BACKGROUND: Acute myeloid leukemia (AML) patients with highly active AKT tend to do poorly. Cell cycle arrest and apoptosis are tightly regulated by AKT via phosphorylation of GSK3alpha and beta isoforms which inactivates these kinases. In the current study we examine the prognostic role of AKT mediated GSK3 phosphorylation in AML. METHODS: We analyzed GSK3alpha/beta phosphorylation by reverse phase protein analysis (RPPA) in a cohort of 511 acute myeloid leukemia (AML) patients. Levels of phosphorylated GSK3 were correlated with patient characteristics including survival and with expression of other proteins important in AML cell survival. RESULTS: High levels of p-GSK3alpha/beta correlated with adverse overall survival and a lower incidence of complete remission duration in patients with intermediate cytogenetics, but not in those with unfavorable cytogenetics. Intermediate cytogenetic patients with FLT3 mutation also fared better respectively when p-GSK3alpha/beta levels were lower. Phosphorylated GSK3alpha/beta expression was compared and contrasted with that of 229 related cell cycle arrest and/or apoptosis proteins. Consistent with p-GSK3alpha/beta as an indicator of AKT activation, RPPA revealed that p-GSK3alpha/beta positively correlated with phosphorylation of AKT, BAD, and P70S6K, and negatively correlated with beta-catenin and FOXO3A. PKCdelta also positively correlated with p-GSK3alpha/beta expression, suggesting crosstalk between the AKT and PKC signaling pathways in AML cells. CONCLUSIONS: These findings suggest that AKT-mediated phosphorylation of GSK3alpha/beta may be beneficial to AML cell survival, and hence detrimental to the overall survival of AML patients. Intrinsically, p-GSK3alpha/beta may serve as an important adverse prognostic factor for a subset of AML patients.