“BCR-ABL非依赖型酪氨酸激酶抑制剂（TKIs)耐药”是导致慢性粒细胞白血病（CML）治疗失败的重要原因，由于机制复杂而不明确，临床至今仍缺乏有效应对方案。血管生成素1（ANG-1）是多种肿瘤预后不良的潜在因子，但其与CML的关系国内外未见报道。本项目前期研究首次发现：ANG-1在BCR-ABL野生型的CML耐药细胞中表达显著升高，其不仅能保护CML细胞和白血病干细胞免受TKIs刺激损伤，还能诱导骨髓间充质干细胞恶性分化。据此，我们推测：ANG-1可能通过多种途径介导CML发生BCR-ABL非依赖型TKIs耐药。为了证实这一假说，本项目拟从临床样本-动物模型-体外细胞实验三个层次，观察基因沉默或药物抑制ANG-1与受体结合对CML耐药的影响；同时借助二代测序、流式细胞术及分子生物学等手段，多角度深入探索相关信号通路。为临床治疗TKIs泛耐药的CML提供新靶点与新思路。

“BCR-ABL independent resistance to tyrosine kinase inhibitors (TKIs)” is a crucial reason for the therapeutic failure in chronic myeloid leukemia (CML). Due to the complex and unclear mechanism, there is still no effective response strategy to overcome it completely in clinic. Angiopoietin 1 (ANG-1) is a potential factor leading to poor prognosis of various tumors, but its relationship with CML has not been reported worldwidely. Our preliminary results firstly found that ANG-1 was overexpressed in CML cells with wild-type BCR-ABL. And we also comfirmed it can not only protects CML cells and leukemia stem cells from TKIs, but also induces malignant differentiation of bone marrow mesenchymal stem cells. Therefore, we speculate that ANG-1 may induce BCR-ABL independent TKIs-resistance through multiple pathways. In order to confirm this hypothesis, this project intends to observe the effects of ANG-1 inhibition by gene silencing or receptor binding blocking on drug-resistance in CML from three levels, including clinical samples, animal models and in vitro experiments. Meanwhile, the related signal pathways will be explored from multiple angles by the methods of next-generation sequencing, flow cytometry and molecular biology. It provides a new target and new therapeutic strategy for CML with pan-resistance to TKIs.