Taken together, our results point to SETD2/H3K36me3 deficiency as a mechanism, already identified by our group in systemic mastocytosis, that is reversible, druggable, and BCR::ABL1‐independent, able to cooperate with BCR::ABL1 in driving genetic instability in CML. The gene discussed is SETD2; the disease is chronic myelogenous leukemia, BCR-ABL1 positive.