Brd4::Nutm1fusion gene initiates NUT carcinomain vivo

Abstract

Nut 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 a BRD4-NUTM1 fusion gene. However, because the BRD4-NUTM1 gene is unequivocally cytotoxic when ectopically expressed in cell lines, there is no experimental evidence of the oncogenic potential of this fusion gene to initiate NC. We report here the first genetically engineered mouse model (GEMM) for NUT carcinoma. By inducing a chromosome translocation event mirroring the human event in mouse epithelial progenitors, we demonstrated that the Brd4-Nutm1 fusion gene could induce aggressive head and neck, and skin carcinomas in mice. The tumors present similar histopathological and molecular features to human NC. As the sole immunocompetent GEMM for NC, the model will have a far-reaching impact on understanding NC oncogenesis and developing NC treatment, including targeted therapies and immune therapies in a preclinical setting, which will benefit NC patients through translational research.