Researchers say they have found a way to target the oncogenic transcription factor MYB in acute myeloid leukemia (AML).
By inducing the expression of a peptide in mouse models of AML, the researchers were able to prevent MYB from promoting leukemia growth.
In fact, the team observed AML regression with no harmful impact on the function of normal cells.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described these findings in Cancer Cell.
“MYB is a dream target in cancer research because it’s involved in so many cancers,” Dr Vakoc said. “In leukemia, it’s special because we know from previous research that, by targeting MYB, you can get AML not just to stop growing but actually to regress.”
With the current research, Dr Vakoc and his colleagues discovered how to selectively target MYB.
First, the researchers found that MYB activates gene expression by docking at a giant gene-co-activation protein called TFIID.
Specifically, the MYB transactivation domain binds to the TAF12/TAF4 histone-fold domain (HFD) heterodimer. TAF12 and TAF4 are subunits of TFIID.
Based on this finding, the researchers hypothesized that “a minimal HFD fragment of TAF4 would be an ideal probe for blocking MYB function, since this peptide binds with high affinity and specificity to the TAF12 HFD.”
The team thought the peptide would form an ineffective complex with TAF12 and MYB, interfering with the endogenous MYB-TFIID interaction.
In in vitro experiments, TAF4-HFD expression inhibited AML growth and blast colony formation, induced differentiation, and destabilized MYB protein.
For their in vivo experiments, the researchers transduced RN2 cells with a dox-inducible TAF4-HFD retroviral vector and transplanted the cells in mice.
The team observed “marked” AML regression and prolonged survival in these mice compared to controls.
While the peptide is not itself a drug, Dr Vakoc said its action could be replicated by a drug.
“It’s a concept we’re now discussing with the pharmaceutical industry,” he said. “It is going to take lots of work before it can result in a medicine leukemia patients might take. But we’re excited about this new approach because MYB is such an important player in many cancers and, until now, has eluded efforts to selectively target it.”