In this study, we compare the short-term, long-term and the post treatment termination effects of ATRA and ATO on NB4 and ATRA-resistant NB4-MR2 APL cells, and characterized the epigenetic modifications of canonical target and differentiation genes RARβ and TGM2. The enhanced effectiveness of ATRA and ATO combination treatment in inducing terminal differentiation and expression of target genes was most evident 96 h after treatment was terminated. Here, TGM2 is linked to acute promyelocytic leukemia.