In the new research published today in Cancer Cell, researchers have figured out a way to prevent MYB, one of the most potent cancer-aiding proteins, from activating genes in AML, an aggressive form of leukaemia. Tested in mice, the new method resulted in dramatic cancer reduction and no harm to healthy cells. This could lead to a new therapy for AML and possibly other cancers.
The new research is to fight the often fatal acute myeloid leukaemia (AML) by disabling parts of the machinery in cells called the transcriptional machinery that determines when genes are switched on and off. Central players in the machinery are proteins called transcription factors, thousands of which are active in regulating genes across our chromosomes.
The question addressed was how to target one of the most troublesome transcription factors, called MYB. It is an oncogenic, or cancer-inducing, a transcription factor that enables cells to blow through the stop signs that normally prevent out-of-control growth. In leukaemia, MYB is special because previous studies showed that by targeting MYB we can get AML not just to stop growing but actually to regress.
In the present study, the team discovered how to selectively take MYB out of the picture in leukaemia by throwing a molecular wrench into the mechanism that the transcription factor normally activates. First, they discovered that MYB activates gene expression by docking at a giant gene-co-activation protein called TFIID (pronounced TF-two-D).
Next, they found a tiny weak spot on the massive protein. This Achilles' heel, called TAF12, is a small, nub-like projection. The team then tricked MYB into binding to short protein fragments, or peptides, that are shaped exactly like the place on TAF12 where MYB binds when it is promoting leukaemia. A major achievement in the study was generating this peptide, which acts as a decoy.
Experiments in mice that model human AML showed that the peptide finds and binds MYB, preventing it from engaging the TFIID co-activator. This resulted in mouse leukaemias shrinking in size by some 80% without causing harm to healthy cells. While the peptide is not itself a drug, its action could be replicated by a drug.
In conclusion, the research team reported that tested in mice, the new method resulted in dramatic cancer reduction and no harm to healthy cells. This could lead to a new therapy for AML and possibly other cancers.