Bcr-Abl癌蛋白不能入核而阻滞在胞浆可激活下游多条致癌信号通路，是引起慢性粒细胞白血病（CML）的重要分子基础。本组前一项已结题NSFC项目采用靶向Bcr-Abl蛋白入核的策略，展示了对CML细胞抑增殖促凋亡效应。然而Bcr-Abl蛋白在细胞内异常定位的机制尚不清楚。本项目拟寻找决定Bcr-Abl异常定位于胞浆、不能入核的关键结构域，并阐明其作用机制。鉴于我们预实验发现Bcr N端CC域和Abl C端FABD结构域共同介导了Bcr-Abl定位改变，故首次提出CC域介导四聚体形成阻碍Bcr-Abl入核；FABD通过结合F-actin影响Bcr-Abl定位；Bcr-Abl中核定位信号未发挥作用；与CC域或FABD结合的蛋白将Bcr-Abl滞留于胞浆的研究思路。研究结果将有助于揭示Bcr-Abl蛋白异常定位机制，为从蛋白定位的角度阐明CML发病机制和治疗提供新思路，为临床药物开发提供新靶点。

The localization of Bcr-Abl oncoprotein in cytoplasma can activate multiple signal pathways leading to chronic myeloid leukemia（CML）, whereas the localization in nucleus is able to induce apoptosis. In our previous NSFC project, we adopted a novel strategy of targeting Bcr-Abl protein into nucleus, which had showed an effect of cells proliferation inhibition and apoptosis induction. However, the mechanism of the fusion protein localization at cytoplasm is far from understood. In this project, we aim to search the key domain in the fusion protein structure, which is responsible for its abnormal localization. At the same time, we shall explore the mechanism behind. In our previous researches, we had identified that the CC domain at N-terminal of Bcr and FABD domain at C-terminal of Abl are responsible for the change of aberrant localization, based on this discovery, here in this project, for the first time, we propose: 1) a CC domain mediated tetramer hinders the trans-localization of protein into the nucleus; 2) FABD affects the localization by binding F-actin; 3) the nuclear localization signal(NLS) in protein doesn’t function; 4) proteins binding to CC domain or FABD domain traps Bcr-Abl in the cytoplasma . This work will reveal the mechanism of aberrant localization of the oncoprotein, which is the key pathology of CML, and will provide potential targets for new drugs developing in the future.