Brd4::Nutm1 fusion gene initiates NUT carcinoma in vivo

• Published in: Life science alliance Vol. 7; no. 7; p. e202402602
• Main Authors: Zheng, Dejin, Elnegiry, Ahmed A, Luo, Chenxiang, Bendahou, Mohammed Amine, Xie, Liangqi, Bell, Diana, Takahashi, Yoko, Hanna, Ehab, Mias, George I, Tsoi, Mayra F, Gu, Bin
• Format: Journal Article
• Language: English
• Published: United States 01.07.2024
• Subjects: Animals; Bromodomain Containing Proteins; Carcinoma - genetics; Carcinoma - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Disease Models, Animal; Humans; Mice; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Proteins, Fusion - genetics; Transcription Factors - genetics; Transcription Factors - metabolism; Translocation, Genetic - genetics
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202402602

NUT carcinoma (NC) is an aggressive cancer with no effective treatment. About 70% of NUT carcinoma is associated with chromosome translocation events that lead to the formation of a fusion gene. Because the gene 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 for NUT carcinoma that recapitulates the human t(15;19) chromosome translocation in mice. We demonstrated that the mouse t(2;17) syntenic chromosome translocation, forming the fusion gene, could induce aggressive carcinomas in mice. The tumors present histopathological and molecular features similar to human NC, with enrichment of undifferentiated cells. Similar to the reports of human NC incidence, can induce NC from a broad range of tissues with a strong phenotypical variability. The consistent induction of poorly differentiated carcinoma demonstrated a strong reprogramming activity of BRD4::NUTM1. The new mouse model provided a critical preclinical model for NC that will lead to better understanding and therapy development for NC.