A few years ago, researchers discovered that inhibiting the protein BRD4 can treat acute myeloid leukemia (AML). However, the mechanism that explains how the protein works has remained a mystery.
Now, investigators have discovered the larger signaling pathway to which BRD4 belongs. The team said their discovery points to additional therapeutic targets for AML and other malignancies.
The group described this work in Molecular Cell.
BRD4: A retrospective
In 2011, Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues identified potential drug targets for AML using RNA interference. Out of that screen came BRD4 and the realization that leukemia cells were “extremely sensitive” to inhibition of this protein.
In a bit of serendipity, drugs to inhibit BRD4 had just been developed for other purposes. Dr Vakoc and his colleagues tested these drugs and found that one in particular, JQ1, worked well against a mouse model of aggressive AML.
In the past few years, several groups have reported similar therapeutic results in mice using JQ1 and closely related drugs.
“It’s been very satisfying to see that other groups have independently validated our findings,” Dr Vakoc said.
Due to the evidence of their effectiveness in mice, inhibitors of BRD4 moved into clinical trials starting in 2013. Currently, there are 12 active clinical trials targeting BRD4 in leukemia and other cancers, including one sponsored by a company to which Dr Vakoc has licensed JQ1.
“Once we published the first paper in 2011, the main objective in our lab has been to understand why these drugs work,” Dr Vakoc said. “Knowing the mechanism of action of a drug is essential to making the drug better because there will likely be many generations of BRD4 inhibitors.”
JQ1 and BRD4: How they work
In the current study, Dr Vakoc and his colleagues discovered that BRD4 works very closely with transcription factors that bind to DNA and selectively control the activity of certain genes. The transcription factors control blood formation and essentially give blood cells their “identity.”
The researchers found that JQ1 can make leukemia cells shed their leukemia characteristics and differentiate into normal white blood cells. The team also identified an intermediary molecule called p300 between BRD4 and the leukemia-associated transcription factors.
Active areas of research in Dr Vakoc’s lab include exploring other players in the pathway, particularly the molecules that BRD4 controls, and learning more about the transcription factors.
“This new work is leading us to realize that transcription factors are the masters of the biological universe,” Dr Vakoc said. “Clearly, they are driving the cancer phenotype.”
