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

Group Heidenreich

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

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
Pages (from-to)	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

Keywords

Acute Disease
Alternative Splicing
Cell Line, Tumor
Core Binding Factor Alpha 2 Subunit/genetics
Gene Expression Profiling/methods
Gene Expression Regulation, Leukemic
Humans
Leukemia, Myeloid/genetics
Models, Genetic
Oncogene Proteins, Fusion/genetics
RNA Interference
RNA Isoforms/genetics
RUNX1 Translocation Partner 1 Protein/genetics
Transcription Initiation Site

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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), 520. Article 520. https://doi.org/10.1038/s41467-020-20848-z

@article{5baf2a5212cb444595bd964332239ffc,

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.",

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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 = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jan,

day = "22",

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

language = "English",

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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, pp. 520. https://doi.org/10.1038/s41467-020-20848-z

TY - JOUR

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

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.

KW - Acute Disease

KW - Alternative Splicing

KW - Cell Line, Tumor

KW - Core Binding Factor Alpha 2 Subunit/genetics

KW - Gene Expression Profiling/methods

KW - Gene Expression Regulation, Leukemic

KW - Humans

KW - Leukemia, Myeloid/genetics

KW - Models, Genetic

KW - Oncogene Proteins, Fusion/genetics

KW - RNA Interference

KW - RNA Isoforms/genetics

KW - RUNX1 Translocation Partner 1 Protein/genetics

KW - Transcription Initiation Site

UR - https://www.scopus.com/pages/publications/85099760145

U2 - 10.1038/s41467-020-20848-z

DO - 10.1038/s41467-020-20848-z

M3 - Article

C2 - 33483506

SN - 2041-1723

VL - 12

SP - 520

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 520

ER -

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

Abstract

Keywords

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