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Molecules 2018, 23(5), 1057;

Targeting General Transcriptional Machinery as a Therapeutic Strategy for Adult T-Cell Leukemia

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka 020-8505, Iwate, Japan
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
14 Medical Drive, Centre for Translational Medicine, #12-01, Singapore 117599, Singapore
Author to whom correspondence should be addressed.
Received: 17 March 2018 / Revised: 27 April 2018 / Accepted: 28 April 2018 / Published: 2 May 2018
(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)
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Cancer cells are highly reliant on certain molecular pathways, which support their survival and proliferation. The fundamental concept of molecularly targeted therapy is to target a protein that is specifically deregulated or overexpressed in cancer cells. However, drug resistance and tumor heterogeneity are major obstacles in the development of specific inhibitors. Additionally, many driver oncogenes exert their oncogenic property via abnormal expression without having genetic mutations. Interestingly, recent accumulating evidence has demonstrated that many critical cancer genes are driven by a unique class of enhancers termed super-enhancers. Genes associated with super-enhancers are relatively more susceptible to the inhibition of general transcriptional machinery compared with genes that are regulated by typical enhancers. Cancer cells are more sensitive to treatment with small-molecule inhibitors of CDK7 or BRD4 than non-transformed cells. These findings proposed a novel strategy to identify functionally important genes as well as novel therapeutic modalities in cancer. This approach would be particularly useful for genetically complicated cancers, such as adult T-cell leukemia (ATL), whereby a large mutational burden is present, but the functional consequences of each mutation have not been well-studied. In this review, we discuss recent findings on super-enhancers, underlying mechanisms, and the efficacy of small-molecule transcriptional inhibitors in ATL. View Full-Text
Keywords: super-enhancer; transcription factor; CDK7; CDK9; BRD4; adult T-cell leukemia super-enhancer; transcription factor; CDK7; CDK9; BRD4; adult T-cell leukemia

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Wong, R.W.J.; Ishida, T.; Sanda, T. Targeting General Transcriptional Machinery as a Therapeutic Strategy for Adult T-Cell Leukemia. Molecules 2018, 23, 1057.

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