Alternative Splicing in Chronic Myeloid Leukemia (CML): A Novel Therapeutic Target?
Alternative Splicing in Chronic Myeloid Leukemia (CML): A Novel Therapeutic Target?
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DOI：
10.2174/15680096113139990083
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发表时间：
2013-09-01
影响因子：
3
通讯作者：
Griffin, James D.
中科院分区：
文献类型：
--
作者：
Adamia, Sophia;Pilarski, Patrick M.;Griffin, James D.
虽然基于伊马替尼的慢性粒细胞白血病(CML)治疗代表着医学的胜利，但由于耐药性和不耐受的发展，并不是所有的CML患者都能从这种药物中受益。伊马替尼治疗中断后，通常会出现临床复发，这表明对残留的白血病干细胞的杀伤失败。有必要为这种疾病确定替代的选择性分子靶点，并开发更有效的治疗方法。选择性前mRNA剪接(AS)是一种表观遗传过程，极大地使转录组的谱系多样化。AS协调各种类型的蛋白质之间以及蛋白质和核酸之间的相互作用。单个剪接事件在细胞中引起的变化很小，然而，“剪接程序”通常会对这些单独的变化做出反应，在细胞增殖、细胞存活和凋亡方面产生相当大的影响。目前的证据表明，AS在白血病中起着关键作用，特别是在骨髓增生异常综合征(MDS)和慢性淋巴细胞白血病(CLL)中。从这些研究和对其他恶性肿瘤的研究可以清楚地看出，剪接异常在恶性转化中起着重要的作用。对慢性粒细胞白血病AS事件的评估可用于识别新的疾病标志物和药物敏感靶点，以克服目前用于治疗CML患者的小分子抑制剂的局限性。使用异常剪接变体作为疾病标记物已有报道，然而，关于剪接异常用作慢性粒细胞白血病药物靶点的报道很少。在这里，我们讨论了潜在的治疗方法，可以用来靶向CML的剪接异常。
Although the imatinib based therapy of chronic myeloid leukemia (CML) represents a triumph of medicine, not all patients with CML benefit from this drug due to the development of resistance and intolerance. The interruption of imatinib treatment is often followed by clinical relapse, suggesting a failure in the killing of residual leukaemic stem cells. There is need to identify alternative selective molecular targets for this disease and develop more effective therapeutic approaches. Alternative pre-mRNA splicing (AS) is an epigenetic process that greatly diversifies the repertoire of the transcriptome. AS orchestrates interactions between various types of proteins and between proteins and nucleic acids. Changes caused by individual splicing events in the cells are small, however, "splicing programs" typically react to these individual changes with considerable effects in cell proliferation, cell survival, and apoptosis. Current evidence suggests a pivotal role of AS in leukemias, particularly in myelodisplastic syndrome (MDS) and chronic lymphocyte leukemia (CLL). From these studies and studies in other malignances, it is clear that splicing abnormalities play a significant role in malignant transformation. Evaluation of AS events in CML can be used to identify novel disease markers and drug-sensitive targets to overcome the limits of the small molecule inhibitors currently used for treating patients with CML. The use of aberrant splice variants as disease markers has been reported, however, little is known about the use of splicing abnormalities as drug targets in CML. Herein we discuss potential therapeutic approaches that can be used to target splicing abnormalities in CML.