骨髓微环境炎性因子HMGB1与血管内皮细胞CXCL12协同支持白血病干细胞的机制与干预

研究发现，骨髓微环境提供支持白血病干细胞(LSC)的外源信号，b-catenin是LSC维持自我更新的关键内源信号；骨髓微环境血管内皮细胞通过分泌CXCL12，激活b-catenin，支持LSC；慢性炎症重塑白血病骨髓微环境，抑制正常造血，但炎性因子如何与血管内皮细胞协同支持LSC，尚不完全清楚。我们前期研究发现: b-catenin在CML LSC中高表达，抑制b-catenin可靶向清除LSC；促炎因子HMGB1与CXCL12协同诱导b-catenin表达和核内定位。综上，我们推测：骨髓微环境炎性因子HMGB1与血管内皮产生的CXCL12，协同激活b-catenin，支持LSC自我更新。本项目拟采用内皮细胞共培养体外模拟微环境、PDX小鼠模型和活体双光子成像等技术，体内外研究HMGB1与血管内皮CXCL12协同支持LSC的分子机制，探索干预骨髓微环境与LSC互话的新策略。

Bone marrow niche is critical to the maintenance of leukemia stem cells (LSC) and beta-catenin is required for self-renewal of LSC. Vascular endothelial niche support LSC via producing CXCL12 and subsequent activation of beta-catenin. Pro-inflammatory environment remodel leukemia niche resulting in reduced capacity to support normal hematopoiesis, but it’s not well-established about pro-inflammatory cytokine interaction with endothelial cell to support LSC. We previously revealed beta-catenin was highly-expressed in CML LSC and inhibition of beta-catenin targeted LSC, pro-inflammatory HMGB1 and CXCL12 synergistically induced beta-catenin. We hypothesize that, pro-inflammatory HMGB1 interacts with CXCL12 from endothelial niche, synergistically activates beta-catenin to support self-renewal of LSC. This project aims to dissect the underlying mechanism of synergy effect of HMGB1 and CXCL12 on self-renewal of LSC, by means of endothelial cell (EC) co-culture mimicking BM niche, patient-derived tumor xenograft (PDX) NOD/SCID IL2rg-/-(NSI) mice model and intravital two-photon microscopy.