Transcription factors are proteins that control gene expression in the cell. When transcription factors are corrupted they bind to the wrong regions of DNA resulting in the wrong genes being expressed, and this results in the development of disease. One such transcription factor is PU.1, and when it’s function is corrupted it promotes the development of myelodysplastic syndrome (MDS). In fact, it is known that greater than 50% of MDS cases have corrupted PU.1 activity, making PU.1 a very attractive therapeutic target. Unfortunately, transcription factors have long been viewed as undruggable… that is until now.

My recent research has shown that it is possible to target PU.1 with a novel class of drugs called “Transcription Factor Redistributors”. These drugs prevent PU.1 from binding to particular regions of DNA and encourage it to bind to other, “pro- differentiation” regions of DNA. As a result, redistributed PU.1 causes the diseased cell to turn into a myeloid cell. I will employ these novel drugs in the context of MDS to understand why and how PU.1 behaves in a corrupted way, and determine if these drugs could provide a therapy to differentiate MDS cells into normal cells in preclinical models. Ultimately, my work will move the MDS field forward by improving our understanding of aberrant transcription factor mechanisms, whilst at the same time determining whether our novel drug has the potential to improve the outcome of MDS patients.