Aberrant GSK3? nuclear localization promotes AML growth and drug resistance.

ABSTRACT: 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 3? (GSK3?). This nuclear fraction drives AML growth and drug resistance. Nuclear, but not cytoplasmic, GSK3? enhances AML colony formation and AML growth in mouse models. Nuclear GSK3? drives AML partially by promoting nuclear localization of the NF-?B subunit, p65. Finally, nuclear GSK3? 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 GSK3? may define a novel oncogenic mechanism in AML and represent a new therapeutic target.

SUBMITTER: Ignatz-Hoover JJ 

PROVIDER: S-EPMC6234355 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature