Multiomic characterization of WDR5 WIN site inhibition reveals actionable synergies for MLL-rearranged leukemia

In this study, we utilized a multi-omics approach to determine the transcriptional, translational, and proteomic responses to WIN Site inhibition in MLL-rearranged leukemia cells via RNA-Seq, Ribo-Seq, and quantitative proteomics, respectively. We also performed both a whole-genome targeting primary CRISPR screen and a secondary CRISPR screen targeting a currated collection of genes to determine genes important for sensitivity to WIN Site inhibition. These combined data sets rationally guided us in assembling a collection of compounds that, when combined with WIN Site inhibitor, synergistically inhibit growth of MLL-rearranged leukemia cells. MV4;11 cells were treated with either DMSO or one of two unique WIN Site inhibitors before performing RNA-Seq to determine transcriptome alterations and Ribo-Seq to determine translatome alterations. CRISPR screens were performed in MV4;11 cells to determine genes altering sensitivity to multiple WIN Site inhibitors.