Impact of U2AF1 mutations on circular RNA expression in myelodysplastic neoplasms

Eileen Wedge, Ulvi Ahmadov, Thomas B Hansen, Zongliang Gao, Morten Tulstrup, Christophe Côme, Sridhar Nonavinkere Srivatsan, Tanzir Ahmed, Jakob S Jespersen, Balthasar C Schlotmann, Claudia Schöllkopf, Klas Raaschou-Jensen, Niels Ødum, Jørgen Kjems, Rasmus O Bak, Matthew J Walter, Kirsten Grønbæk*, Lasse S Kristensen*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

Mutations in U2AF1 are relatively common in myelodysplastic neoplasms (MDS) and are associated with an inferior prognosis, but the molecular mechanisms underlying this are not fully elucidated. Circular RNAs (circRNAs) have been implicated in cancer, but it is unknown how mutations in splicing factors may impact on circRNA biogenesis. Here, we used RNA-sequencing to investigate the effects of U2AF1 mutations on circRNA expression in K562 cells with a doxycycline-inducible U2AF1 S34 mutation, in a mouse model with a doxycycline-inducible U2AF1 S34 mutation, and in FACS-sorted CD34+ bone marrow cells from MDS patients with either U2AF1 S34 or U2AF1 Q157 mutations. In all contexts, we found an increase in global circRNA levels in the U2AF1-mutated setting, which was independent of expression changes in the cognate linear host genes. In patients, the U2AF1 S34 and U2AF1 Q157 mutations were both associated with an overall increased expression of circRNAs. circRNAs generated by a non-Alu-mediated mechanism generally showed the largest increase in expression levels. Several well-described cancer-associated circRNAs, including circZNF609 and circCSNK1G3, were upregulated in MDS patients with U2AF1 mutations compared to U2AF1-wildtype MDS controls. In conclusion, high circRNA expression is observed in association with U2AF1 mutations in three biological systems, presenting an interesting possibility for biomarker and therapeutic investigation.

Original languageEnglish
JournalLeukemia
Volume37
Issue5
Pages (from-to)1113-1125
Number of pages13
ISSN0887-6924
DOIs
Publication statusPublished - May 2023

Keywords

  • Animals
  • Doxycycline
  • Mice
  • Mutation
  • Myelodysplastic Syndromes/genetics
  • Neoplasms
  • RNA Splicing
  • RNA Splicing Factors/genetics
  • RNA, Circular/genetics
  • Splicing Factor U2AF/genetics

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