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

Research output: Contribution to journalArticlepeer-review

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
  • Tatsiana V Ramanouskaya
  • Olaf Heidenreich

Colleges, School and Institutes

External organisations

  • Belarusian State University
  • Princess Maxima Center for Pediatric Oncology
  • Newcastle University

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.

Bibliographic 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).

Details

Original languageEnglish
Article number520
JournalNature Communications
Volume12
Issue number1
Publication statusPublished - 22 Jan 2021