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Blood. 2018 Sep 20;132(12):1225-1240. doi: 10.1182/blood-2018-04-843771. Epub 2018 Jun 21.

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

Author information

Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
Haematology Theme Oxford Biomedical Research Centre, Oxford, United Kingdom.
Wellcome Trust Centre for Human Genetics and.
The Computational Biology Research Group, Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, United Kingdom.
Department of Internal Medicine V, University Hospital Heidelberg, Germany.
Clinic for Oncology, Hematology, and Palliative Medicine, Marien Hospital Düsseldorf, Germany.
Medical Research Council Molecular Hematology Unit, WIMM, University of Oxford, United Kingdom.
Department of Hematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.
Molecular Diagnostics Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.
Department of Epidemiology-Biostatistics, Center for Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY.
Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom.
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
European Molecular Biology Laboratory Structural and Computational Biology Unit, Heidelberg, Germany.
Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Sweden; and.
Department of Biochemistry and.
Department of Pathology, University of Cambridge, Cambridge, United Kingdom.


SF3B1, SRSF2, and U2AF1 are the most frequently mutated splicing factor genes in the myelodysplastic syndromes (MDS). We have performed a comprehensive and systematic analysis to determine the effect of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant MDS. Using RNA-seq, we determined the aberrantly spliced genes and dysregulated pathways in CD34+ cells of 84 patients with MDS. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis, and mitochondrial dysfunction, suggesting common mechanisms of action in MDS. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology associated with splicing factor mutations in MDS, whereas several others have not been previously associated with MDS, such as sirtuin signaling. We identified aberrantly spliced events associated with clinical variables, and isoforms that independently predict survival in MDS and implicate dysregulation of focal adhesion and extracellular exosomes as drivers of poor survival. Aberrantly spliced genes and dysregulated pathways were identified in the MDS-affected lineages in splicing factor mutant MDS. Functional studies demonstrated that knockdown of the mitosis regulators SEPT2 and AKAP8, aberrantly spliced target genes of SF3B1 and SRSF2 mutations, respectively, led to impaired erythroid cell growth and differentiation. This study illuminates the effect of the common spliceosome mutations on the MDS phenotype and provides novel insights into disease pathophysiology.

[Available on 2019-03-20]

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