Aberrant GSK3β nuclear localization promotes AML growth and drug resistance
Open accessAbstract
Abstract Acute myeloid leukemia (AML) is a devastating disease with poor patient survival. As targetable mutations in AML are rare, novel oncogenic mechanisms are needed to define new therapeutic 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) and mediates 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.
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An aberrant pool of nuclear GSK3b is present in some AMLs and drives AML growth and drug resistance.
“Previous studies also showed that an aberrant pool of nuclear GSK3b is seen in some of AMLs which drives AML growth and drug resistance.”
From FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1 (2021) · cites this paper as [47]
Nuclear GSK3b enhances AML colony formation and AML growth in mouse models.
“This nuclear, but not cytoplasmic, GSK3b was shown to enhance AML colony formation and AML growth in mouse models (47).”
From FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1 (2021) · cites this paper as [47]
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- Authors
- Ignatz-Hoover, J. J., Wang, V., Mackowski, N. M., Roe, A. J., Ghansah, I. K., Ueda, M., Lazarus, H. M., de Lima, M., Paietta, E., Fernandez, H., Cripe, L., Tallman, M., & Wald, D. N.
- Affiliations
- Case Western Reserve University (US)
- Eastern Cooperative Oncology Group (US)
- University Hospitals Cleveland Medical Center (US)
- Department of Hematology and Oncology, University Hospitals Case Medical Center and Case Western Reserve University, Cleveland, OH;
- Montefiore Medical Center (US)
- Moffitt Cancer Center (US)
- Indiana University Indianapolis (US)
- Memorial Sloan Kettering Cancer Center (US)
- ORCID
- Venue
- Blood Advances
- Publisher
- American Society of Hematology
- Published
- 2018-11-01
- Volume
- 2
- Issue
- 21
- Pages
- 2890-2903
- ISSN
- 2473-9529 (ISSN-L)
- 2473-9537
- PMC
- PMC6234355
- OpenAlex
- W2898654974
- Cited by
- 27
- References
- 51
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 3 · 2022: 10 · 2021: 2 · 2020: 7 · 2019: 2
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Blood Advances (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (U10CA049883, U10CA066636, U10CA180820, U10CA180791, U10CA014958, UG1CA189859, U10CA180828, U10CA073590, U10CA011083, U10CA014548, U10CA180795, U10CA180794, U10CA023318, U10CA021115, U10CA180853, P30CA008748, P30CA043703, U24CA196172)
- National Institute of General Medical Sciences (T32GM007250)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- acute myeloid leukemia, GSK3β, nuclear localization, drug resistance, NF-κB p65, colony formation, patient survival, therapeutic target
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Antineoplastic Agents, Cell Nucleus, Cell Survival, Female, Humans, Transplantation, Heterologous, Leukemia, Myeloid, Acute, Oncogene Proteins, Fusion, Up-Regulation, Survival Rate, Proportional Hazards Models, NF-kappa B, Mice, SCID, Mice, Inbred NOD, Drug Resistance, Neoplasm, Cell Line, Tumor, Cell Proliferation, Mice, Myeloid-Lymphoid Leukemia Protein
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