High-throughput approaches to uncover synergistic drug combinations in leukemia

We report a comprehensive drug synergy study in acute myeloid leukemia (AML). In this work, we investigate a panel of cell lines spanning both MLL-rearranged and non-rearranged subtypes. The work comprises a resource for the community, with many synergistic drug combinations that could not have been predicted a priori , and open source code for automation and analyses . We base our definitions of drug synergy on the Chou-Talalay method, which is useful for visualizations of synergy experiments in isobolograms, and median-effects plots, among other representations. Our key findings include drug synergies affecting the chromatin state, specifically in the context of regulation of the modification state of histone H3 lysine-27. We report open source high throughput methodology such that multidimensional drug screening can be accomplished with equipment that is accessible to most laboratories. This study will enable preclinical investigation of new drug combinations in a lethal blood cancer, with data analysis and automation workflows freely available to the community.

Automated summary

We conducted a comprehensive study on drug synergy in acute myeloid leukemia (AML), using a panel of cell lines representing different subtypes. Our study provides a valuable resource for the community, offering many unexpected synergistic drug combinations and open source code for automation and analysis. We identified drug synergies that affect the chromatin state, particularly in relation to the modification of histone H3 lysine-27. Additionally, we developed an open source high throughput methodology that allows multidimensional drug screening with widely accessible equipment.