Arsenic trioxide(As2O3) is one of the most effective therapeutic agents used for patients with acute promyelocytic leukemia (APL).The probable explanation for As2O3-induced cell differentiation is the direct targeting of PML-RARα oncoprotein, which results in initiation of PML-RARα degradation.However, after injection, AS2O3 is rapidly methylated in body to different intermediate metabolites such as trivalent monomethylarsonous acid (MMAⅢ) and dimethylarsinous acid (DMAⅢ), therefore, it remains unknown that which arsenic specie is actually responsible for the therapeutic effects against APL.We found inorganic iAsⅢ predominantly showed induction of cell differentiation, while MMAⅢ and DMAⅢ specifically showed to induce mitochondria and endoplasmic reticulum-mediated apoptosis, respectively.On the other hand, in contrast to iAsⅢ, MMAⅢ showed stronger binding affinity for ring domain of PML recombinant protein, however, could not induce PML protein SUMOylation and ubiquitin/proteasome degradation.In summary, our results suggest that the binding of arsenicals to the ring domain of PML proteins is not associated with the degradation of PML-RARα fusion protein.Moreover, methylated arsenicals can efficiently lead to cellular apoptosis, however, they are incapable of inducing NB4 cell differentiation.