Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis

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 and Omar Abdel-Wahab ()
Additional contact information
Akihide Yoshimi: Memorial Sloan Kettering Cancer Center
Kuan-Ting Lin: Cold Spring Harbor Laboratory
Daniel H. Wiseman: The University of Manchester
Mohammad Alinoor Rahman: Cold Spring Harbor Laboratory
Alessandro Pastore: Memorial Sloan Kettering Cancer Center
Bo Wang: Memorial Sloan Kettering Cancer Center
Stanley Chun-Wei Lee: Memorial Sloan Kettering Cancer Center
Jean-Baptiste Micol: Université Paris-Saclay
Xiao Jing Zhang: Memorial Sloan Kettering Cancer Center
Stephane de Botton: Université Paris-Saclay
Virginie Penard-Lacronique: Université Paris-Saclay
Eytan M. Stein: Memorial Sloan Kettering Cancer Center
Hana Cho: Memorial Sloan Kettering Cancer Center
Rachel E. Miles: Memorial Sloan Kettering Cancer Center
Daichi Inoue: Memorial Sloan Kettering Cancer Center
Todd R. Albrecht: The University of Texas Medical Branch at Galveston
Tim C. P. Somervaille: The University of Manchester
Kiran Batta: The University of Manchester
Fabio Amaral: The University of Manchester
Fabrizio Simeoni: The University of Manchester
Deepti P. Wilks: The University of Manchester
Catherine Cargo: St James’s University Hospital
Andrew M. Intlekofer: Memorial Sloan Kettering Cancer Center
Ross L. Levine: Memorial Sloan Kettering Cancer Center
Heidi Dvinge: University of Wisconsin-Madison
Robert K. Bradley: Public Health Sciences Division, Fred Hutchinson Cancer Research Center
Eric J. Wagner: The University of Texas Medical Branch at Galveston
Adrian R. Krainer: Cold Spring Harbor Laboratory
Omar Abdel-Wahab: Memorial Sloan Kettering Cancer Center

Nature, 2019, vol. 574, issue 7777, 273-277

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1618-0

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