Our findings highlight the presence of the EVI1/KDM6B/H3K27me3/LAPTM4B signaling axis in EVI1-overexpressed myeloid malignancies and suggest the therapeutic potential of inhibition of the KDM6B/H3K27me3/LAPTM4B signaling axis in patients with EVI1hi malignancies. This evidence concerns the gene RUNX1 and myeloid neoplasm.