Tweaking Transcription to Stop AML Cell Growth

A new way to alter gene expression in leukemia cells may offer a fast track to treatment, according to a recent study in Nature. Matthew D. Shair, PhD, and colleagues at Harvard University in Cambridge, MA, show that a natural product derived from sea sponges possesses potent anticancer activity against acute myeloid leukemia (AML) cell lines in vitro and in a mouse model, without apparent toxicity. They found that the compound, cortistatin A (CA), is a highly specific inhibitor of the cyclin-dependent kinases (CDK) 8 and 19, which help to modulate gene expression through DNA regulatory elements known as super-enhancers (SE).

CA “may represent a unique new way we can perturb transcription,” says Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in New York, who was not involved in the work.

CA is not the first molecule to target transcriptional regulation in cancer cells. Several antitumor drugs in development, including inhibitors of the bromodomain protein BRD4 and CDK7, suppress the activity of SE-associated proteins to cause widespread dampening of transcription.

However, CA appears to work differently. As part of the study, the researchers performed transcriptome analysis and found that CA did not decrease overall transcription, but it upregulated a small number of SE-controlled genes, which was sufficient to suppress leukemia cell growth.

The results suggest that cancers use SEs not only to turn up gene expression, but also to fine-tune expression levels. Shair thinks that AML must be very sensitive to the dosage of some genes. “Like in the story of Goldilocks—it has to be just right,” he says.

“It really suggests that the transcriptional circuitry of cancer cells, and leukemia cells in particular, is quite fragile,” says Ross L. Levine, MD, of Memorial Sloan Kettering Cancer Center, New York, NY, who was not involved in the study. Even small changes can “push cells over the edge.”

Going forward, “It will be very interesting to understand what genotypes of leukemia, and what specific mutational drivers, are associated with response and resistance to the drug,” says Benjamin L. Ebert, MD, PhD, of Brigham and Women's Hospital in Boston, MA, who was also not involved in the study. “They used mainly cell lines to characterize the drug so far. It will be really interesting to understand what the responses look like in primary tumor samples with a wide range of genotypes.”

In the meantime, Shair said his group has synthesized new, structurally simpler compounds related to CA that can be given orally, can be made more easily on a large scale than CA, and work in animal models of AML. They are talking with potential industry partners about moving these new lead compounds into clinical trials.

The need for new treatments for AML is pressing, notes Levine. “The treatment for AML has not changed for more than 30 years, so to have this novel drug against a novel target with potential efficacy is really exciting,” he says.