Impact of U2AF1mutations on circular RNA expression in myelodysplastic neoplasms

Autor: Wedge, Eileen, Ahmadov, Ulvi, Hansen, Thomas B., Gao, Zongliang, Tulstrup, Morten, Côme, Christophe, Nonavinkere Srivatsan, Sridhar, Ahmed, Tanzir, Jespersen, Jakob S., Schlotmann, Balthasar C., Schöllkopf, Claudia, Raaschou-Jensen, Klas, Ødum, Niels, Kjems, Jørgen, Bak, Rasmus O., Walter, Matthew J., Grønbæk, Kirsten, Kristensen, Lasse S.
Zdroj: Leukemia; 20230101, Issue: Preprints p1-13, 13p
Abstrakt: Mutations in U2AF1are 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 U2AF1mutations on circRNA expression in K562 cells with a doxycycline-inducible U2AF1S34mutation, in a mouse model with a doxycycline-inducible U2AF1S34mutation, and in FACS-sorted CD34+ bone marrow cells from MDS patients with either U2AF1S34or U2AF1Q157mutations. 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 U2AF1S34and U2AF1Q157mutations 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 U2AF1mutations compared to U2AF1-wildtype MDS controls. In conclusion, high circRNA expression is observed in association with U2AF1mutations in three biological systems, presenting an interesting possibility for biomarker and therapeutic investigation.
Databáze: Supplemental Index