酪氨酸激酶抑制剂在慢性粒细胞白血病(CML)治疗中的复发和耐药问题日益凸显。但是，Bcr/Abl非依赖的TKIs耐药机制，目前还没有系统的研究和确切的结论，更没有有效的逆转耐药方案。本研究以多种特异性的Bcl-2家族蛋白抑制剂，包括我们自主研发的磷酸化Bcl-2蛋白的抑制剂作为小分子研究工具，直接作用于筛选和诱导的Bcr/Abl非依赖型TKI耐药的CML细胞，研究Bcl-2家族蛋白，尤其是磷酸化Bcl-2蛋白与促凋亡伴侣蛋白的二聚体的形成和解离与CML耐药和逆转耐药的关系，揭示Bcl-2蛋白磷酸化在这种耐药中的关键作用和意义；发现参与Bcl-2磷酸化的、Bcr/Abl之外的激酶通路，在理解Bcr/Abl非依赖型TKI耐药的分子机制的同时，为克服耐药提供新的治疗靶点和联合用药的治疗策略，以期提高TKIs对CML的治愈率。

The tyrosine kinase inhibitor Gleevec has undoubtedly revolutionized the therapy of chronic myeloid leukaemia (CML).However, relapse and drug resistance is increasingly more serious in CML therapy. A clearcut molecular mechanism or molecular player in BCR-ABL-independent resistance to Gleevec has not yet evolved. In this study, a variety of specific inhibitors of Bcl-2 family proteins, including the small molecules inhibitor of phosphorylation Bcl-2 developed by ourselves is used as a research tool. These small molecules play a direct role in screening and induction of Bcr/Abl-independent TKI resistant CML cells. We also use these tools to study the function of Bcl-2 family proteins, especially the relationship between the combination and dissociation of phosphorylated Bcl-2 and its pro-apoptotic partner and the drug resistance of CML. This study will reveal the key role of Bcl-2 phosphorylation in drug resistance. We will also study the crosstalk between Bcl-2 family proteins and kinase pathway. Besides Bcr/Abl, we will found the new kinase pathway involved in the development of CML. This study will explain the Bcr / Abl-independent molecular mechanisms of TKI resistance and provide new therapeutic targets to overcome this resistance. We will also provide the therapeutic strategies of combination therapy, in order to truly improve the cure rate of TKIs in CML.