选择性剪接(AS)是一个严格调控的过程,从单个基因产生多个mRNA变体,从而促进蛋白质组的多样性。全转录组测序研究揭示了功能协调剪接事件的网络,产生具有不同或甚至相反功能的同工型。迄今为止,AS的几种机制在白血病细胞中失调,主要是由于剪接和/或表观遗传调节因子的突变和剪接因子(SF)的表达改变。在这次审查中,我们讨论了影响SF(SF3B1,U2AF1,SRSR2和ZRSR2)的突变诱导的异常剪接事件,剪接体组件(PRPF8、LUC7L2、DDX41和HNRNPH1),和表观遗传调节剂(IDH1和IDH2)。最后,我们提供了与凋亡调节有关的基因异常同工型的生物学相关性的广泛概述(例如g.BCL-X,MCL-1,FAS,和c-FLIP),激活关键的细胞信号通路(CASP8,MAP3K7和NOTCH2),和细胞代谢(PKM)。
Alternative splicing (AS) is a strictly regulated process that generates multiple mRNA variants from a single gene, thus contributing to proteome diversity. Transcriptome-wide sequencing studies revealed networks of functionally coordinated splicing events, which produce isoforms with distinct or even opposing functions. To date, several mechanisms of AS are deregulated in leukemic cells, mainly due to mutations in splicing and/or epigenetic regulators and altered expression of splicing factors (SFs). In this review, we discuss aberrant splicing events induced by mutations affecting SFs (SF3B1, U2AF1, SRSR2, and ZRSR2), spliceosome components (PRPF8, LUC7L2, DDX41, and HNRNPH1), and epigenetic modulators (IDH1 and IDH2). Finally, we provide an extensive overview of the biological relevance of aberrant isoforms of genes involved in the regulation of apoptosis (e. g. BCL-X, MCL-1, FAS, and c-FLIP), activation of key cellular signaling pathways (CASP8, MAP3K7, and NOTCH2), and cell metabolism (PKM).