Histones are proteins that play an important role in packaging DNA into chromosomes and in regulating gene transcription. One mechanism by which histones facilitate transcription is through interaction with BET proteins, which promote the release of RNA polymerase that has “paused” at transcription start sites of genes. Some cancers, particularly acute myelogenous leukemia (AML), rely heavily on the action of BET proteins to support their proliferation and survival. These cancers are highly susceptible to growth inhibition by inhibitors that block the association of BET proteins with histones, but the exact effects of these inhibitors are not well understood. To address this question, Basic Sciences investigators Scott Heibert and Bryan Venters used a technique called PRO-seq to map the location of all RNA polymerases in the genome of AML cells, enabling them to closely examine the effects of BET protein inhibitors on gene transcription. They discovered that BET inhibitors suppressed transcription of over 1,900 genes in AML cells. Of particular interest was the finding that expression of KIT, a cell surface receptor that plays a prominent role in aggressive AML, was strongly suppressed. In contrast, expression of MCL-1, a protein that helps cancer cells evade death, increased in response to BET protein inhibitors. This finding helps to explain why these inhibitors suppress the growth of, but do not kill, AML cells. Consistently, the investigators discovered that treatment of the cells with inhibitors of both BET proteins and MCL-1 resulted in cell death, while neither inhibitor alone was effective. These results pave the way to a new approach for the treatment of AML using combinations of BET protein and MCL-1 inhibitors. The work is published in the journal Cell Reports [Y. Zhao, et al. (2016), Cell Rep., 16, 2003].
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Figure reproduced under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International license from Y. Zhao, et al. (2016), Cell Rep., 16, 2003.