The Biological and Clinical Consequences of RNA Splicing Factor U2AF1 Mutation in Myeloid Malignancies

SIMPLE SUMMARY: U2 small nuclear RNA auxiliary factor 1 (U2AF1) is one of the most important RNA splicing genes involved in regulating the alternative splicing of pre-mRNA. U2AF1 mutation is a genetic driver event in the initiation of myelodysplastic syndromes (MDSs) and frequently occurs in myeloid malignancies. U2AF1 mutation can severely impair hematopoiesis, drive tumor progression, adversely affect disease prognosis, and promote leukemic transformation. This review summarizes the biological and clinical implications of the oncogenic role of U2AF1 mutation in myeloid tumors. Our work provides important and comprehensive insights into the development of the U2AF1 mutation as a novel prognostic biomarker and therapeutic target for myeloid malignancies. ABSTRACT: Mutations of spliceosome genes have been frequently identified in myeloid malignancies with the large-scale application of advanced sequencing technology. U2 small nuclear RNA auxiliary factor 1 (U2AF1), an essential component of U2AF heterodimer, plays a pivotal role in the pre-mRNA splicing processes to generate functional mRNAs. Over the past few decades, the mutation landscape of U2AF1 (most frequently involved S34 and Q157 hotspots) has been drawn in multiple cancers, particularly in myeloid malignancies. As a recognized early driver of myelodysplastic syndromes (MDSs), U2AF1 mutates most frequently in MDS, followed by acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs). Here, for the first time, we summarize the research progress of U2AF1 mutations in myeloid malignancies, including the correlations between U2AF1 mutations with clinical and genetic characteristics, prognosis, and the leukemic transformation of patients. We also summarize the adverse effects of U2AF1 mutations on hematopoietic function, and the alterations in downstream alternative gene splicing and biological pathways, thus providing comprehensive insights into the roles of U2AF1 mutations in the myeloid malignancy pathogenesis. U2AF1 mutations are expected to be potential novel molecular markers for myeloid malignancies, especially for risk stratification, prognosis assessment, and a therapeutic target of MDS patients.