In a recent paper published in Nature, the mechanisms of action and resistance in histone lysine methylation-targeted treatment of adult T-cell leukemia/lymphoma (ATL) were characterised.1 The study showed tumor regression begins as early as the first week of valemetostat treatment with patients enrolled in Phase I and II trials achieving complete remission. This is mediated by reducing histone methylation and activating the expression of tumor suppressor genes (TSG). This innovative study defined new mechanisms of cancer resistance highlighting the importance of epigenetic influences that could be targeted to improve drug efficacy.