U2AF1 (U2 small nuclear RNA auxiliary factor 1) is a critical component of the pre-mRNA splicing machinery that mediates 3'-splice site selection. It recruits the U2 snRNP complex to the branch point and functions as a bridge between the U2AF2 protein and enhancer complexes to facilitate spliceosome assembly 1. U2AF1 operates within the U2AF1/2 heterodimeric complex, which recruits the SF3b complex to the 3' splice site 1. U2AF1 mutations are clinically significant across multiple myeloid malignancies. In polycythemia vera and essential thrombocytemia, U2AF1 mutations are classified as adverse mutations associated with poor survival outcomes and myelofibrosis progression 2. U2AF1 represents a recurrent high-risk mutation in chr21 neutrophilic leukemia and atypical chr21 myeloid leukemia, with identified cases showing U2AF1 Q157P variants 34. U2AF1 mutations also occur in lung adenocarcinoma as recurrent somatic alterations 5. U2AF1-mutant clones demonstrate among the highest growth rates in clonal hematopoiesis evolution, comparable to JAK2 mutations, indicating aggressive biological behavior 6. Spliceosome-mutant cancers including U2AF1-mutated tumors show preferential vulnerability to splicing modulators, suggesting therapeutic opportunities 7.