Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations

Author:

Pellagatti Andrea12ORCID,Armstrong Richard N.12ORCID,Steeples Violetta12,Sharma Eshita3,Repapi Emmanouela4,Singh Shalini12,Sanchi Andrea12,Radujkovic Aleksandar5,Horn Patrick5,Dolatshad Hamid12,Roy Swagata12,Broxholme John3,Lockstone Helen3,Taylor Stephen4,Giagounidis Aristoteles6,Vyas Paresh728,Schuh Anna9,Hamblin Angela9,Papaemmanuil Elli10,Killick Sally11,Malcovati Luca1213,Hennrich Marco L.14,Gavin Anne-Claude14,Ho Anthony D.5,Luft Thomas5,Hellström-Lindberg Eva15,Cazzola Mario1213,Smith Christopher W. J.16,Smith Stephen17,Boultwood Jacqueline12ORCID

Affiliation:

1. Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom;

2. Haematology Theme Oxford Biomedical Research Centre, Oxford, United Kingdom;

3. Wellcome Trust Centre for Human Genetics and

4. The Computational Biology Research Group, Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, United Kingdom;

5. Department of Internal Medicine V, University Hospital Heidelberg, Germany;

6. Clinic for Oncology, Hematology, and Palliative Medicine, Marien Hospital Düsseldorf, Germany;

7. Medical Research Council Molecular Hematology Unit, WIMM, University of Oxford, United Kingdom;

8. Department of Hematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom;

9. Molecular Diagnostics Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom;

10. Department of Epidemiology-Biostatistics, Center for Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY;

11. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom;

12. Department of Molecular Medicine, University of Pavia, Pavia, Italy;

13. Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy;

14. European Molecular Biology Laboratory Structural and Computational Biology Unit, Heidelberg, Germany;

15. Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Sweden; and

16. Department of Biochemistry and

17. Department of Pathology, University of Cambridge, Cambridge, United Kingdom

Abstract

Key Points RNA-seq analysis of CD34+ cells identifies novel aberrantly spliced genes and dysregulated pathways in splicing factor mutant MDS. Aberrantly spliced isoforms predict MDS survival and implicate dysregulation of focal adhesion and exosomes as drivers of poor survival.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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