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RUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia

Author

Listed:
  • Vasily V. Grinev

    (Belarusian State University)

  • Farnaz Barneh

    (Princess Maxima Center for Pediatric Oncology)

  • Ilya M. Ilyushonak

    (Belarusian State University)

  • Sirintra Nakjang

    (Newcastle University)

  • Job Smink

    (Princess Maxima Center for Pediatric Oncology)

  • Anita Oort

    (Princess Maxima Center for Pediatric Oncology)

  • Richard Clough

    (Newcastle University)

  • Michael Seyani

    (Newcastle University)

  • Hesta McNeill

    (Newcastle University)

  • Mojgan Reza

    (Newcastle University)

  • Natalia Martinez-Soria

    (Newcastle University)

  • Salam A. Assi

    (University of Birmingham)

  • Tatsiana V. Ramanouskaya

    (Belarusian State University)

  • Constanze Bonifer

    (University of Birmingham)

  • Olaf Heidenreich

    (Princess Maxima Center for Pediatric Oncology
    Newcastle University
    Newcastle University)

Abstract

The fusion oncogene RUNX1/RUNX1T1 encodes an aberrant transcription factor, which plays a key role in the initiation and maintenance of acute myeloid leukemia. Here we show that the RUNX1/RUNX1T1 oncogene is a regulator of alternative RNA splicing in leukemic cells. The comprehensive analysis of RUNX1/RUNX1T1-associated splicing events identifies two principal mechanisms that underlie the differential production of RNA isoforms: (i) RUNX1/RUNX1T1-mediated regulation of alternative transcription start site selection, and (ii) direct or indirect control of the expression of genes encoding splicing factors. The first mechanism leads to the expression of RNA isoforms with alternative structure of the 5’-UTR regions. The second mechanism generates alternative transcripts with new junctions between internal cassettes and constitutive exons. We also show that RUNX1/RUNX1T1-mediated differential splicing affects several functional groups of genes and produces proteins with unique conserved domain structures. In summary, this study reveals alternative splicing as an important component of transcriptome re-organization in leukemia by an aberrant transcriptional regulator.

Suggested Citation

  • Vasily V. Grinev & Farnaz Barneh & Ilya M. Ilyushonak & Sirintra Nakjang & Job Smink & Anita Oort & Richard Clough & Michael Seyani & Hesta McNeill & Mojgan Reza & Natalia Martinez-Soria & Salam A. As, 2021. "RUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20848-z
    DOI: 10.1038/s41467-020-20848-z
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