The small molecule inhibitor JQ1 could be used in the treatment of acute myeloid leukaemia (AML) concludes a study published in Nature.

Epigenetic pathways can regulate gene expression through controlling and interpreting chromatin modifications. Cancer cells commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programmes. Although such chromatin alterations are in principle reversible the therapeutic promise of targeting such pathways has been limited by incomplete understanding of cancer-specific dependencies on epigenetic regulators.

In the current study by screening a custom library of small hairpin RNAs targeting known chromatin regulators in a genetically defined AML mouse models Christopher Vakoc and colleagues from Cold spring Harbor Laboratory (New York, USA) identified the protein bromodomain-containing 4 (Brd4) as being critical for disease maintenance.

Brd4 acts by influencing the expression of the cancer-promoting gene Myc, which itself induces a gene expression programme that drives tumorigenesis by altering the chemical composition of nuclear proteins, without change in DNA sequence.

The team furthermore showed that suppression of Brd4 with the small –molecule inhibitor JQ1 led to robust antileukaemic effects both in vitro and invivo. In a variety of human AML cell lines and primary patient samples they went on to show similar sensitivities.

"Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and , potentially other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention," write the authors.

Reference

J Zuber, J Shi, E Wang et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. Doi:10.1038/nature10334