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

Bon Ham Yip, Violetta Steeples, Emmanouela Repapi, Richard N. Armstrong, Miriam Llorian, Swagata Roy, Jacqueline Shaw, Hamid Dolatshad, Stephen Taylor, Amit K. Verma, Matthias Bartenstein, Paresh Vyas, Nicholas C.P. Cross, Luca Malcovati, Mario Cazzola, Eva Hellström-Lindberg, Seishi Ogawa, Christopher W.J. Smith, Andrea Pellagatti, Jacqueline Boultwood

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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.

Original languageEnglish (US)
Pages (from-to)2206-2221
Number of pages16
JournalJournal of Clinical Investigation
Volume127
Issue number6
DOIs
StatePublished - Jun 1 2017

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Myelodysplastic Syndromes
Mutation
Erythroid Cells
Protein Isoforms
RNA Sequence Analysis
Granulocyte Precursor Cells
Messenger RNA
Protein-Serine-Threonine Kinases
Cell Lineage
Granulocytes
Histones
Genes
Anemia
Exons
Neoplasms
Bone Marrow
Phenotype
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yip, B. H., Steeples, V., Repapi, E., Armstrong, R. N., Llorian, M., Roy, S., ... Boultwood, J. (2017). The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes. Journal of Clinical Investigation, 127(6), 2206-2221. https://doi.org/10.1172/JCI91363

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes. / Yip, Bon Ham; Steeples, Violetta; Repapi, Emmanouela; Armstrong, Richard N.; Llorian, Miriam; Roy, Swagata; Shaw, Jacqueline; Dolatshad, Hamid; Taylor, Stephen; Verma, Amit K.; Bartenstein, Matthias; Vyas, Paresh; Cross, Nicholas C.P.; Malcovati, Luca; Cazzola, Mario; Hellström-Lindberg, Eva; Ogawa, Seishi; Smith, Christopher W.J.; Pellagatti, Andrea; Boultwood, Jacqueline.

In: Journal of Clinical Investigation, Vol. 127, No. 6, 01.06.2017, p. 2206-2221.

Research output: Contribution to journalArticle

Yip, BH, Steeples, V, Repapi, E, Armstrong, RN, Llorian, M, Roy, S, Shaw, J, Dolatshad, H, Taylor, S, Verma, AK, Bartenstein, M, Vyas, P, Cross, NCP, Malcovati, L, Cazzola, M, Hellström-Lindberg, E, Ogawa, S, Smith, CWJ, Pellagatti, A & Boultwood, J 2017, 'The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes', Journal of Clinical Investigation, vol. 127, no. 6, pp. 2206-2221. https://doi.org/10.1172/JCI91363
Yip, Bon Ham ; Steeples, Violetta ; Repapi, Emmanouela ; Armstrong, Richard N. ; Llorian, Miriam ; Roy, Swagata ; Shaw, Jacqueline ; Dolatshad, Hamid ; Taylor, Stephen ; Verma, Amit K. ; Bartenstein, Matthias ; Vyas, Paresh ; Cross, Nicholas C.P. ; Malcovati, Luca ; Cazzola, Mario ; Hellström-Lindberg, Eva ; Ogawa, Seishi ; Smith, Christopher W.J. ; Pellagatti, Andrea ; Boultwood, Jacqueline. / The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 6. pp. 2206-2221.
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AU - Steeples, Violetta

AU - Repapi, Emmanouela

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AU - Llorian, Miriam

AU - Roy, Swagata

AU - Shaw, Jacqueline

AU - Dolatshad, Hamid

AU - Taylor, Stephen

AU - Verma, Amit K.

AU - Bartenstein, Matthias

AU - Vyas, Paresh

AU - Cross, Nicholas C.P.

AU - Malcovati, Luca

AU - Cazzola, Mario

AU - Hellström-Lindberg, Eva

AU - Ogawa, Seishi

AU - Smith, Christopher W.J.

AU - Pellagatti, Andrea

AU - Boultwood, Jacqueline

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N2 - 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.

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