New Insights into the Molecular Resistance Mechanisms of Chronic Myeloid Leukemia
New Insights into the Molecular Resistance Mechanisms of Chronic Myeloid Leukemia
复制标题
DOI：
10.2174/1568009615666150921141004
复制
发表时间：
2016-01-01
影响因子：
3
通讯作者：
Li, Yuhua
中科院分区：
文献类型：
--
作者：
Huang, Rui;Kang, Qian;Li, Yuhua
慢性粒细胞白血病（CML）是一种骨髓增生性肿瘤，其特征在于致病癌蛋白BCR-ABL 1（断点簇区/Abelson激酶），这是一种具有组成性酪氨酸激酶活性的融合蛋白。第一种酪氨酸激酶抑制剂（TKI）伊马替尼彻底改变了CML的治疗。尽管伊马替尼的壮观的效果，原发性和获得性耐药以及不耐受伊马替尼仍然存在。BCR-ABL 1点突变、BCR-ABL 1基因扩增和外排药物转运蛋白表达增加的机制在耐药中发挥重要作用，已被广泛描述。因此，已经探索了第二代和第三代TKI以克服耐药性。然而，一些CML患者对所有可用的TKI均难治。此外，大多数患者在停止TKI治疗后复发，这是由于CML干细胞的存在，这些干细胞已被证明主要对TKI耐药。因此，单独的TKI不足以治愈CML，有必要进一步研究CML的本体细胞和干细胞中的分子耐药机制，以确定克服耐药和根除残留CML干细胞的新靶点。本文综述了CML的各种分子耐药机制的新见解，并讨论了基于最近发现的耐药分子机制中发挥重要作用的靶点的治疗策略。
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the causative oncoprotein BCR-ABL1 (Breakpoint-cluster region/Abelson kinase), which is a fusion protein with constitutive tyrosine kinase activity. The first tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of CML. Despite the spectacular effects of imatinib, primary and acquired resistance as well as intolerance to imatinib still exist. The mechanisms of BCR-ABL1 point mutations, amplification of the BCR-ABL1 gene and increased expression of efflux drug transporters, which play important roles in resistance, have been extensively described. Consequently, second-and third-generation TKIs have been explored to overcome resistance. However, some CML patients are refractory to all available TKIs. In addition, most patients relapse after discontinuing TKI therapy, due to the existence of CML stem cells, which have been demonstrated to be primarily resistant to TKIs. Thus, TKIs alone are not sufficient to cure CML, and it is necessary to further investigate the molecular resistance mechanisms in both the bulk and stem cells of CML to identify new targets to overcome resistance and eradicate the residual CML stem cells. This article reviews new insights into the various molecular resistance mechanisms of CML and discusses treatment strategies based on the targets that have recently been found to play an important role in the molecular mechanisms of resistance.