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PMID: 27040177 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Repression of GSK3 restores NK cell cytotoxicity in AML patients.

Nature communications ·Vol. 7 ·2016-04-04 ·Pages 11154

Parameswaran R, Ramakrishnan P, Moreton SA, Xia Z, Hou Y, Lee DA, Gupta K, deLima M, Beck RC, Wald DN

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.

MeSH Terms
Aminophenols/chemistry,pharmacology Animals Cellular Microenvironment Glycogen Synthase Kinase 3/antagonists & inhibitors,metabolism Glycogen Synthase Kinase 3 beta Heterocyclic Compounds, 3-Ring/chemistry,pharmacology Immunotherapy Intercellular Adhesion Molecule-1/metabolism Killer Cells, Natural/immunology Leukemia, Myeloid, Acute/immunology Maleimides/chemistry,pharmacology Mice NF-kappa B/metabolism Thiadiazoles/chemistry,pharmacology Tumor Necrosis Factor-alpha
Chemicals
3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione 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 Aminophenols Heterocyclic Compounds, 3-Ring Maleimides NF-kappa B Thiadiazoles Tumor Necrosis Factor-alpha Intercellular Adhesion Molecule-1 GSK3B protein, human Glycogen Synthase Kinase 3 beta Gsk3b protein, mouse Glycogen Synthase Kinase 3 tideglusib
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Parameswaran Reshmi
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Ramakrishnan Parameswaran
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Moreton Stephen A
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. | Invenio Therapeutics, Lexington, Kentucky 40506, USA.
Xia Zhiqiang
Invenio Therapeutics, Lexington, Kentucky 40506, USA.
Hou Yongchun
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Lee Dean A
Division of pediatrics, The University of Texas Health Sciences Center, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Gupta Kalpana
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
deLima Marcos
Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
Beck Rose C
Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
Wald David N
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. | Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms11154
Published
2016-04-04
Epub
2016-00-04
Pages
11154
Language
English
Region
England
NLM ID
101528555
PMCID
PMC4822012
Subset
IM
Grants
NCI NIH HHS · P30 CA043703 · United States
NCI NIH HHS · P50 CA150964 · United States
NCI NIH HHS · P30CA043703 · United States
NCI NIH HHS · P530CA150964 · United States
External Links
PubMed source DOI: 10.1038/ncomms11154 PMC Full Text View journal details
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