RUNX1/RUNX1T1 Mediates Alternative Splicing and Reorganises the Transcriptional Landscape in Leukemia

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Jan 23

PMID 33483506

Citations 17

Authors

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

Affiliations

Soon will be listed here.

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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