Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis

Yoshimi, A., Lin, K. T., Wiseman, D. H., Rahman, M. A., Pastore, A., Wang, B., Lee, S. C., Micol, J. B., Zhang, X. J., de Botton, S., Penard-Lacronique, V., Stein, E. M., Cho, H., Miles, R. E., Inoue, D., Albrecht, T. R., Somervaille, T. C. P., Batta, K., Amaral, F., Simeoni, F., Wilks, D. P., Cargo, C., Intlekofer, A. M., Levine, R. L., Dvinge, H., Bradley, R. K., Wagner, E. J., Krainer, A. R., Abdel-Wahab, O. (October 2019) Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis. Nature, 574 (7777). pp. 273-277. ISSN 0028-0836

URL: https://www.ncbi.nlm.nih.gov/pubmed/31578525
DOI: 10.1038/s41586-019-1618-0

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 leukaemia(1,2). 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 complex(3), 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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing
diseases & disorders > cancer > cancer types > leukemia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing
CSHL Authors:
Communities: CSHL labs > Krainer lab
Depositing User: Matthew Dunn
Date: 2 October 2019
Date Deposited: 07 Oct 2019 19:58
Last Modified: 08 Nov 2019 17:21
Related URLs:
URI: http://repository.cshl.edu/id/eprint/38492

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