Abstract 4064: NSD3 is a critical cofactor that enables fusion oncoprotein-driven 3D genome reorganization and activation of oncogenic transcriptional programs

Abstract Fusion oncoprotein transcription factors such as BRD4-NUT reprogram chromatin organization to activate oncogenic transcriptional programs, yet the mechanisms by which they reshape gene regulatory architecture remain poorly understood. BRD4-NUT and NUT variant fusions drive NUT carcinoma, an aggressive squamous malignancy with a median survival of only 6.5 months. Although BRD4-NUT induces de novo tumor formation by reorganizing chromatin to activate pro-growth transcriptional programs, the chromatin-level mechanisms underlying this process have not been established. Here, we identify the chromatin regulator NSD3—also a recurrent NUT fusion partner—as a critical cofactor required for fusion oncoprotein-mediated chromatin reorganization and transcriptional regulation. Using CUT Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4064.