小柯机器人

美国纪念斯隆-凯特琳癌症中心Omar Abdel-Wahab小组近日发现，RNA剪接和表观遗传调控的协调变化驱动白血病发生。相关论文2019年10月2日在线发表于《自然》杂志。

通过分析982例急性髓性白血病患者的转录组，研究人员发现IDH2和SRSF2基因突变的频繁重叠，通过对表观基因组和RNA剪接的协同作用共同促进白血病的发生。尽管IDH2或SRSF2中的突变赋予明显的剪接变化，但突变体IDH2的共表达改变了突变体SRSF2的剪接效果，并导致比单独的任一突变更明显的剪接变化。与此相一致，突变体IDH2和SRSF2的共表达导致具有体内增殖特征的致死性骨髓增生异常，并且以单独两种突变均未观察到的方式增强了自我更新。IDH2和SRSF2双突变细胞表现出异常的剪接和INTS3基因（整合子复合物3的成员）的表达降低，与RNA聚合酶II的失速增加相一致。异常的INTS3剪接与突变IDH2协同促成白血病的发生，并且依赖于突变SRSF2与INTS3 mRNA中的顺式元件结合以及INTS3的DNA甲基化增加。

这些数据确定了一部分白血病中表观遗传状态的改变和剪接之间的致病性互作，提供了剪接因子突变驱动髓系恶性肿瘤发展的功能证据，并确定了剪接体变化是IDH2突变性白血病发生的介导者。

据了解，转录和mRNA剪接是控制基因表达的关键步骤，而调节这些过程中的每一个的基因突变在白血病中都很常见。尽管影响白血病的表观遗传调控和剪接的突变经常重叠，但尚不清楚这些过程如何相互影响以促进白血病的发生，据研究人员所知，没有功能证据表明RNA剪接因子中的突变会引发白血病。

附：英文原文

Title: Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis

Author: Akihide Yoshimi, Kuan-Ting Lin, Daniel H. Wiseman, Mohammad Alinoor Rahman, Alessandro Pastore, Bo Wang, Stanley Chun-Wei Lee, Jean-Baptiste Micol, Xiao Jing Zhang, Stephane de Botton, Virginie Penard-Lacronique, Eytan M. Stein, Hana Cho, Rachel E. Miles, Daichi Inoue, Todd R. Albrecht, Tim C. P. Somervaille, Kiran Batta, Fabio Amaral, Fabrizio Simeoni, Deepti P. Wilks, Catherine Cargo, Andrew M. Intlekofer, Ross L. Levine, Heidi Dvinge, Robert K. Bradley, Eric J. Wagner, Adrian R. Krainer, Omar Abdel-Wahab

Issue&Volume: 2019-10-02

Abstract: 

Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia1,2. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex3, concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis.

DOI: 10.1038/s41586-019-1618-0

Source:https://www.nature.com/articles/s41586-019-1618-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html