Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, 2050, Australia.
Gene Regulation in Cancer Laboratory, Centenary Institute, University of Sydney, Camperdown, 2050, Australia.
Leukemia. 2018 May;32(5):1081-1093. doi: 10.1038/s41375-018-0021-4. Epub 2018 Jan 30.
Alternative splicing expands the transcriptome thereby promoting protein diversity. It governs critical cellular processes such as differentiation, proliferation and apoptosis in a tissue-specific manner. Aberrant splicing consequent to mutations in splicing factors and disruption of isoform ratios in key regulatory genes provides an important contribution to the pathogenesis of the myelodysplastic syndromes and myeloid leukemia. We review here the central role of alternative splicing in regulating myelopoiesis, and provide clear examples of how global splicing disruption or specific aberrant splicing events might promote leukemogenesis. We discuss the growing number of mechanistic links between epigenetic factors and alternative splicing. Finally, we address the potential utility of alternatively spliced isoforms as biomarkers and the development of novel therapies that modulate alternative splicing in myeloid and other malignancies.
可变剪接扩大了转录组，从而促进了蛋白质的多样性。它以组织特异性的方式控制着细胞的关键过程，如分化、增殖和凋亡。由于剪接因子的突变和关键调节基因的异构体比例的破坏导致的剪接异常，为骨髓增生异常综合征和髓系白血病的发病机制提供了重要贡献。我们在这里回顾了可变剪接在调节髓系造血中的核心作用，并提供了明确的例子，说明全局剪接破坏或特定的异常剪接事件如何促进白血病的发生。我们讨论了越来越多的表观遗传因子与可变剪接之间的机制联系。最后，我们探讨了作为生物标志物的可变剪接异构体的潜在应用以及调节髓系和其他恶性肿瘤中可变剪接的新型疗法的发展。
