Aberrant GSK3β nuclear localization promotes AML growth and drug resistance

James J. Ignatz-Hoover, Victoria Wang, Nathan M. Mackowski, Anne J. Roe, Isaac K. Ghansah, Masumi Ueda, Hillard M. Lazarus, Marcos De Lima, Elisabeth Paietta, Hugo Fernandez, Larry Cripe, Martin Tallman, David N. Wald

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Abstract

Acutemyeloid leukemia (AML) is a devastatingdisease withpoor patient survival.As targetable mutations in AMLare rare, novel oncogenicmechanisms are needed to define newtherapeutic 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) andmediates 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.

Original languageEnglish (US)
Pages (from-to)2890-2903
Number of pages14
JournalBlood Advances
Volume2
Issue number21
DOIs
StatePublished - Nov 13 2018

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ignatz-Hoover, J. J., Wang, V., Mackowski, N. M., Roe, A. J., Ghansah, I. K., Ueda, M., Lazarus, H. M., Lima, M. D., Paietta, E., Fernandez, H., Cripe, L., Tallman, M., & Wald, D. N. (2018). Aberrant GSK3β nuclear localization promotes AML growth and drug resistance. Blood Advances, 2(21), 2890-2903. https://doi.org/10.1182/bloodadvances.2018016006