细胞白血病骨质破坏的治疗提供实验依据和理论基础。

本项目以白血病细胞自分泌超高剂量的EPO为切入点，从新的视角分析了超高剂量的EPO在ALL儿童骨质破坏的机制，即EPO/EPOR信号通过JAK2-STAT3信号的活化介导OPG/RANKL/RANK信号，引起骨形成和骨吸收的失衡，最终导致ALL儿童骨质的破坏。国内外尚无相似报道，本研究不仅阐明了超高剂量的EPO与生理剂量的EPO在骨代谢中的作用截然相反，拓宽了EPO/EPOR信号的作用新机制，为ALL儿童骨质破坏的研究提供新思路和新的治疗靶点。