骨髓微环境通过Tim-3/HMGB1/beta-catenin通路支持CML白血病干细胞的机制与干预

研究发现，b-catenin是CML白血病干细胞(LSC)维持自我更新所需的关键信号，参与CML发生、耐药和急变；骨髓微环境可激活LSC b-catenin表达，但机制尚不清楚。我们前期研究发现：靶向抑制b-catenin，可逆转TKI耐药、破坏LSC植入、杀伤LSC；Tim-3是CML LSC的新标记，其高表达与b-catenin激活相关；Tim-3的配体HMGB1，在骨髓微环境MSC和巨噬细胞中广泛表达。综上，我们推测：骨髓微环境细胞分泌HMGB1，与LSC表面Tim-3结合，形成Tim-3/HMGB1通路，激活b-catenin，支持LSC自我更新。本项目拟通过体内外实验，研究骨髓微环境与LSC之间的Tim-3/HMGB1通路互话对LSC b-catenin激活/核内定位/下游基因和植入功能的影响，揭示骨髓微环境支持LSC自我更新的新机制，探索干预LSC与骨髓微环境相互作用的新靶点。

Beta-catenin is required for self-renewal maintenance of leukemia stem cells (LSC) in chronic myeloid leukemia (CML), which is involved in leukemogenesis, tyrosine kinase inhibitor (TKI) resistance and disease progression. Bone marrow niche induces beta-catenin activation in CML, but the underlying mechanism is not well understood. We previously revealed that inhibition of beta-catenin restored sensitivity of TKI-resistant CML cells to nilotinib, impaired engraftment of LSC and killed LSC in vitro and in vivo; furthermore, Tim-3 defines a novel Tim-3high GMP LSC, with highest beta-catenin expression among CML stem/progenitor subsets. Tim-3 ligand HMGB1 was secreted from MSCs and macrophage in bone marrow niche. Based on the aforementioned researches, we hypothesize that Tim-3/HMGB1 pathway mediates the crosstalk between bone marrow niche and LSC, activates beta-catenin and supports LSC self-renewal. The study focus on the crosstalk between Tim-3 in LSC and HMGB1 secretion of bone marrow niche and the subsequent effect on b-catenin activation, nuclear translocation and regulation on downstream genes of beta-catenin, aiming to dissect novel mechanism of interaction between bone marrow niche and LSC and figuring out new targets for potential intervention of the interaction.