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RUNX1/RUNX1T1 controls alternative splicing in the t(8;21)-positive acute myeloid leukemia cells

View ORCID ProfileVasily Grinev, View ORCID ProfileIlia Ilyushonak, Richard Clough, Sirintra Nakjang, Job Smink, Natalia Martinez-Soria, View ORCID ProfileTatsiana Ramanouskaya, View ORCID ProfileConstanze Bonifer, View ORCID ProfileOlaf Heidenreich
doi: https://doi.org/10.1101/628040
Vasily Grinev
1Department of Genetics, the Faculty of Biology, Belarusian State University, 220030 Minsk, Republic of Belarus
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  • For correspondence: grinev_vv@bsu.by olaf.heidenreich@ncl.ac.uk
Ilia Ilyushonak
1Department of Genetics, the Faculty of Biology, Belarusian State University, 220030 Minsk, Republic of Belarus
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Richard Clough
2Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK
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Sirintra Nakjang
2Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK
3Bioinformatics Support Unit, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK
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Job Smink
4Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
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Natalia Martinez-Soria
2Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK
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Tatsiana Ramanouskaya
1Department of Genetics, the Faculty of Biology, Belarusian State University, 220030 Minsk, Republic of Belarus
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Constanze Bonifer
5Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
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Olaf Heidenreich
2Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK
4Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
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  • For correspondence: grinev_vv@bsu.by olaf.heidenreich@ncl.ac.uk
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SUMMARY

The fusion oncogene RUNX1/RUNX1T1 encodes an aberrant transcription factor, which plays a key role in the initiation and maintenance of the t(8;21)-positive acute myeloid leukemia. Here we show that this oncogene is a regulator of the alternative RNA splicing for a sub-set of genes in the leukemia cells. We found two primary mechanisms underlying changes in the production of RNA isoforms: (i) RUNX1/RUNX1T1-mediated regulation of alternative transcription start sites selection in target genes, and (ii) direct or indirect control of the expression of the 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 a novel layer of RUNX1/RUNX1T1-dependent transcriptome organization in t(8;21)-positive acute myeloid leukemia.

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Posted May 04, 2019.
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RUNX1/RUNX1T1 controls alternative splicing in the t(8;21)-positive acute myeloid leukemia cells
Vasily Grinev, Ilia Ilyushonak, Richard Clough, Sirintra Nakjang, Job Smink, Natalia Martinez-Soria, Tatsiana Ramanouskaya, Constanze Bonifer, Olaf Heidenreich
bioRxiv 628040; doi: https://doi.org/10.1101/628040
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RUNX1/RUNX1T1 controls alternative splicing in the t(8;21)-positive acute myeloid leukemia cells
Vasily Grinev, Ilia Ilyushonak, Richard Clough, Sirintra Nakjang, Job Smink, Natalia Martinez-Soria, Tatsiana Ramanouskaya, Constanze Bonifer, Olaf Heidenreich
bioRxiv 628040; doi: https://doi.org/10.1101/628040

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