Aberrant GSK3β nuclear localization promotes AML growth and drug resistance Journal Article
| Authors: | Ignatz-Hoover, J. J.; Wang, V.; Mackowski, N. M.; Roe, A. J.; Ghansah, I. K.; Ueda, M.; Lazarus, H. M.; de Lima, M.; Paietta, E.; Fernandez, H.; Cripe, L.; Tallman, M.; Wald, D. N. |
| Article Title: | Aberrant GSK3β nuclear localization promotes AML growth and drug resistance |
| Abstract: | Acutemyeloid 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 beta (GSK3 beta). This nuclear fraction drives AML growth and drug resistance. Nuclear, but not cytoplasmic, GSK3 beta enhances AML colony formation and AML growth in mouse models. Nuclear GSK3 beta drives AML partially by promoting nuclear localization of the NF-kappa B subunit, p65. Finally, nuclear GSK3 beta localization has clinical significance as it strongly correlates to worse patient survival (n = 86; hazard ratio = 2.2; P <. 01) andmediates drug resistance in cell and animal models. Nuclear localization of GSK3 beta may define a novel oncogenic mechanism in AML and represent a new therapeutic target. |
| Keywords: | therapeutic target; gene-expression; prostate-cancer; nf-kappa-b; inhibition; hematopoietic stem-cells; acute myelogenous leukemia; acute myeloid-leukemia; activity; dna-binding; glycogen-synthase kinase-3-beta |
| Journal Title: | Blood Advances |
| Volume: | 2 |
| Issue: | 21 |
| ISSN: | 2473-9529 |
| Publisher: | American Society of Hematology |
| Date Published: | 2018-11-13 |
| Start Page: | 2890 |
| End Page: | 2903 |
| Language: | English |
| ACCESSION: | WOS:000450684800009 |
| DOI: | 10.1182/bloodadvances.2018016006 |
| PROVIDER: | wos |
| PMCID: | PMC6234355 |
| PUBMED: | 30385433 |
| Notes: | Article -- Source: Wos |
