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

Lookup NU author(s): Professor Vasily Grinev, Dr Sirintra Nakjang, Hesta McNeill, Dr Mojgan Reza, Dr Natalia Martinez Soria, Professor Olaf Heidenreich

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2021, The Author(s).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.


Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2021

Volume: 12

Issue: 1

Online publication date: 22/01/2021

Acceptance date: 14/12/2020

Date deposited: 24/03/2021

ISSN (electronic): 2041-1723

Publisher: Nature Research

URL: https://doi.org/10.1038/s41467-020-20848-z

DOI: 10.1038/s41467-020-20848-z


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