Here, we identify a druggable mediator of HDACis response in 3q26 AML and mechanistically demonstrate evidence of targeted suppression of EVI1 using phenotypic and genome-based in silico small molecule screen approaches and a proteomic analysis of the EVI1 chromatin complex in preclinical-3q26-leukemia-models and leukemia patients. This evidence concerns the gene MECOM and leukemia.