在前期工作中，我们发现了蛋白酶体抑制剂能特异地杀死表现为pro-B ALL的MLL白血病细胞。我们进一步发现，MLL白血病细胞对蛋白酶体抑制剂的高度敏感性不仅与细胞周期抑制因子p27的诱导表达相关，也与未折叠蛋白反应的发生相关。但是其它未折叠蛋白反应的诱导剂不能像蛋白酶体抑制剂一样特异地杀死MLL白血病细胞。根据我们前期实验的结果，我们推测MLL白血病细胞对蛋白酶体抑制剂的高度敏感性与MLL融合蛋白改变了未折叠蛋白反应发生的阈值有关，并且蛋白酶体抑制剂激活未折叠蛋白反应信号通路的方式与其它诱导剂不一样。本项目将通过对不同细胞以及不同诱导剂之间的比较，对蛋白酶体抑制剂在MLL白血病细胞中特异地诱导未折叠蛋白反应发生的机制进行深入研究，阐明未折叠蛋白反应在细胞对蛋白酶体抑制剂的高度敏感性中的作用。这项研究对更好地在临床上预测蛋白酶体抑制剂治疗的有效性和克服耐药具有重要意义。

In previous study, we found that proteasome inhibitor can selectively kill pro-B MLL leukemia cells. The extreme sensitivity of MLL leukemia cells to proteasome inhibitors is correlated with the induction of CDK inhibitor p27 and the unfolded protein response (UPR). However, unlike proteasome inhibitors, other URP inducers can’t selectively kill pro-B MLL leukemia cells. Based on our prior experiments, our hypothesis is MLL-fusions would alter the threshold to proteasome inhibitors induced UPR, while proteasome inhibitors and other URP inducers activated UPR through different mechanism. In this proposed study, by comparing different cells’ response to different UPR inducers, we’ll further investigate the mechanism underlying the extreme sensitivity of MLL leukemia cells to proteasome inhibitors, especially the role of URP. This study will help to better predict the clinic efficacy of proteasome inhibitor and overcome the drug resistance.