急性白血病骨髓微环境在治疗过程中的微生态演化

骨髓是个微生态系统，各级造血细胞与其所处的微环境（niche）相互依存和调节，组成和维持造血稳态。当白血病细胞浸润其中，造血发生紊乱，特别在治疗过程中，骨髓微生态环境发生显著改变。最近申请者率先报道，治疗过程诱导形成保护白血病干细胞的微环境，即治疗诱导微环境(therapy-induced niche, TI-niche)，导致治疗失败，但是TI-niche改变骨髓微生态环境的生物学特性及其保护白血病细胞和影响正常造血的机制亟待深入研究。本项目将在申请者前期的新发现和新概念的指导下，结合使用先进的生物学、影像学、原位组学技术，研究TI-niche组成细胞的来源和生物学特性；TI-niche中白血病细胞的亚克隆结构和演化规律；TI-niche抑制正常造血的微生态学机制。为进一步研究合理的治疗方法，有效清除白血病细胞，同时促进正常造血恢复提供理论指导和实验依据。

Bone marrow (BM) microenvironment is a microecosystem in which the hematopoietic cells and its niches hierarchically coexist and mutually regulate to fulfill hematopoiesis. The homeostasis of hematopoiesis will be markedly disturbed by leukemia infiltration and therapy. Recently we for the first time reported that leukemia-propagating cells (LPCs) build a protective niche in the BM to evade therapy. The niche is called therapy-induced niche (TI-niche). But the ecological changes in the BM caused by the TI-niche and its influences in “normal” hematopoiesis and the mechanism in which TI-niche protects LPCs remain to be investigated. In the proposed project we will address these key issues by using the modern biological imaging systems in combined with in situ omics and functional assays in our advanced leukemia models. The studies will have implications in further exploring appropriate therapeutic methods eliminating LPCs and promoting recovery of hematopoiesis.