Brd4::Nutm1fusion gene initiates NUT carcinomain vivo

Abstract

AbstractNut carcinoma (NC) is an aggressive cancer with no effective treatment. The majority (70%) of NUT carcinoma is associated with chromosome translocation events that lead to the formation of aBRD4::NUTM1fusion gene. However, because theBRD4::NUTM1gene is unequivocally cytotoxic when ectopically expressed in cell lines, questions remain on whether the fusion gene can initiate NC. Here, we report the first genetically engineered mouse model (GEMM) for NUT carcinoma recapitulating the human mutation. By stochastically inducing a chromosome translocation mirroring the human event, we demonstrated that theBrd4::Nutm1fusion gene could induce aggressive carcinomas in mice. The tumors present histopathological and molecular features similar to human NC, with an enrichment of undifferentiated cells. Similar to the reports of human NC incidence,Brd4::Nutm1can induce NC from a broad range of tissues, demonstrating that its oncogenic potential is not lineage-restricted. The consistent induction of tumors of squamous phenotypes, even from ductal epithelial and mesenchymal tissues, demonstrated a strong reprogramming activity of BRD4::NUTM1. The new mouse model provided a critical preclinical model for NC and opens new opportunities for understanding the oncogenic mechanism and developing new therapies.