Cited by 68Hematopoietic Stem Cell TransplantationWnt/β-catenin signaling in development and cancerMesenchymal stem cell research

Glycogen Synthase Kinase-3 β Inhibition Preserves Hematopoietic Stem Cell Activity and Inhibits Leukemic Cell Growth

Holmes, Tiffany, O'Brien, Tracey A., Knight, Robert, Lindeman, Robert, Shen, Sylvie, Song, Emma, Symonds, Geoff, Dolnikov, Alla·2008·Stem Cells

Abstract

Ex vivo expansion of cord blood cells generally results in reduced stem cell activity in vivo. Glycogen synthase kinase-3beta (GSK-3beta) regulates the degradation of beta-catenin, a critical regulator of hematopoietic stem cells (HSCs). Here we show that GSK-3beta inhibition activates beta-catenin in cord blood CD34(+) cells and upregulates beta-catenin transcriptional targets c-myc and HoxB4, both known to regulate HSC self-renewal. GSK-3beta inhibition resulted in delayed ex vivo expansion of CD34(+) cells, yet enhanced the preservation of stem cell activity as tested in long-term culture with bone marrow stroma. Delayed cell cycling, reduced apoptosis, and increased adherence of hematopoietic progenitor cells to bone marrow stroma were observed in these long-term cultures treated with GSK-3beta inhibitor. This improved adherence to stroma was mediated via upregulation of CXCR4. In addition, GSK-3beta inhibition preserved severe combined immunodeficiency (SCID) repopulating cells as tested in the nonobese diabetic/SCID mouse model. Our data suggest the involvement of GSK-3beta inhibition in the preservation of HSC and their interaction with the bone marrow environment. Methods for the inhibition of GSK-3beta may be developed for clinical ex vivo expansion of HSC for transplantation. In addition, GSK-3beta inhibition suppressed leukemic cell growth via the induction of apoptosis mediated by the downregulation of survivin. Modulators of GSK-3beta may increase the range of novel drugs that specifically kill leukemic cells while sparing normal stem cells.

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Crossref · 10.1634/stemcells.2007-0600

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  • Active GSK3b regulates pathways that influence leukemogenesis, leukemia cell survival, myeloid differentiation, and resistance to chemotherapy.

    “Plethora of studies in last decade showed that active GSK3b is involved in the regulation of number of pathways that can influence leukemogenesis, leukemia cell survival (13,46), myeloid differentiation, and resistance to chemotherapy.”

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Authors
Holmes, T., O'Brien, T. A., Knight, R., Lindeman, R., Shen, S., Song, E., Symonds, G., & Dolnikov, A.
Affiliations
  • Sydney Children's Hospital (AU)
  • Prince of Wales Hospital (AU)
  • Children's Cancer Institute Australia (AU)
Corresponding author
Dolnikov, Alla
Venue
Stem Cells
Published
2008-03-06
Volume
26
Issue
5
Pages
1288-1297
ISSN
  • 1066-5099 (ISSN-L)
  • 1549-4918
OpenAlex
W2003799931
Cited by
68
References
29
Citations by year
2026: 2 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 8 · 2015: 2 · 2014: 3 · 2013: 4 · 2012: 11
FWCI
4.10
Type
journal article
Language
en
Open access
closed
Locations
  • Stem Cells (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
glycogen synthase kinase-3β, GSK-3β inhibition, hematopoietic stem cells, umbilical cord blood, β-catenin, ex vivo stem cell expansion, HSC self-renewal, c-Myc, HOXB4, CXCR4, bone marrow stroma, SCID-repopulating cells, apoptosis, survivin
MeSH terms
Glycogen Synthase Kinase 3 beta, Animals, Disease Models, Animal, Hematopoietic Stem Cells, Humans, Indoles, Leukemia, Oximes, Time Factors, Umbilical Cord, Mice, SCID, Stromal Cells, Coculture Techniques, Antigens, CD34, Cord Blood Stem Cell Transplantation, Glycogen Synthase Kinase 3, Cell Line, Tumor, Cell Proliferation, beta Catenin, Mice

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