Here, we analyzed the role of KMT2D and the KMT2D variant p. (Arg191Trp) and further epigenetic modifiers using an in vitro-imatinib resistance model providing new insights into the role of KMT2D in TKI-resistant CML. This evidence concerns the gene KMT2D and chronic myelogenous leukemia, BCR-ABL1 positive.