دورية أكاديمية
The U2AF1$^{S34F}$ mutation induces lineage-specific splicing alterations in myelodysplastic syndromes
| العنوان: | The U2AF1$^{S34F}$ mutation induces lineage-specific splicing alterations in myelodysplastic syndromes |
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| المؤلفون: | Yip, BH, Steeples, V, Repapi, E, Armstrong, RN, Llorian, M, Roy, S, Shaw, J, Dolatshad, H, Taylor, S, Verma, A, Bartenstein, M, Vyas, P, Cross, NC, Malcovati, L, Cazzola, M, Hellström-Lindberg, E, Ogawa, S, Smith, CW, Pellagatti, A, Boultwood, J |
| بيانات النشر: | American Society for Clinical Investigation //dx.doi.org/10.1172/jci91363 The Journal of Clinical Investigation |
| سنة النشر: | 2017 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | Case-Control Studies, Cell Lineage, Cell Proliferation, Cells, Cultured, Erythropoiesis, Gene Ontology, Granulocytes, Humans, Mutation, Missense, Myelodysplastic Syndromes, Protein Isoforms, RNA Splicing, Splicing Factor U2AF |
| الوصف: | 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 U2AF1$^{S34F}$ mutation on cellular function and mRNA splicing in the main cell lineages affected in MDS. We demonstrated that U2AF1$^{S34F}$ expression in human hematopoietic progenitors impairs erythroid differentiation and skews granulomonocytic differentiation toward granulocytes. RNA sequencing of erythroid and granulomonocytic colonies revealed that U2AF1$^{S34F}$ induced a higher number of cassette exon splicing events in granulomonocytic cells than in erythroid cells. U2AF1$^{S34F}$ 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 U2AF1$^{S34F}$ target genes H2AFY, encoding an H2A histone variant, and STRAP, encoding serine/threonine kinase receptor-associated protein, recapitulated phenotypes associated with U2AF1$^{S34F}$ 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 U2AF1$^{S34F}$ 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. ; This work was supported by Bloodwise (United Kingdom). ML was supported by a grant from the Wellcome Trust (092900). LM acknowledges support from the Associazione Italiana Ricerca sul Cancro (AIRC) (IG 15356). |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://www.repository.cam.ac.uk/handle/1810/265019Test |
| DOI: | 10.17863/CAM.10730 |
| الإتاحة: | https://doi.org/10.17863/CAM.10730Test https://www.repository.cam.ac.uk/handle/1810/265019Test |
| حقوق: | Attribution 4.0 International ; http://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.C83CE6BB |
| قاعدة البيانات: | BASE |
| DOI: | 10.17863/CAM.10730 |
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