POU2AF3 is a transcriptional coactivator that functions as a paralog of the B-cell-specific protein OCA-B, operating within a conserved gene cluster on chromosome 11 1. POU2AF3 specifically binds to the POU class 2 transcription factor POU2F3 through a conserved peptide motif, forming a bivalent complex that recognizes DNA octamer sequences 1. This POU2F3-POU2AF3 complex serves as the master regulator of tuft cell identity and development 1—rare chemosensory cells that coordinate immune and neural responses within mucosal epithelial tissues 1. In normal physiology, POU2AF2 (the paralogous coactivator) controls tuft cell transcriptional programs and exerts tumor-suppressive effects in colorectal tissue 2. Genetically, common variants at 11q23.1 near POU2AF3 show association with colorectal cancer risk through dysregulation of tuft cell development 2. Clinically, POU2AF3 is also a fusion partner in aggressive sarcomas, particularly EWSR1::POU2AF3 fusions occurring in sinonasal and other sites, defining a novel sarcoma entity with poor prognosis and polyphenotypic morphology [PMID:37742928; 3; 45]. Co-expression of POU2F3 and its coactivators marks tuft cell differentiation in neuroendocrine tumors 5.