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

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. Assi, Tatsiana V. Ramanouskaya, Constanze Bonifer and Olaf Heidenreich ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20848-z

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