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J Clin Invest. 2017 Jun 1;127(6):2206-2221. doi: 10.1172/JCI91363. Epub 2017 Apr 24.

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes.

Author information

1
Bloodwise Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, and BRC Blood Theme, National Institute for Health Research (NIHR) Oxford Biomedical Centre, Oxford University Hospital, Oxford, United Kingdom.
2
The Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
3
Department of Biochemistry, Downing Site, University of Cambridge, Cambridge, United Kingdom.
4
Albert Einstein College of Medicine, Bronx, New York, USA.
5
Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, and Department of Hematology, Oxford University Hospital National Health Service Trust, Oxford, United Kingdom.
6
Faculty of Medicine, University of Southampton, Southampton, and National Genetics Reference Laboratory (Wessex), Salisbury, United Kingdom.
7
Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
8
Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
9
Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.

Abstract

Mutations of the splicing factor-encoding gene U2AF1 are frequent in the myelodysplastic syndromes (MDS), a myeloid malignancy, and other cancers. Patients with MDS suffer from peripheral blood cytopenias, including anemia, and an increasing percentage of bone marrow myeloblasts. We studied the impact of the common U2AF1S34F mutation on cellular function and mRNA splicing in the main cell lineages affected in MDS. We demonstrated that U2AF1S34F expression in human hematopoietic progenitors impairs erythroid differentiation and skews granulomonocytic differentiation toward granulocytes. RNA sequencing of erythroid and granulomonocytic colonies revealed that U2AF1S34F induced a higher number of cassette exon splicing events in granulomonocytic cells than in erythroid cells. U2AF1S34F altered mRNA splicing of many transcripts that were expressed in both cell types in a lineage-specific manner. In hematopoietic progenitors, the introduction of isoform changes identified in the U2AF1S34F target genes H2AFY, encoding an H2A histone variant, and STRAP, encoding serine/threonine kinase receptor-associated protein, recapitulated phenotypes associated with U2AF1S34F expression in erythroid and granulomonocytic cells, suggesting a causal link. Furthermore, we showed that isoform modulation of H2AFY and STRAP rescues the erythroid differentiation defect in U2AF1S34F MDS cells, suggesting that splicing modulators could be used therapeutically. These data have critical implications for understanding MDS phenotypic heterogeneity and support the development of therapies targeting splicing abnormalities.

PMID:
28436936
PMCID:
PMC5451246
DOI:
10.1172/JCI91363
[Indexed for MEDLINE]
Free PMC Article

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