Continuing advances in epigenetics have indicated that the histone modifiers associated with imatinib‐resistant CML are potential therapeutic targets, with several histone deacetylase inhibitors cited as attractive drug candidates already under clinical development for therapeutic interventions.20, 31 In the present study, we found that the small molecule JIB‐04, an inhibitor of several demethylases, could efficiently eliminate LSCs through the apoptosis triggered by correction of the imbalanced epigenetics to restore the level of H3K36me3. This evidence concerns the gene MBD2 and chronic myelogenous leukemia, BCR-ABL1 positive.