抑制RAB27B靶向重启急性髓系白血病干细胞衰老同时阻止其干性维持与机制的研究

除少数预后良好的急性髓系白血病（AML）外，现有的治疗方法很难根治AML，其根本原因是不能清除白血病干细胞（LSC）。我们与他人的研究已证明：重启衰老可促进LSC清除；但尚未找到靶向重启AML（非急性早幼粒细胞白血病）干细胞衰老的理想靶分子。我们进一步的研究发现：①RAB27B，一种细胞外泌体释放的调节分子，选择性高表达于AML干细胞；②LSC来源外泌体诱导骨髓间充质细胞（MSC）衰老并高表达RAB27B;③LSC和衰老MSC高表达的RAB27B调节的外泌体释放可能介导“LSC衰老抵抗-MSC衰老-LSC干性维持”环路。本项目将以AML患者原代与细胞系的LSC为对象，在体外与多种小鼠模型中运用分子、细胞与免疫学技术从不同层面进行证明并解读其机制。本项目的完成将证明：RAB27B抑制剂同时靶向LSC与衰老MSC（一箭双靶）能否高效促进AML干细胞衰老与清除，为根治AML提供新思路。

With the exception of a few acute myeloid leukemia (AML) patients with favorable prognosis,the most of them could not be cured by now available therapies.The underlying reason of which is that leukemia stem cells (LSCs) could not be eradicated.Although our and other studies have shown that LSCs could be eradicated by restarting their senescence, but the special targeting molecules to restart senescence of LSCs from patients with AML (non-acute promyelocytic leukemia) have not been found.Our further study found that RAB27B, a regulatory molecule of exosomes efflux, has a selectively high expression in AML stem cells;and that LSCs-derived exosomes induce senescence and a high RAB27B expression of bone marrow mesenchymal stromal cells (MSCs);and that the exosomes excretion promoted by the high expression of RAB27B in LSCs and senescent MSCs could mediate the "LSCs senescence resistance - MSCs senescence - LSCs stemness maintenance" loop.In this project we will confirm the hypothesis and reveal its mechanisms of LSCs from AML patients and cell lines in vitro and in vivo mouse models. Thus, this project will demonstrate whether the simultaneous targetting of LSCs and senescent MSCs with RAB27B inhibitors could effectively induce senescence and clearance of AML stem cells, and protect normal hematopoiesis at the same time, which will provide a new insight for promoting the cure of AML.