The BRD4-NUT fusion alone drives malignant transformation of NUT carcinoma

R. Taylor Durall
Brigham and Women's Hospital
July 20, 2023
Cancer Res
https://pubmed.ncbi.nlm.nih.gov/37819236

This article is currently being updated. View its version on PubMed.

https://pubmed.ncbi.nlm.nih.gov/37819236

Research summary

This study investigates the oncogenic potential of the BRD4-NUT fusion protein in NUT carcinoma (NC). Using a genetically engineered mouse model (GEMM) expressing BRD4-NUT specifically in squamous epithelial cells, researchers demonstrate that the fusion protein alone is sufficient to drive malignant transformation.

Key outcome of the study

Mice expressing BRD4-NUT developed aggressive tumors with 100% penetrance, confirming that the fusion protein alone is sufficient for malignant transformation. Treatment with BET bromodomain inhibitors (BETi) induced differentiation and tumor growth arrest, mirroring clinical responses observed in human NUT carcinoma.

Mouse model

BRD4-NUT inducible Knockin mouse model developed using: - Tamoxifen-inducible Cre recombinase (CreER(T2)) under the Sox2 promoter for temporal regulation of gene expression. - Internal Ribosome Entry Site (IRES) for bicistronic expression of BRD4-NUT and a reporter gene. - Reporter gene (e.g., luciferase or fluorescent protein) integrated for in vivo tracking of tumor development.

TARGET:
Brd4, Nutm1
Bromodomain-containing protein 4, Nuclear protein in testis midline carcinoma 1

Keywords

NUT carcinoma, BET inhibitors, BRD4-NUT fusion, Squamous cell carcinoma, Targeted therapy

Technical specifications

Knockin mouse model, Flex technology, Tamoxifen-inducible CreER<sup>T2</sup>, IRES-mediated bicistronic expression, Reporter gene (fluorescence/luciferase)

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Reporter KI mouse

Use a reporter mouse Knockin for in vivo monitoring of transcriptional promoter activity, protein localization, cell trafficking, etc.