Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis
| Autor: | Rachel E. Miles, Catherine Cargo, Mohammad Alinoor Rahman, Omar Abdel-Wahab, Adrian R. Krainer, Heidi Dvinge, Hana Cho, Robert K. Bradley, Todd R. Albrecht, Fabio M. R. Amaral, Ross L. Levine, Kiran Batta, Daichi Inoue, Fabrizio Simeoni, Deepti P. Wilks, Alessandro Pastore, Bo Wang, Xiao Jing Zhang, Daniel H. Wiseman, Eric J. Wagner, Stéphane de Botton, Eytan M. Stein, Tim C. P. Somervaille, Jean Baptiste Micol, Virginie Penard-Lacronique, Andrew M. Intlekofer, Stanley Chun-Wei Lee, Akihide Yoshimi, Kuan-Ting Lin |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine RNA Splicing Factors Carcinogenesis RNA polymerase II Article Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine Transcription (biology) Cell Line Tumor Gene expression Animals Humans Gene Cell Proliferation Multidisciplinary Serine-Arginine Splicing Factors biology Alternative splicing Epigenome DNA Methylation Isocitrate Dehydrogenase Cell biology DNA-Binding Proteins Gene Expression Regulation Neoplastic Alternative Splicing Leukemia Myeloid Acute 030104 developmental biology 030220 oncology & carcinogenesis Mutation RNA splicing biology.protein Female RNA Polymerase II Transcriptome |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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. Analyses of transcriptomes from patients with acute myeloid leukaemia identified frequently co-occurring mutations of IDH2 and SRSF2, which functional analyses showed to have distinct and coordinated leukaemogenic effects on the epigenome and RNA splicing. |
| Databáze: | OpenAIRE |
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