Glycogen Synthase Kinase-3 β Inhibition Preserves Hematopoietic Stem Cell Activity and Inhibits Leukemic Cell Growth
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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.”
From FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1 (2021) · cites this paper as [46]
Cites
A role for Wnt signalling in self-renewal of haematopoietic stem cells
Reya, T., Duncan, A. W., Ailles, L., Domen, J., Scherer, D. C., Willert, K., Hintz, L., Nusse, R., & Weissman, I. L. (2003) · Nature · doi:10.1038/nature01593 · Cited by 2,159 · see citing works
Sato, N., Meijer, L., Skaltsounis, A., Greengard, P., & Brivanlou, A. H. (2003) · Nature Medicine · doi:10.1038/nm979 · Cited by 2,107 · see citing works
Caught up in a Wnt storm: Wnt signaling in cancer
Giles, R. H., van Es, J. H., & Clevers, H. (2003) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(03)00005-2 · Cited by 1,482 · see citing works
HOXB4-Induced Expansion of Adult Hematopoietic Stem Cells Ex Vivo
Antonchuk, J., Sauvageau, G., & Humphries, R. K. (2002) · Cell · doi:10.1016/s0092-8674(02)00697-9 · Cited by 700 · see citing works
Activation of the Wnt Signaling Pathway: A Molecular Mechanism for Lithium Action
Hedgepeth, C. M., Conrad, L. J., Zhang, J., Huang, H., Lee, V. M.-Y., & Klein, P. S. (1997) · Developmental Biology · doi:10.1006/dbio.1997.8552 · Cited by 637 · see citing works
Wnt Signaling Controls the Phosphorylation Status of β-Catenin
van Noort, M., Meeldijk, J., van der Zee, R., Destrée, O., & Clevers, H. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111635200 · Cited by 468 · see citing works
Preferential induction of apoptosis for primary human leukemic stem cells
Guzmán, M. L., Swiderski, C. F., Howard, D. S., Grimes, B. A., Rossi, R. M., Szilvassy, S. J., & Jordan, C. T. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.252462599 · Cited by 426 · see citing works
Hematopoietic stem cell and multilineage defects generated by constitutive β-catenin activation
Scheller, M., Huelsken, J., Rosenbauer, F., Taketo, M. M., Birchmeier, W., Tenen, D. G., & Leutz, A. (2006) · Nature Immunology · doi:10.1038/ni1387 · Cited by 394 · see citing works
A Role for the Wnt Gene Family in Hematopoiesis: Expansion of Multilineage Progenitor Cells
Austin, T. W., Solar, G. P., Ziegler, F. C., Liem, L. M., & Matthews, W. (1997) · Blood · doi:10.1182/blood.v89.10.3624 · Cited by 358 · see citing works
Role of Members of the Wnt Gene Family in Human Hematopoiesis
Berg, D. V. D., Sharma, A. K., Bruno, E., & Hoffman, R. (1998) · Blood · doi:10.1182/blood.v92.9.3189 · Cited by 338 · see citing works
WNT signalling and haematopoiesis: a WNT–WNT situation
Staal, F. J. T., & Clevers, H. C. (2005) · Nature reviews. Immunology · doi:10.1038/nri1529 · Cited by 330 · see citing works
In Vitro Self-Renewal Division of Hematopoietic Stem Cells
Ema, H., Takano, H., Sudo, K., & Nakauchi, H. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.9.1281 · Cited by 286 · see citing works
Regulation of β-Catenin Signaling in the Wnt Pathway
Kikuchi, A. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.1860 · Cited by 256 · see citing works
Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation
Trowbridge, J. J., Xenocostas, A., Moon, R. T., & Bhatia, M. (2005) · Nature Medicine · doi:10.1038/nm1339 · Cited by 247 · see citing works
Hofmeister, C. C., Zhang, J., Knight, K. L., Le, P. T., & Stiff, P. J. (2006) · Bone Marrow Transplantation · doi:10.1038/sj.bmt.1705538 · Cited by 218 · see citing works
Murdoch, B., Chadwick, K., Martin, M. A., Shojaei, F., Shah, K. V., Gallacher, L. M., Moon, R. T., & Bhatia, M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0130233100 · Cited by 214 · see citing works
Ougolkov, A. V., Bone, N. D., Fernández-Zapico, M. E., Kay, N. E., & Billadeau, D. D. (2007) · Blood · doi:10.1182/blood-2006-12-060947 · Cited by 183 · see citing works
Clinical Use of Umbilical Cord Blood Hematopoietic Stem Cells
Rocha, V., & Gluckman, É. (2006) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2005.09.006 · Cited by 175 · see citing works
de Toni, F., Racaud‐Sultan, C., Chicanne, G., Mas, V. M., Cariven, C., Briand‐Mésange, F., Salles, J., Demur, C., Allouche, M., Payrastre, B., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1209346 · Cited by 132 · see citing works
Induction of cell death in adult T-cell leukemia cells by a novel IκB kinase inhibitor
Sanda, T., Asamitsu, K., Ogura, H., Iida, S., Utsunomiya, A., Ueda, R., & Okamoto, T. (2006) · Leukemia · doi:10.1038/sj.leu.2404129 · Cited by 47 · see citing works
Shen, J., Tai, Y., Zhou, J., Wong, C.-H. S., Cheang, P. T. S., Wong, W. S. F., Xie, Z., Khan, M., Han, J.-H., & Chen, C.-S. (2006) · Experimental Hematology · doi:10.1016/j.exphem.2006.09.007 · Cited by 38 · see citing works
Shen, S., Dolnikov, A., Passioura, T., et al. (2004) · Experimental Hematology · doi:10.1016/j.exphem.2004.06.001 · Cited by 26 · see citing works
Self-citationBarker, J. N., & Verfaillie, C. M. (2000) · Leukemia · doi:10.1038/sj.leu.2401869 · Cited by 24 · see citing works
Bcl-2 expression and apoptosis in the regulation of hematopoietic stem cells
Orelio, C. C., & Dzierzak, E. A. (2007) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428190601032529 · Cited by 20 · see citing works
Marone, M., Pierelli, L., Mozzetti, S., Masciullo, V., Bonanno, G., Roberta Morosetti, A., Rutella, S., Battaglia, A., Rumi, C., Mancuso, S., et al. (2000) · British Journal of Haematology · doi:10.1046/j.1365-2141.2000.02227.x · Cited by 17 · see citing works
Passioura, T., Shen, S., Symonds, G. P., & Dolnikov, A. (2005) · Oncogene · doi:10.1038/sj.onc.1208877 · Cited by 15 · see citing works
Self-citationNovitzky, N., Makgoka, S. J., & Mohamed, R. (2001) · Experimental Hematology · doi:10.1016/s0301-472x(01)00744-5 · Cited by 13 · see citing works
Interaction of primitive human myeloid and lymphoid progenitors with the marrow microenvironment.
McGlave, P. B., Verfaillie, C. M., & Miller, J. S. (1994) · PubMed · Cited by 6 · see citing works
Induced p21WAF1 expression acts to reverse myc myelomonocytic cell transformation
Dolnikov, A., Millington, M., Sun, L., et al. (2000) · Cancer Gene Therapy · doi:10.1038/sj.cgt.7700229 · Cited by 5 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb
Zhou, F., Zhang, L., van Laar, T., van Dam, H., & ten Dijke, P. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-06-0483 · Cited by 55 · see citing works
GSK3 is a regulator of RAR-mediated differentiation
Gupta, K., Gulen, F., Sun, L., Aguilera, R., Chakrabarti, A., Kiselar, J., Agarwal, M. K., & Wald, D. N. (2012) · Leukemia · doi:10.1038/leu.2012.2 · Cited by 50 · see citing works
GSK-3 inhibition sensitizes acute myeloid leukemia cells to 1,25D-mediated differentiation
Gupta, K., Stefan, T., Ignatz-Hoover, J., Moreton, S., Parizher, G., Saunthararajah, Y., & Wald, D. N. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-2290 · Cited by 44 · see citing works
Mishra, M., Thacker, G., Sharma, A., Singh, A. K., Upadhyay, V., Sanyal, S., Verma, S. P., Tripathi, A. K., Bhatt, M. L. B., & Trivedi, A. K. (2021) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-20-0268 · Cited by 30 · see citing works
- 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
- Publisher
- Oxford University Press (OUP)
- 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
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review