Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy
Open accessAbstract
Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine kinase that participates in numerous signalling pathways involved in diverse physiological processes. Several of these pathways are implicated in disease pathogenesis, which has prompted efforts to develop GSK3-specific inhibitors for therapeutic applications. However, before now, there has been no strong rationale for targeting GSK3 in malignancies. Here we report pharmacological, physiological and genetic studies that demonstrate an oncogenic requirement for GSK3 in the maintenance of a specific subtype of poor prognosis human leukaemia, genetically defined by mutations of the MLL proto-oncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signalling pathways, GSK3 paradoxically supports MLL leukaemia cell proliferation and transformation by a mechanism that ultimately involves destabilization of the cyclin-dependent kinase inhibitor p27(Kip1). Inhibition of GSK3 in a preclinical murine model of MLL leukaemia provides promising evidence of efficacy and earmarks GSK3 as a candidate cancer drug target.
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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.”
From FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1 (2021) · cites this paper as [13]
The Discussion and the section ‘GSK3 dependence is a general feature of MLL transformed cells’ link GSK3 activity to MLL leukemogenesis and continued proliferation, and report myeloid differentiation after GSK3 inhibition. The paper does not establish resistance to chemotherapy. It also finds that GSK3α and GSK3β cooperate, so these findings cannot be assigned solely to active GSK3β. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn some AMLs, GSK3β acts as tumor promoter by targeting tumor suppressors such as p27.
“in some of the AMLs, GSK3b was shown to act as tumor promoter by targeting tumor suppressors such as p27 (13).”
From FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1 (2021) · cites this paper as [13]
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- Authors
- Wang, Z., Smith, K. S., Murphy, M., Piloto, O., Somervaille, T. C. P., & Cleary, M. L.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Cleary, Michael L.
- Venue
- Nature
- Published
- 2008-09-17
- Volume
- 455
- Issue
- 7217
- Pages
- 1205-1209
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4084721
- OpenAlex
- W1964632863
- Cited by
- 265
- References
- 43
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 9 · 2021: 10 · 2020: 17 · 2019: 14 · 2018: 13 · 2017: 13 · 2016: 14 · 2015: 14 · 2014: 23 · 2013: 29 · 2012: 26
- FWCI
- 19.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- David and Lucile Packard Foundation
- Lawrence Foundation
- National Cancer Institute (CA 116606, R01CA116606, CA-55029, R01CA055029)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- glycogen synthase kinase-3, p27, cyclin-dependent kinase inhibitors, GSK-3 inhibitors, oncogenic signaling, therapeutic target
- MeSH terms
- Proto-Oncogene Mas, Animals, Cell Division, Cell Line, Transformed, Cell Transformation, Neoplastic, Disease Models, Animal, Humans, Isoenzymes, Leukemia, Lymphoid, Mice, Inbred C57BL, Histone-Lysine N-Methyltransferase, G1 Phase, Mice, SCID, Myeloid Progenitor Cells, Glycogen Synthase Kinase 3, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p27, Mice, Myeloid-Lymphoid Leukemia Protein, Precursor Cells, B-Lymphoid
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