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Leukemia. 2014 Jan;28(1):15-33. doi: 10.1038/leu.2013.184. Epub 2013 Jun 19.

Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention.

Author information

1
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
2
Department of Oncology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
3
Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy.
4
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
5
Department of Bio-Medical Sciences, University of Catania, Catania, Italy.
6
Experimental Oncology 1, CRO IRCCS, National Cancer Institute, Aviano, Italy.
7
1] Department of Medicine, University of Göttingen, Göttingen, Germany [2] Sanct-Josef-Hospital Cloppenburg, Department of Hematology and Oncology, Cloppenburg, Germany.
8
Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.
9
Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare 'Alberto Monroy', Palermo, Italy.
10
1] Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy [2] Institute of Molecular Genetics, National Research Council-IOR, Bologna, Italy.

Abstract

Glycogen 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.

PMID:
23778311
PMCID:
PMC3887408
DOI:
10.1038/leu.2013.184
[Indexed for MEDLINE]
Free PMC Article

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