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BACKGROUND The intertwining between cancer pathogenesis and aberrant expression of either oncogenes or tumor suppressor proteins ushered the cancer therapeutic approaches into a limitless road of modern therapies. For the nonce and among the plethora of promising anticancer agents, intense interest has focused on pioglitazone, a first in-class of thiazolidinedione (TZD) drugs that is currently used to treat patients with diabetes. OBJECTIVE Intrigued by the overexpression of PPARγ in acute promylocytic leukemia (APL), this study was designed to investigate the effects of pioglitazone in APL-derived NB4 cells. METHODS To assess the anti-leukemic effect of pioglitazone on myeloid leukemia cell lines, we used MTT and trypan blue assays. Given to the higher expression level of PPARγ in NB4 cells, we then expanded our experiments on this cell line. For ascertain the molecular mechanism action of pioglitazone in APL-derived NB4 cells, we evaluated the expression levels of large cohort of target genes responsible for the regulation of apoptosis, autophagy and cell proliferation. Afterward, to examine whether there is a correlation between PPARγ and the PI3K signaling pathway, the amount of Akt phosphorylation was evaluated using western blot analysis. RESULTS Our results showed that pioglitazone exerted its cytotoxic effect in wild-type PTEN-expressing NB4 cells, but not in leukemic K562 cells harboring mutant PTEN; suggesting that probably this member of TZD drugs induced its antileukemic effects through a PTEN-mediated manner. Moreover, we found that not only pioglitazone reduced the survival rate of NB4 through the induction of p21-mediated G1 arrest, also elevated the intracellular level of reactive oxygen species (ROS) which was coupled with upregulated FOXO3a. Notably, this study proposed for the first time that the stimulation of autophagy as a result of the compensatory activation of PI3K pathway may act as a plausible mechanism through which the anti-leukemic effect of pioglitazone may be attenuated; suggestive of the application of either PI3K or autophagy inhibitors along with pioglitazone in APL. CONCLUSION By suggesting a mechanistic pathway, the results of the present study shed more light on the favorable antileukemic effect of pioglitazone and suggest it as a promising drug which should be clinically investigated in APL patients.