26 January 2018

Scientists have reported developing a ‘molecular wrench’ to stop a mechanism that enables acute myeloid leukaemia (AML) cells to proliferate.

Writing in Cancer Cell, the researchers at Cold Spring Harbor Laboratory, New York, USA, say the results in murine models suggest the technique could effectively ‘melt away’ aggressive cancers while having no harmful impact on the function of normal cells

Christopher Vakoc and colleagues have been investigating ways to disable aberrant  transcriptional activity in cancer cells. In this study, the team looked at how to target MYB, an oncogenic transcription factor.

 “MYB is a dream target in cancer research because it's involved in so many cancers” says Professor Vakoc.

 “In leukaemia 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.”

Lead researcher Yali Xu discovered that she could remove MYB from leukaemia cells by throwing a ‘molecular wrench’ into the mechanism that the transcription factor normally activates.

The researchers discovered that MYB activates gene expression by docking at the co-activator TFIID. They then identified the area of TFIID that interacts with MYC when promoting leaukaemia and were able to produce peptides that mimicked the shape of this subunit. These decoy peptides were designed to 'trick' MYB into binding them rather than TFIID, thus disabling the oncogenic interaction.

In mice, the peptides found and bound MYB, preventing it from engaging the TFIID co-activator. This resulted in marked AML regression and extension of survival. In some cases the tumours shrank by approximately 80%.

Professor Vakoc says this peptide-based ‘squelching’ strategy could be used to develop novel AML treatments.

 “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 leukaemia 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.”

 Source: Yali Xu, Joseph P. Milazzo, Tim D.D. Somerville, Yusuke Tarumoto, Yu-Han Huang, Elizabeth L. Ostrander, John E. Wilkinson, Grant A. Challen, Christopher R. Vakoc. A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia. Cancer Cell, 2018; 33 (1): 13 DOI: 10.1016/j.ccell.2017.12.002

Link: http://www.cell.com/cancer-cell/fulltext/S1535-6108(17)30554-8


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