Gain-of-function mutations in chromatin regulators as a tumorigenic mechanism and opportunity for therapeutic intervention

Shen, C., Vakoc, C. R. (2015) Gain-of-function mutations in chromatin regulators as a tumorigenic mechanism and opportunity for therapeutic intervention. Current Opinion in Oncology, 27 (1). pp. 57-63. ISSN 1040-8746

URL: http://www.ncbi.nlm.nih.gov/pubmed/25402979
DOI: 10.1097/cco.0000000000000151

Abstract

PURPOSE OF REVIEW: Somatic gain-of-function mutations that drive cancer pathogenesis are well established opportunities for therapeutic intervention, as demonstrated by the clinical efficacy of kinase inhibitors in kinase-mutant malignancies. Here, we discuss the recently discovered gain-of-function mutations in chromatin-regulatory machineries that promote the pathogenesis of cancer. The current understanding of the underlying molecular mechanisms and the therapeutic potential for direct chemical inhibition will be reviewed. RECENT FINDINGS: Point mutations that increase the catalytic activity of EZH2 and NSD2 histone methyltransferases are found in distinct subsets of B-cell neoplasms, which promote cell transformation by elevating the global level of H3K27 tri-methylation or H3K36 di-methylation, respectively. In addition, mutations in histone H3 have been identified in certain pediatric cancers which cause reprogramming of H3K27 and H3K36 methylation by interfering with the histone methyltransferase activity. Finally, chromosomal translocations involving chromatin regulator genes can lead to the formation of fusion oncoproteins that directly modify chromatin as their mechanism of action. SUMMARY: Although relatively rare in aggregate, gain-of-function mutations in chromatin regulators represent compelling therapeutic targets in genetically defined subsets of cancer patients. However, a broader clinical impact for epigenetic therapies in oncology will require an increased understanding of how nonmutated chromatin regulators function as cancer-specific dependencies.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Chromatin dynamics
diseases & disorders > cancer > drugs and therapies
CSHL Authors:
Communities: CSHL labs > Vakoc lab
CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
Depositing User: Matt Covey
Date Deposited: 21 Nov 2014 16:10
Last Modified: 13 Oct 2015 16:20
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30921

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