| Summary: | Components of the pre-messenger RNA splicing machinery are frequently mutated in myeloid malignancies. Mutations in <i>LUC7L2, PRPF8,</i> <i>SF3B1</i>, <i>SRSF2</i>, <i>U2AF1</i>, and <i>ZRSR2</i> genes occur at various frequencies ranging between 40% and 85% in different subtypes of myelodysplastic syndrome (MDS) and 5% and 10% of acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs). In some instances, splicing factor (SF) mutations have provided diagnostic utility and information on clinical outcomes as exemplified by <i>SF3B1</i> mutations associated with increased ring sideroblasts (RS) in MDS-RS or MDS/MPN-RS with thrombocytosis. <i>SF3B1</i> mutations are associated with better survival outcomes, while <i>SRSF2</i> mutations are associated with a shorter survival time and increased AML progression, and <i>U2AF1</i> mutations with a lower remission rate and shorter survival time. Beside the presence of mutations, transcriptomics technologies have shown that one third of genes in AML patients are differentially expressed, leading to altered transcript stability, interruption of protein function, and improper translation compared to those of healthy individuals. The detection of SF mutations demonstrates the importance of splicing abnormalities in the hematopoiesis of MDS and AML patients given the fact that abnormal splicing regulates the function of several transcriptional factors (<i>PU.1, RUNX1,</i> etc.) crucial in hematopoietic function. This review provides a summary of the significance of the most frequently mutated SF genes in myeloid malignancies and an update on novel targeted therapies in experimental and clinical trial stages.
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