复发与耐药是进一步提高儿童急性淋巴细胞白血病（ALL）疗效、改善预后的主要障碍。我们的前期研究发现，胞浆p27Kip1蛋白增多与儿童ALL复发、耐药相关；白血病细胞的胞浆 p27Kip1蛋白可经非常规途径分泌并在细胞间传递，因而推测ALL细胞通过胞浆p27Kip1分泌与传递，导致耐药性增加。拟从分子、细胞及动物水平，明确p27Kip1与白血病细胞膜上关键结合蛋白LRP1B特异性结合并启动细胞内吞的分子机制，并证明摄入胞浆的p27Kip1通过与PRDX1相互作用，激活EMT通路及增强白血病细胞干性，从而导致白血病细胞耐药与复发。创新点是首次发现并探索了白血病细胞中p27Kip1分泌并进行细胞间传递的分子机制，创新性地从蛋白质分泌、细胞间相互影响的角度，来探讨儿童ALL中胞浆p27Kip1增多导致耐药、复发的机制，为相关研究开拓新的思路，并为复发/难治性患儿探寻新的治疗靶点提供理论依据。

Relapse and chemoresistance remain to be the major obstacle for improving the treatment outcome of childhood acute lymphoblastic leukemia (ALL). We have found that increase of cytoplasmic p27Kip1 was associated with relapse and chemoresistance, and cytoplasmic p27Kip1 of leukemia cells could be secreted by unconventional pathway and transferred between cells. Based on these results, we proposed a hypothesis that secretion and transmission of cytoplasmic p27Kip1 in ALL cells could lead to increase of chemoresistance of leukemia cells. We plan to carry out studies at molecular, cellular, and experimental animal levels as follows: cytoplasmic p27Kip1 transmission could be initiated by binding LRP1B on plasma membrane. Intake of p27Kip1 in cytoplasm could activate EMT pathway and enhance leukemic cell stemness by interacting with PRDX1, which would lead to drug resistance and relapse. The innovation of this study is to explore for the first time the mechanism of p27Kip1 secretion and transmission in leukemia cells. The mechanism of chemoresistance and relapse caused by the increase of cytoplasmic p27Kip1 in childhood ALL will be explored innovatively from the perspective of protein secretion and interaction between leukemia cells. This study will be of great help to open up new ideas for relevant research and provide theoretical basis for finding new therapeutic targets for relapsed or refractory patients with childhood ALL.