Transcription factors — proteins that regulate gene expression — play critical roles in cell fate decisions and are frequent targets of mutation in a variety of human cancers. Understanding how transcription factors contribute to disease requires the identification of their direct gene targets, but traditional methods are time-consuming and make it difficult to distinguish direct from secondary changes.
Kristy Stengel, PhD, Scott Hiebert, PhD, and colleagues have now devised a chemical genetic approach that speeds transcription factor analysis from days to minutes.
Reporting in Molecular Cell, the researchers applied the new approach to analysis of the fusion protein AML1-ETO, the most frequent chromosomal translocation in acute myeloid leukemia. They defined a small core network of about 60 direct AML1-ETO-regulated genes, including mediators of myeloid differentiation and cell fate decisions.
Their findings demonstrated that AML1-ETO repression of this small network impairs myeloid differentiation, and the mechanistic insights point to novel therapeutic strategies.
This research was supported by the T.J. Martell Foundation, Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, National Institutes of Health (grants CA178030, CA164605, CA064140, DK058404, CA068485, TR000445, CA009582) and American Cancer Society.