慢性粒细胞白血病(CML)患者获得完全缓解后，少量的CML细胞聚集于骨髓微环境中形成微小残留病灶(MRD)，是导致耐药和复发的根源。低氧骨髓微环境和高表达HIF-1α为MRD提供了天然庇护所，其下游效应分子SDF-1和CXCR4在MRD的形成和发展中发挥了重要调控功能，靶向HIF-1α/SDF-1/CXCR4轴的药物开发有助于体内MRD的清除，改善患者预后。结合前期研究结果，本课题以丹参酮为研究对象，系统研究其对CML骨髓微环境和MRD的作用，评价丹参酮联合伊马替尼的体内外药效，检测丹参酮对微环境中氧分压和HIF-1α表达的影响，明确丹参酮对CML粘附和趋化的调控功能，“多途径、多靶点”阐明丹参酮调控HIF-1α/SDF-1/CXCR4轴的分子机制。本研究将明确丹参酮对MRD的干预作用，为其后续的开发奠定基础，为改善缓解期患者的复发提供新的策略，有助于患者无病生存期的延长。

Chronic Myeloid leukemia (CML) is a hematopoietic cell disease that is characterized by the existence of the Bcr-Abl fusion oncogene resulting from the reciprocal translocation. Imatinib mesylate (IM), a specific tyrosine kinase inhibitor of Bcr-Abl, achieves durable responses in most patients with newly diagnosed CML in the chronic phase. However, despite the success of IM in treating CML, the majority of patients continue to present with minimal residual disease (MRD) contained within the bone marrow (BM) microenvironment. The persistence minimal residual disease may be responsible for CML resistance and results in hematologic relapse. Thus, therapeutic strategies targeting MRD would increase the sensitivity of IM in CML cells.. .The bone marrow microenvironment is comprised of multiple sub-domains which vary in cellular composition and gradients of soluble factors and matrix composition. Experimental evidence indicates that bone marrow microenvironment confer a multi-drug resistance phenotype for minimal residual leukemia. In the context of CML, the BM is highly hypoxic, and that progression of the disease is associated with expansion of hypoxic niches and stabilization of the oncogenic hypoxia-inducible factor (HIF)-1α. HIF-1α also directly up-regulates the expression of stromal derived factor-1 (SDF-1) and its receptor CXCR4. While the interaction between CXCL12 and CXCR4 activates the intrinsic pathway of homing and engraftment in CML cells. Since the importance of BM microenvironment in drug resistance and minimal residual disease development, disruption of the crosstalk of CML cells with BM microenvironment would lead to their re-sensitization to therapeutic agents, and contribute the elimination of the MRD...Tanshinones, diterpene compounds from the root of Salvia miltiorrhiza Bunge, have exhibited significant activities in improving hypoxia-induced injury and HIF-1α inhibition. Our previous results demonstrated that Tanshinones could inhibit the expression of HIF-1α induced by hypoxia in CML cells, indicating potential applications in overcoming bone marrow microenvironment mediated imatinib resistance. The aim of this study was to determine the effect of Tanshinones on the minimal residual disease in BM microenvironment, and elucidate its specific mechanisms. We would measure the MRD levels and imatinib sensitivity after Tanshinones treatment, investigate the activities of HIF-1α/SDF-1/CXCR4 axis and O2 partial pressure in bone marrow microenvironment, evaluate the ability of CML adhesion and trafficking in vivo and in vitro. The combination of Tanshinones and imatinib might be beneficial to target MRD, providing a potential therapeutic strategy to override drug resistance in CML and suppress or eradicate residual disease. Furthermore, elucidating the role and mechanism of HIF-1α/SDF-1/CXCR4 axis in the response to chemo-therapeutic treatment may contribute to the development of novel agents targeting hypoxic bone marrow microenvironment in CML.