Bromodomain-containing protein 4-Nuclear protein in testis fusion protein (BRD4-NUT) (BRD4-NUT)

The BRD4-NUT fusion protein is the primary oncogenic driver of NUT midline carcinoma (NMC), a rare and highly aggressive form of squamous cell epithelioma. It typically results from a chromosomal translocation, most commonly t(15;19), which fuses the bromodomain-containing protein 4 (BRD4) gene to the NUT midline carcinoma family member 1 (NUTM1) gene [1][2]. This fusion protein functions as an aberrant transcription factor that recruits the histone acetyltransferase p300 to specific genomic regions, creating large 'megadomains' of hyperacetylated chromatin [3]. These megadomains drive the constitutive expression of potent oncogenes, such as MYC and TP63, while simultaneously blocking cellular differentiation [4]. Therapeutic strategies primarily focus on Bromodomain and Extra-Terminal (BET) inhibitors, which competitively bind to the bromodomains of BRD4, displacing the fusion protein from chromatin and inducing rapid cell cycle arrest and squamous differentiation [5]. Despite initial responses to BET inhibitors in clinical trials, the development of resistance and systemic toxicities like thrombocytopenia remain significant challenges in treating NMC [6]. Sources: [1] French CA. NUT midline carcinoma. Cancer Genet Cytogenet. 2010. [2] French CA, et al. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003. [3] Reynoird N, et al. BRD4-NUT-induced epigenetic reprogramming and oncogenic gene expression. Genes Dev. 2010. [4] Alekseyenko AA, et al. The NUT adapter drives BRD4-NUT-mediated oncogenesis. Genes Dev. 2015. [5] Filippakopoulos P, et al. Selective inhibition of BET bromodomains. Nature. 2010. [6] Piha-Paul SA, et al. Phase 1 study of BET inhibitor OTX015 in patients with NUT midline carcinoma. Lancet Oncol. 2016.

Other names

BRD4-NUTM1 fusion proteinNUT midline carcinoma fusion proteint(15;19) translocation protein

Competitive inhibition of the bromodomains (BD1 and BD2) within the BRD4 portion of the fusion protein, preventing its binding to acetylated lysine residues on histones. This leads to the displacement of the BRD4-NUT-p300 complex from chromatin, the collapse of oncogenic megadomains, and the subsequent induction of squamous differentiation and cell cycle arrest.