title: Phosphorylation of GSK3α/β correlates with activation of AKT and is prognostic for poor overall survival in acute myeloid leukemia patients.
abstract: 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 GSK3α and β isoforms which inactivates these kinases. In the current study we examine the prognostic role of AKT mediated GSK3 phosphorylation in AML.
  
  
  METHODS
  We analyzed GSK3α/β 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-GSK3α/β 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-GSK3α/β levels were lower. Phosphorylated GSK3α/β expression was compared and contrasted with that of 229 related cell cycle arrest and/or apoptosis proteins. Consistent with p-GSK3α/β as an indicator of AKT activation, RPPA revealed that p-GSK3α/β positively correlated with phosphorylation of AKT, BAD, and P70S6K, and negatively correlated with β-catenin and FOXO3A. PKCδ also positively correlated with p-GSK3α/β expression, suggesting crosstalk between the AKT and PKC signaling pathways in AML cells.
  
  
  CONCLUSIONS
  These findings suggest that AKT-mediated phosphorylation of GSK3α/β may be beneficial to AML cell survival, and hence detrimental to the overall survival of AML patients. Intrinsically, p-GSK3α/β may serve as an important adverse prognostic factor for a subset of AML patients.
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Ruvolo
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: YiHua
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States ; Department of Biomedical Informatics, Ohio State University Medical Center, Columbus, OH 43210, United States.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.affiliation: Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States.
authors.forename: Nianxiang
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Statistics, Brigham Young University, Provo, UT, United States.
authors.forename: E Shannon
authors.initials: ES
authors.lastname: Neeley
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Vivian R
authors.initials: VR
authors.lastname: Ruvolo
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Numsen
authors.initials: N
authors.lastname: Hail
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
keywords: AKT; GSK3; Leukemia; PKC delta; RPPA; Signal transduction