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MYELODYSPLASTIC NEOPLASM

Impact of U2AF1 mutations on circular RNA expression in myelodysplastic neoplasms

Leukemia volume 37, pages 1113–1125 (2023)Cite this article

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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 U2AF1S34 mutation, in a mouse model with a doxycycline-inducible U2AF1S34 mutation, and in FACS-sorted CD34+ bone marrow cells from MDS patients with either U2AF1S34 or U2AF1Q157 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 U2AF1S34 and U2AF1Q157 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.

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Fig. 1: U2AF1 mutations lead to increased circRNA expression, independent of changes in expression of cognate linear host genes.
Fig. 2: U2AF1S34 and U2AF1Q157 are both associated with higher circRNA expression but with broadly similar expression patterns.
Fig. 3: Genomic features may influence circRNA expression in the context of U2AF1 mutations.
Fig. 4: circRNA biogenesis is associated with differences in the effect of U2AF1 mutations on circRNA expression.
Fig. 5: Validation of key findings in an independent cohort of patients with U2AF1 mutations and healthy controls.
Fig. 6: Identification of unique circRNAs upregulated in the context of U2AF1 mutation and functional investigation of selected circRNAs by knockdown experiments.

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Data availability

Raw RNAseq data from the K562 cell line with doxycycline-induced U2AF1S34F/WT is available at accession number GSE224576 on GEO datasets, whilst RNAseq data from the mouse model are available at accession number GSE89834. The raw RNA sequencing data from patients and healthy controls generated in this study are available under restricted access, since all genomic data are considered sensitive personal data according to Danish Law and the European Union General Data Protection Regulation (GDPR), and thus cannot be shared with third parties without prior approval. To access the RNA data, an application must be sent to Kirsten.Groenbaek@regionh.dk. Applications will be reviewed by the DCCC/PTH board and subsequently by the Danish Data Protection Agency (DDPA). Access can only be granted for research purposes, and only if a data processor or data transfer agreement can be made in accordance with Danish and European law at the given time.

Code availability

The novel code for polypyrimidine tract detection and evaluation has been deposited at https://github.com/omiics/PPT_finder10. All other code utilized previously published methods (see Bioinformatics above, and Supplementary Methods).

Change history

  • 24 March 2023

    Figure 1 has been corrected.

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Acknowledgements

The study was supported by a grant to LSK from the Lundbeck Foundation (R307-2018-3433), a center grant from the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; grant NNF17CC0027852) and the Greater Copenhagen Health Science Partners (Clinical Academic Group in Translational Hematology). The project is part of the Danish Research Center for Precision Medicine in Blood Cancers funded by Danish Cancer Society grant R223-A13071. EW received additional funding from Rigshospitalets Forskningsfond and the University of Copenhagen. M.J. Walter received the Siteman Investment Program (5124) from Washington University, a Developmental Research Program (DRP-1901) of the SPORE in Leukemia (NIH/NCI, P50CA171963), Edward P. Evans Foundation, and Leukemia and Lymphoma Society (7024-21). Bioinformatics were carried out with the assistance of Omiics (Aarhus, Denmark).

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  1. These authors contributed equally: Kirsten Grønbæk and Lasse S. Kristensen.

Authors and Affiliations

  1. Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark

    Eileen Wedge, Morten Tulstrup, Claudia Schöllkopf & Kirsten Grønbæk

  2. Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark

    Eileen Wedge, Morten Tulstrup, Christophe Côme, Jakob S. Jespersen, Balthasar C. Schlotmann & Kirsten Grønbæk

  3. The Danish Stem Cell Center (Danstem), University of Copenhagen, Copenhagen, Denmark

    Eileen Wedge, Morten Tulstrup, Christophe Côme, Jakob S. Jespersen, Balthasar C. Schlotmann & Kirsten Grønbæk

  4. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Ulvi Ahmadov, Zongliang Gao, Rasmus O. Bak & Lasse S. Kristensen

  5. Department of Molecular Biology and Genetics, Aarhus, Denmark

    Thomas B. Hansen & Jørgen Kjems

  6. Division of Oncology, Washington University School of Medicine, St Louis, MO, USA

    Sridhar Nonavinkere Srivatsan, Tanzir Ahmed & Matthew J. Walter

  7. The Finsen Laboratory, Copenhagen University Hospital, Copenhagen, Denmark

    Jakob S. Jespersen & Balthasar C. Schlotmann

  8. Department of Hematology, Odense University Hospital, Odense, Denmark

    Klas Raaschou-Jensen

  9. Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark

    Niels Ødum

  10. Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark

    Jørgen Kjems

  11. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Kirsten Grønbæk

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  1. Eileen Wedge
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Contributions

EW, KG, and LSK conceived of the idea for the project. EW carried out laboratory work with patient samples, along with statistical analysis of all data sets and manuscript writing. UA carried out knockdown experiments, performed rMATS analyses, assisted with manuscript writing and editing, and figure production. TBH carried out bioinformatics and contributed to data interpretation. ZG and ROB carried out CRISPR-Cas9 laboratory experiments. MT contributed to data interpretation and analysis strategy, in addition to variant filtering. CC carried out FACS sorting of patient samples. SNS and MJW were involved in data interpretation as well as contributing the K562 cell line data. TA carried out the K562 cell line experiments. JSJ and BCS carried out NGS panel sequencing and variant filtering. CS and KRJ were involved in patient inclusion and characterization. NØ and JK contributed to project development and data interpretation. KG and LSK were involved in project planning, data interpretation and manuscript development. All authors contributed intellectual input and revised and approved the final manuscript.

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Correspondence to Kirsten Grønbæk or Lasse S. Kristensen.

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Wedge, E., Ahmadov, U., Hansen, T.B. et al. Impact of U2AF1 mutations on circular RNA expression in myelodysplastic neoplasms. Leukemia 37, 1113–1125 (2023). https://doi.org/10.1038/s41375-023-01866-4

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