期刊
ANNUAL REVIEW OF PATHOLOGY: MECHANISMS OF DISEASE, VOL 7
卷 7, 期 -, 页码 247-265出版社
ANNUAL REVIEWS
DOI: 10.1146/annurev-pathol-011811-132438
关键词
BRD4-NUT; BET inhibitor; histone deacetylase inhibitor; histone acetyltransferase; http://www.NMCRegistry.org; differentiation therapy
类别
资金
- NCI NIH HHS [N01-CO-12400, 1R01CA124633, 5P30CA06516-44, 1K08CA128972, 1K08CA92158-01] Funding Source: Medline
- NHLBI NIH HHS [T32-HL07627] Funding Source: Medline
NUT midline carcinoma (NMC), an aggressive form of squamous cell carcinoma, is defined by the presence of acquired chromosomal re-arrangements involving NUT, usually BRD4-NUT fusion genes and, less commonly, NUT-variant fusion genes involving BRD3 or still-uncharacterized genes. Improved diagnostic tests reveal that although rare, NMCs occur in people of any age and may be indistinguishable from more common squamous cell carcinomas of adulthood. NMCs have simple karyotypes whose hallmark is genomic instability, suggesting that NMC arises through a distinct pathogenic pathway representing a genetic shortcut to the phenotype of squamous cell carcinoma. Mechanistically, BRD-NUT fusion proteins appear to act by blocking differentiation, possibly by sequestering histone acetyltransferase activity. Accordingly, histone deacetylase inhibitors or BET inhibitors, the latter of which inhibit binding of BRD-NUT proteins to chromatin, induce terminal differentiation of NMC cells. These insights provide a rationale for targeted therapy of NMC, which is almost uniformly refractory to conventional chemotherapy and radiotherapy.
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