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.