This study investigates the mechanisms of action and resistance in histone methylation-targeted therapy, focusing on the EZH1–EZH2 dual inhibitor valemetsotat in patients with adult T cell leukemia/lymphoma (ATL). Valemetsotat effectively reduced tumor size and demonstrated durable clinical responses in aggressive lymphomas with multiple genetic mutations. Single-cell analyses revealed that valemetsotat abolished highly condensed chromatin structures formed by H3K27me3 and neutralized multiple gene loci, including tumor suppressor genes. However, long-term treatment led to the emergence of resistant clones with reconstructed aggregate chromatin, resembling the pre-dose state. Acquired mutations at the PRC2–compound interface resulted in increased H3K27me3 expression, while *TET2* mutations or elevated *DNMT3A* expression caused similar chromatin recondensation through de novo DNA methylation. The study also identified subpopulations with distinct metabolic and gene translation characteristics, which were implicated in primary susceptibility until the acquisition of heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for sustained epigenetic cancer therapies.This study investigates the mechanisms of action and resistance in histone methylation-targeted therapy, focusing on the EZH1–EZH2 dual inhibitor valemetsotat in patients with adult T cell leukemia/lymphoma (ATL). Valemetsotat effectively reduced tumor size and demonstrated durable clinical responses in aggressive lymphomas with multiple genetic mutations. Single-cell analyses revealed that valemetsotat abolished highly condensed chromatin structures formed by H3K27me3 and neutralized multiple gene loci, including tumor suppressor genes. However, long-term treatment led to the emergence of resistant clones with reconstructed aggregate chromatin, resembling the pre-dose state. Acquired mutations at the PRC2–compound interface resulted in increased H3K27me3 expression, while *TET2* mutations or elevated *DNMT3A* expression caused similar chromatin recondensation through de novo DNA methylation. The study also identified subpopulations with distinct metabolic and gene translation characteristics, which were implicated in primary susceptibility until the acquisition of heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for sustained epigenetic cancer therapies.