Abstract
Components of the pre-messenger RNA splicing machinery are frequently mutated in myeloid malignancies. Mutations in LUC7L2, PRPF8, SF3B1, SRSF2, U2AF1, and ZRSR2 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 SF3B1 mutations associated with increased ring sideroblasts (RS) in MDS-RS or MDS/MPN-RS with thrombocytosis. SF3B1 mutations are associated with better survival outcomes, while SRSF2 mutations are associated with a shorter survival time and increased AML progression, and U2AF1 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 (PU.1, RUNX1, 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.
Highlights
Components of the pre-messenger RNA splicing machinery are frequently mutated in myeloid malignancies
This review provides a summary of the significance of the most frequently mutated splicing factor (SF) genes in myeloid malignancies and an update on novel targeted therapies in experimental and clinical trial stages
Mutations in SF3B1, SRSF2, and U2AF1 have been associated with specific disease subtypes with with SF3B1 being mostly mutated in myelodysplastic syndrome (MDS)-ring sideroblasts (RS), SRSF2 occurring mostly in chronic myelomonocytic
Summary
Myelodysplastic syndromes (MDS) are a genetically and clinically diverse group of clonal stem cell malignancies characterized by inefficient hematopoiesis, peripheral blood cytopenias, and an increased risk of transformation to acute myeloid leukemia (AML). RNA and ligates coding sequences (exons) in order to form mature mRNA transcripts through early. ZRSR2 and U2AF1L4 (other two RNA-binding proteins) are both U2AF2 and the splicing factor SRSF2. ZRSR2 and U2AF1L4 (other two RNA-binding proteins) recruited to interact with U2AF complex (U2AF1 and U2AF2) in order to recognize the 30 SS. Mutations in the SF genes occur in the same spots in MDS and AML. Missense mutations are a hallmark of SF3B1, SRSF2, and U2AF1 and inactivating mutations (nonsense or frameshift) are often detected in of SF3B1, SRSF2, and U2AF1 and inactivating mutations (nonsense or frameshift) are often detected the ZRSR2 gene These SF mutations are the most commonly observed mutations in MDS and AML, in the ZRSR2 gene.
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