Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

Significance Chromatin factors generally act within large, multisubunit complexes; thus, identifying both their normal and aberrant interactors in cancer should provide important information regarding potential targets for therapeutic intervention. Here, we apply this principle to analysis of BRD4–NUT, a fusion oncoprotein that drives an aggressive subtype of squamous cell cancer. We identify ZNF532 as a prominent BRD4–NUT–interacting protein in an established NUT midline carcinoma patient cell line, and independently discover ZNF532 fused directly to NUT in a newly analyzed patient. Like BRD4–NUT, ZNF532–NUT forms unusually large (100-kb to 1-Mb) domains of hyperactive chromatin, including at the MYC locus, and drives self-reinforcing regulatory loops that are likely to be a powerful strategy for the growth advantage of cancer cells.