We therefore speculated that combinatorial targeting of HDAC and DNMT could (i) exert synergistic cytotoxic effect on RR-DLBCL; (ii) be a safe and active therapeutic strategy in patients with aggressive RR-DLBCL; (iii) achieve a greater degree of chemosensitization compared to DNMTI alone in RR-DLBCL. This evidence concerns the gene DNMT1 and diffuse large B-cell lymphoma.