MR-1阻断对慢粒白血病急性期的疗效及机制研究

Chemotherapy is an important means for the treatment of leukemia. However, the rate of complete remission and long-term survival in leukemia treatment is still low, thus looking for novel target molecules and therapeutic approach is still an important research topic. Our institute discovered a new gene MR-1 that is associated with the tumorigenesis, development and metastasis, and also found that MR-1 is highly expressed in leukemia cells. Clinical data show that high expression of MR-1 in chronic myeloid leukemia cells in blase phase, but low expression in the chronic phase and that knockdown of MR-1 can inhibit leukemia cell proliferation and differentiation, but its further mechanism is not clear. In this study, we explore the relationship of the MR-1 and cell proliferation, differentiation, and its function of action. The bone marrow transplanted mouse model of retroviral replication virus is established, and the effects of MR-1 over-expression on hematopoietic cell differentiation and MR-1 blocking on chemotherapy drugs are explored. Furthermore, the relationship between MR-1 and BCR-ABL, and regulation of BCR-ABL activity by MR-1 are measured. We will clarify the possibility of MR-1 as blast phase markers of chronic myeloid leukemia, and potential drug targets. In vitro and in vivo the efficacy of MR-1 blockers on leukemia and the synergistic effects of chemotherapy drugs are verified, and then to clarify its mechanism of action. In this study, based on the concept of translational medicine, a new strategy of the clinical selective treatment and the new combination therapy for chronic myeloid leukemia in blast phase.

化疗是治疗白血病的重要手段，然而白血病的缓解率和生存率仍然低下，因此寻找新靶分子和治疗途径仍是重要研究课题。我所发现的新基因MR-1与肿瘤发生、发展和转移相关，并在白血病细胞中高表达。临床显示MR-1在慢粒白血病慢性期细胞中低表达，在急性期高表达。下调MR-1能抑制白血病细胞增殖和促进分化，但机制不很清楚。本课题①探讨MR-1与细胞增殖、分化的关系及其功能作用；②建立MR-1逆转录病毒感染小鼠骨髓细胞的移植模型，探索MR-1在体内高表达对造血细胞抑制分化的作用，MR-1阻断对细胞恶性表型逆转的影响；③探明MR-1与BCR-ABL的相互关系，MR-1对BCR-ABL活性的调控作用；④探讨MR-1作为慢粒白血病急性期标志物和潜在药靶，构建MR-1阻断剂，体内外验证阻断剂的疗效和对化疗药物的增效作用，阐明其作用机制。本研究基于转化医学理念，将为临床慢粒白血病急性期特效治疗及联合治疗提供新的策略。

我们以前的研究发现，新基因MR-1（肌原纤维形成调节因子1）与肿瘤发生、发展和转移相关，并在多种白血病细胞中高表达。临床数据显示，MR-1在慢粒白血病慢性期细胞中低表达，在急性期高表达，并且与BCR-ABL的表达有相关性。下调MR-1水平能抑制白血病细胞增殖和促进分化，但机制不很清楚。主要研究内容包括：比较MR-1基因在健康人、慢粒早期和慢粒急性期病人中的表达情况；实验验证MR-1在慢粒急性变的发生发展中是否具有促进作用；建立小鼠骨髓移植模型，观察MR-1是否促进了急性变的发生；探讨MR-1是否依赖于BCR-ABL融合蛋白来发挥其抑制分化的作用；探讨MR-1抑制分化促进增殖的相关信号转导机制,以及MR-1发挥作用的活性区域即分子功能区。本研究确定了MR-1在慢粒急性病细胞中的特异性表达，其抗体可以用于慢粒白血病恶变期的诊断剂；阐明了MR-1在体外对细胞分化、增殖和凋亡中的影响及信号通路；阐明了MR-1在调控分化通路中与其直接相互作用的BCR-ABL蛋白以及与MR-1发挥作用的部分分子功能区；阐明MR-1依赖于BCR-ABL来促使慢性期的细胞进入急性期；研究证明靶向MR-1分子的RNA干扰剂阻断慢粒急性变，干扰剂对化疗药物格列卫具有增效作用，并阐明MR-1在白血病发生中的作用机制。本研究为临床慢粒白血病急性期有效诊断、治疗及联合治疗提供新的策略。