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The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34(+) cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript and/or exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicing/processing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expression/splicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34(+) cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.

Original publication




Journal article



Publication Date





1092 - 1103


Alternative Splicing, Anemia, Refractory, with Excess of Blasts, Antigens, CD34, Cell Cycle, Cell Differentiation, Cell Proliferation, Exons, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Hematopoietic Stem Cells, Heterozygote, Homeostasis, Humans, K562 Cells, Male, Mutation, Myelodysplastic Syndromes, Phosphoproteins, Point Mutation, RNA, RNA Splicing, RNA Splicing Factors, Ribonucleoprotein, U2 Small Nuclear, Sequence Analysis, RNA, Stem Cells