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Aberrant GSK3β nuclear localization promotes AML growth and drug resistance

James J Ignatz-Hoover1, Victoria Wang2, Nathan M Mackowski1

  • 1Department of Pathology, Case Western Reserve University, Cleveland, OH.

Blood Advances
|November 3, 2018
PubMed

Insights

Aberrant nuclear glycogen synthase kinase 3 beta (GSK3β) drives acute myeloid leukemia (AML) growth and drug resistance. Targeting nuclear GSK3β may offer a novel therapeutic strategy for AML patients with poor survival outcomes.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Acute myeloid leukemia (AML) presents a significant clinical challenge due to poor patient survival rates.
  • Limited targetable mutations in AML necessitate the discovery of novel oncogenic mechanisms for therapeutic development.

Purpose of the Study:

  • To investigate the role of nuclear glycogen synthase kinase 3 beta (GSK3β) in AML pathogenesis.
  • To determine if nuclear GSK3β represents a potential therapeutic target for AML.

Main Methods:

  • Analysis of nuclear GSK3β pools in AML cells.
  • Assessment of GSK3β's impact on AML colony formation and in vivo tumor growth.
  • Investigation of GSK3β's role in NF-κB pathway activation.
  • Correlation of nuclear GSK3β localization with patient survival data.

Main Results:

  • AML cells exhibit an aberrant pool of nuclear GSK3β, which promotes AML growth and drug resistance.
  • Nuclear GSK3β enhances AML colony formation and tumor growth in mouse models.
  • Nuclear GSK3β contributes to AML progression partly by promoting nuclear localization of p65, an NF-κB subunit.
  • Nuclear GSK3β localization significantly correlates with worse patient survival (HR=2.2, P<.01) and mediates drug resistance.

Conclusions:

  • Aberrant nuclear localization of GSK3β is a novel oncogenic mechanism in AML.
  • Nuclear GSK3β is a potential therapeutic target for improving outcomes in AML patients.
  • Targeting nuclear GSK3β may overcome drug resistance and improve survival in AML.

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