The U2AF1(S34F) mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

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

来源：Journal of Clinical Investigation, 2017, 127(6): 2206-2221.

DOI：10.1172/JCI91363

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.

• 出版日期2017-6-1