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 van Oort; Richard Clough; Michael Seyani; Hesta McNeill; Mojgan Reza; Natalia Martinez-Soria; Salam A Assi; Tatsiana V Ramanouskaya; Constanze Bonifer; Olaf Heidenreich

doi:10.1038/s41467-020-20848-z

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 van Oort, Richard Clough, Michael Seyani, Hesta McNeill, Mojgan Reza, Natalia Martinez-Soria, Salam A Assi, Tatsiana V Ramanouskaya, Constanze Bonifer, Olaf Heidenreich

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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.

Original language	English
Article number	520
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20848-z
Publication status	Published - 22 Jan 2021

Bibliographical note

Funding Information:
The authors thank Dr. Aliaksandra Radzisheuskaya (Cell Biology Program and Center for Epigenetics, Memorial Sloan Kettering Cancer Center, New York, USA) for carefully reading and improving the manuscript, Dr. Petr Nazarov (Luxembourg Institute of Health, Strassen, Luxembourg) for excellent practical ideas with independent component analysis, Dr. Paul Boutz (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, USA) for comprehensive discussion of the pipeline and tips on identifying retained introns, and Dr. Thomas Langer (University of Cologne, Cologne, Germany) for providing us with original anti-PARL antibodies. Research in the V.V.G. laboratory was supported in part by the Ministry of Education of the Republic of Belarus, grant #3.08.3 (947/54, 469/54). O.H. is supported by grants from Cancer Research UK (C27943/A12788), Bloodwise (15005), Kay Kendall Leukemia Fund (KKL1142), the North of England Children’s Cancer Fund and KIKA (329). C.B. is supported by Bloodwise (15001).

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Cite this

Grinev, V. V., Barneh, F., Ilyushonak, I. M., Nakjang, S., Smink, J., van Oort, A., Clough, R., Seyani, M., McNeill, H., Reza, M., Martinez-Soria, N., Assi, S. A., Ramanouskaya, T. V., Bonifer, C., & Heidenreich, O. (2021). RUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia. Nature Communications, 12(1), Article 520. https://doi.org/10.1038/s41467-020-20848-z

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title = "RUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia",

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.",

author = "Grinev, {Vasily V} and Farnaz Barneh and Ilyushonak, {Ilya M} and Sirintra Nakjang and Job Smink and {van Oort}, Anita and Richard Clough and Michael Seyani and Hesta McNeill and Mojgan Reza and Natalia Martinez-Soria and Assi, {Salam A} and Ramanouskaya, {Tatsiana V} and Constanze Bonifer and Olaf Heidenreich",

note = "Funding Information: The authors thank Dr. Aliaksandra Radzisheuskaya (Cell Biology Program and Center for Epigenetics, Memorial Sloan Kettering Cancer Center, New York, USA) for carefully reading and improving the manuscript, Dr. Petr Nazarov (Luxembourg Institute of Health, Strassen, Luxembourg) for excellent practical ideas with independent component analysis, Dr. Paul Boutz (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, USA) for comprehensive discussion of the pipeline and tips on identifying retained introns, and Dr. Thomas Langer (University of Cologne, Cologne, Germany) for providing us with original anti-PARL antibodies. Research in the V.V.G. laboratory was supported in part by the Ministry of Education of the Republic of Belarus, grant #3.08.3 (947/54, 469/54). O.H. is supported by grants from Cancer Research UK (C27943/A12788), Bloodwise (15005), Kay Kendall Leukemia Fund (KKL1142), the North of England Children{\textquoteright}s Cancer Fund and KIKA (329). C.B. is supported by Bloodwise (15001).",

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doi = "10.1038/s41467-020-20848-z",

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Grinev, VV, Barneh, F, Ilyushonak, IM, Nakjang, S, Smink, J, van Oort, A, Clough, R, Seyani, M, McNeill, H, Reza, M, Martinez-Soria, N, Assi, SA, Ramanouskaya, TV, Bonifer, C & Heidenreich, O 2021, 'RUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia', Nature Communications, vol. 12, no. 1, 520. https://doi.org/10.1038/s41467-020-20848-z

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T1 - RUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia

AU - Grinev, Vasily V

AU - Barneh, Farnaz

AU - Ilyushonak, Ilya M

AU - Nakjang, Sirintra

AU - Smink, Job

AU - van Oort, Anita

AU - Clough, Richard

AU - Seyani, Michael

AU - McNeill, Hesta

AU - Reza, Mojgan

AU - Martinez-Soria, Natalia

AU - Assi, Salam A

AU - Ramanouskaya, Tatsiana V

AU - Bonifer, Constanze

AU - Heidenreich, Olaf

N1 - Funding Information: The authors thank Dr. Aliaksandra Radzisheuskaya (Cell Biology Program and Center for Epigenetics, Memorial Sloan Kettering Cancer Center, New York, USA) for carefully reading and improving the manuscript, Dr. Petr Nazarov (Luxembourg Institute of Health, Strassen, Luxembourg) for excellent practical ideas with independent component analysis, Dr. Paul Boutz (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, USA) for comprehensive discussion of the pipeline and tips on identifying retained introns, and Dr. Thomas Langer (University of Cologne, Cologne, Germany) for providing us with original anti-PARL antibodies. Research in the V.V.G. laboratory was supported in part by the Ministry of Education of the Republic of Belarus, grant #3.08.3 (947/54, 469/54). O.H. is supported by grants from Cancer Research UK (C27943/A12788), Bloodwise (15005), Kay Kendall Leukemia Fund (KKL1142), the North of England Children’s Cancer Fund and KIKA (329). C.B. is supported by Bloodwise (15001).

PY - 2021/1/22

Y1 - 2021/1/22

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-020-20848-z

DO - 10.1038/s41467-020-20848-z

M3 - Article

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SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 520

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

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