title: Repression of GSK3 restores NK cell cytotoxicity in AML patients.
abstract: Natural killer cells from acute myeloid leukaemia patients (AML-NK) show a dramatic impairment in cytotoxic activity. The exact reasons for this dysfunction are not fully understood. Here we show that the glycogen synthase kinase beta (GSK3β) expression is elevated in AML-NK cells. Interestingly, GSK3 overexpression in normal NK cells impairs their ability to kill AML cells, while genetic or pharmacological GSK3 inactivation enhances their cytotoxic activity. Mechanistic studies reveal that the increased cytotoxic activity correlates with an increase in AML-NK cell conjugates. GSK3 inhibition promotes the conjugate formation by upregulating LFA expression on NK cells and by inducing ICAM-1 expression on AML cells. The latter is mediated by increased NF-κB activation in response to TNF-α production by NK cells. Finally, GSK3-inhibited NK cells show significant efficacy in human AML mouse models. Overall, our work provides mechanistic insights into the AML-NK dysfunction and a potential NK cell therapy strategy.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Reshmi
authors.initials: R
authors.lastname: Parameswaran
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Ramakrishnan
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.|Invenio Therapeutics, Lexington, Kentucky 40506, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Moreton
authors.affiliation: Invenio Therapeutics, Lexington, Kentucky 40506, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Yongchun
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Division of pediatrics, The University of Texas Health Sciences Center, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Lee
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Marcos
authors.initials: M
authors.lastname: deLima
authors.affiliation: Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Rose C
authors.initials: RC
authors.lastname: Beck
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.|Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Wald
mesh_terms: D000627:Aminophenols / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D060833:Cellular Microenvironment; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology; D007167:Immunotherapy; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology*; D008301:Maleimides / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha
chemical_list: C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; C584053:3-(9-fluoro-2-(piperidin-1-ylcarbonyl)-1,2,3,4-tetrahydro(1,4)diazepino(6,7,1-hi)indol-7-yl)-4-imidazo(1,2-a)pyridin-3-yl-1H-pyrrole-2,5-dione; D000627:Aminophenols; D006575:Heterocyclic Compounds, 3-Ring; D008301:Maleimides; D016328:NF-kappa B; D013830:Thiadiazoles; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C520571:tideglusib