AFF2 (ALF transcription elongation factor 2) is an X-linked RNA-binding protein that functions as a transcriptional regulator involved in gene expression control and RNA processing. The protein participates in transcription elongation as part of the super elongation complex and regulates alternative splicing through interactions with G-quadruplex RNA structures 1. AFF2 plays crucial roles in nervous system development and brain function, with its disruption linked to neurodevelopmental disorders. CGG trinucleotide repeat expansions in AFF2 can lead to epigenetic silencing through DNA hypermethylation, contributing to intellectual developmental disorder, X-linked 109 1. Additionally, intragenic duplications in AFF2 have been associated with Cornelia de Lange syndrome phenotypes, where reduced AFF2 expression levels correlate with classic clinical features 2. In oncology, AFF2 has gained significance through DEK::AFF2 fusion events that drive aggressive sinonasal carcinomas. These fusion-positive tumors exhibit distinctive morphological features including papillary growth patterns and neutrophilic infiltrates, despite often bland cytology 34. AFF2 immunohistochemistry serves as a valuable diagnostic marker for identifying these fusion carcinomas, which demonstrate high rates of local recurrence and metastasis 56.