McCubrey, James A.Steelman, L. S.Bertrand, Fred E.Davis, Nicole MarieAbrams, Stephen L.Montalto, GiuseppeD'Assoro, Antonino B.Libra, MassimoNicoletti, FerdinandoMaestro, RobertaBasecke, JorgCocco, LucioCervello, MelchiorreMartelli, Alberto M.2016-06-162016-06-162014-01Leukemia; 28:1 p. 15-330887-6924http://hdl.handle.net/10342/5674Glycogen synthase kinase-3 (GSK-3) is well documented to participate in a complex array of critical cellular processes. It was initially identified in rat skeletal muscle as a serine/threonine kinase that phosphorylated and inactivated glycogen synthase. This versatile protein is involved in numerous signaling pathways that influence metabolism, embryogenesis, differentiation, migration, cell cycle progression and survival. Recently, GSK-3 has been implicated in leukemia stem cell pathophysiology and may be an appropriate target for its eradication. In this review, we will discuss the roles that GSK-3 plays in hematopoiesis and leukemogenesis as how this pivotal kinase can interact with multiple signaling pathways such as: Wnt/β-catenin, phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/extracellular signal-regulated kinase (ERK), Notch and others. Moreover, we will discuss how targeting GSK-3 and these other pathways can improve leukemia therapy and may overcome therapeutic resistance. In summary, GSK-3 is a crucial regulatory kinase interacting with multiple pathways to control various physiological processes, as well as leukemia stem cells, leukemia progression and therapeutic resistance. GSK-3 and Wnt are clearly intriguing therapeutic targets.GSK-3leukemia stem cellsWnt/β-cateninAkttargeted therapytherapy resistanceMultifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic interventionArticlepmc388740810.1038/leu.2013.184