Aberrant GSK3β nuclear localization promotes AML growth and drug resistance

Acute myeloid leukemia (AML) is a devastating disease with poor patient survival. As targetable mutations in AML are rare, novel oncogenic mechanisms are needed to define new therapeutic targets. We identified AML cells that exhibit an aberrant pool of nuclear glycogen synthase kinase 3β (GSK3β). Th...

Full description

Saved in:

Bibliographic Details
Published in:	Blood advances Vol. 2; no. 21; pp. 2890 - 2903
Main Authors:	Ignatz-Hoover, James J., Wang, Victoria, Mackowski, Nathan M., Roe, Anne J., Ghansah, Isaac K., Ueda, Masumi, Lazarus, Hillard M., de Lima, Marcos, Paietta, Elisabeth, Fernandez, Hugo, Cripe, Larry, Tallman, Martin, Wald, David N.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 13-11-2018 American Society of Hematology
Subjects:	Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Cell Line, Tumor Cell Nucleus - metabolism Cell Proliferation - drug effects Cell Survival - drug effects Drug Resistance, Neoplasm Female Glycogen Synthase Kinase 3 beta - metabolism Humans Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - mortality Leukemia, Myeloid, Acute - pathology Mice Mice, Inbred NOD Mice, SCID Myeloid Neoplasia Myeloid-Lymphoid Leukemia Protein - metabolism NF-kappa B - metabolism Oncogene Proteins, Fusion - metabolism Proportional Hazards Models Survival Rate Transplantation, Heterologous Up-Regulation
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Acute myeloid leukemia (AML) is a devastating disease with poor patient survival. As targetable mutations in AML are rare, novel oncogenic mechanisms are needed to define new therapeutic targets. We identified AML cells that exhibit an aberrant pool of nuclear glycogen synthase kinase 3β (GSK3β). This nuclear fraction drives AML growth and drug resistance. Nuclear, but not cytoplasmic, GSK3β enhances AML colony formation and AML growth in mouse models. Nuclear GSK3β drives AML partially by promoting nuclear localization of the NF-κB subunit, p65. Finally, nuclear GSK3β localization has clinical significance as it strongly correlates to worse patient survival (n = 86; hazard ratio = 2.2; P < .01) and mediates drug resistance in cell and animal models. Nuclear localization of GSK3β may define a novel oncogenic mechanism in AML and represent a new therapeutic target. •GSK3β is upregulated and more nuclear in localization in AML, allowing it to promote a more aggressive disease in vivo and in vitro.•Nuclear localization of GSK3β is correlated with poorer overall survival and drug resistance. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2473-9529 2473-9537
DOI:	10.1182/bloodadvances.2018016006