An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia (T-ALL) is reported in a study published this week in Nature Genetics. This work highlights that drug resistance in this disease may be overcome by using drugs that target epigenetic regulators.

Michelle Kelliher, Bradley Bernstein and colleagues isolated human T-ALL cells that are resistant to gamma-secretase inhibitors, drugs that show transient therapeutic effects when used to treat T-ALL. They performed a screen to identify genes required for survival of resistant leukemia cells and identified chromatin regulators as being important in this survival process. They show that JQ1, a small molecule inhibitor of the BRD4 chromatin regulator, induces cell death in resistant cells, and gamma-secretase inhibitor plus JQ1 combination therapy prolongs cell survival in mice engrafted with primary human T-ALLs when compared to single-agent therapy. They suggest that drug resistance may be overcome with drugs that target epigenetic regulators.