Chromatin mods should be good drug targets for cancer therapies, but sort of like Facebook’s privacy policy, cancer epigenetics is so complex that no one completely understands all the nuances. So instead of spending time on the usual epigenetic suspects, researchers at Cold Spring Harbor in New York kept an open mind and performed an unbiased screen to find new potential targets.
The approach seemed to work—they found that Brd4 looks like a good target and a small-molecule inhibitor called JQ1 shows promise as a treatment for acute myeloid leukemia (AML).
The researchers transduced a custom small hairpin RNA (shRNA) library into an AML mouse model and identified Brd4, a BET family bromodomain-containing protein that binds to acetylated histones, as a “top scorer” in the screen. It’s known to be mutated in another form of cancer, but this is the first time it’s shown up as a player in AML. Here’s more evidence that they’ve got a good suspect:
- Suppressing Brd4 stopped AML cells from dividing and even wound up killing them, but had no effect on other cell types.
- JQ1, an inhibitor of BET bromodomains, had pretty much the same effect as suppressing Brd4.
- In vivo, Brd4 knockdown and JQ1 treatment delayed leukemia progression and helped mice live longer.
- Suppressing Brd4 and treating cells with JQ1 caused leukemia cells to mature, bringing them out of a cancer-like state. It also reduced expression of leukemia stem cell signatures.
- The data suggest that Brd4 keeps Myc levels high, keeping AML cells undifferentiated and cancer-like.
The researchers say that not only is Brd4 a good AML target, but this unbiased screen strategy could be used to find other epigenetic cancer suspects.
Read more about how the Brd4-AML connection was made at Nature, August 2011.