All-trans Retinoic Acid (ATRA) induces granulocytic differentiation in cultured leukemic HL-60 cells, and it is clinically effective as the differentiation therapy of inducing high remission rates in patients with acute promyelocytic leukemia (APL).During the process, it has been demonstrated that the PP2A activity is decreased, and the inhibitor of PP2A can augment the ATRA-induced differentiation.However, there is almost no data on the role of serine/threonine protein phosphatases during the differentiation of NB4 cell induced by ATRA and the resistance of MR2 cells to ATRA.In this report, we directly show okadaic acid (OKA) can augment the differentiation of NB4 induced by ATRA, and when combined with ATRA induced the slight differentiation of MR2 cells.Phosphatase assay showed a decreased PP2A activity in NB4 after ATRA treatment.OKA augmented the inhibitory effect of ATRA on the activity in NB4.When OKA in combination with ATRA was incubated with MR2, MR2 also showed the decreased activity of PP2A.All of these data taken together suggests the reduction of PP2A activity and paralleled augmentation of differentiation degree in NB4 and MR2 cells induced by ATRA.Western blot analysis showed that the level of PP2A catalytic subunit (PP2A-C) was decreased during the course of ATRA-induced differentiation in NB4 cells, whereas expressions of all other subunits of PP2A in MR2 ceils were relatively unaltered.The results were identical to the change of PP2A activity.In conclusion, PP2A possibly plays an important role in the mechanism of 2differentiation of NB4 induced by ATRA and in resistance of MR2 to ATRA.