骨髓血管微环境介导MLL-AF4型急性淋巴细胞白血病耐药复发的机制研究

MLL-AF4阳性急性淋巴细胞白血病（MA4+急淋）是一类好发于婴幼儿且预后极差的恶性血液肿瘤，其与骨髓微环境的相互作用在疾病耐药复发中的作用及机制尚不清楚。我们前期研究发现，儿童急淋细胞移植后浸润并破坏正常骨髓微环境结构，化疗后急淋细胞分泌细胞因子招募正常骨髓细胞重建动态演化微环境，藉此保护残留的急淋细胞。我们新近研究发现，MA4+急淋化疗后残留细胞重塑骨髓血管内皮细胞并与其共定位，体外共培养结果发现血管内皮细胞赋予急淋细胞化疗抵抗，提示MA4+急淋细胞通过重塑骨髓血管微环境调控其耐药复发。本项目拟动态分析化疗后残留MA4+急淋细胞与骨髓微环境细胞之间的三维时空定位关系；研究化疗后MA4+急淋细胞重塑骨髓血管微环境的作用及机制；探讨骨髓血管微环境介导MA4+急淋细胞耐药复发的分子机制。项目将以全新的视角阐明MA4+急淋耐药复发的关键分子及骨髓微环境基础，为该型白血病的防治提供新靶点。

MLL-AF4-positive acute lymphoblastic leukemia (MA4+ ALL) is one kind of malignant hematologic tumor with poor prognosis, which occurs frequently in infants and children. The role and mechanism of the interaction between MA4+ ALL and bone marrow (BM) niche in the drug resistance and recurrence of ALL are not clear. Our previous study found that transplanted childhood ALL cells infiltrate and destroy normal structure of BM niche. ALL cells rebuild an evolving niche by recruiting normal BM cells and secreting cytokines to protect the residual ALL cells after chemotherapy. Recently, we found that MA4+ ALL cells remodel and co-localize the BM vascular endothelial cells after chemotherapy. The results of co-culture in vitro showed that the vascular endothelial cells endow MA4+ ALL cells with chemotherapy resistance, which indicated that MA4+ ALL cells remodel BM vascular niche to mediate the drug resistance and recurrence of residual ALL cells. Based on the success of building ALL mouse model, this project is plan to dynamically analyze the relationship of three-dimensional spatio-temporal location between the MA4+ ALL cells and BM niches. Meanwhile, to explore the mechanism of remodeling of BM vascular niche mediated by MA4+ ALL cells. Furthermore, to reveal the mechanism of chemotherapy resistance and recurrence of MA4+ ALL mediated by BM vascular niche. This project will clarify the key molecules and BM niche foundation of MA4+ ALL drug resistance and recurrence from a new perspective, and provide a new target for the prevention and treatment of infant leukemia.