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Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma
- Source :
- Blood. 134:363-373
- Publication Year :
- 2019
- Publisher :
- American Society of Hematology, 2019.
-
Abstract
- Targeting the B-cell receptor and phosphatidylinositol 3-kinase/mTOR signaling pathways has shown meaningful, but incomplete, antitumor activity in lymphoma. Glycogen synthase kinase 3 (GSK3) α and β are 2 homologous and functionally overlapping serine/threonine kinases that phosphorylate multiple protein substrates in several key signaling pathways. To date, no agent targeting GSK3 has been approved for lymphoma therapy. We show that lymphoma cells abundantly express GSK3α and GSK3β compared with normal B and T lymphocytes at the messenger RNA and protein levels. Utilizing a new GSK3 inhibitor 9-ING-41 and by genetic deletion of GSK3α and GSK3β genes using CRISPR/CAS9 knockout, GSK3 was demonstrated to be functionally important to lymphoma cell growth and proliferation. GSK3β binds to centrosomes and microtubules, and lymphoma cells treated with 9-ING-41 become arrested in mitotic prophase, supporting the notion that GSK3β is necessary for the progression of mitosis. By analyzing recently published RNA sequencing data on 234 diffuse large B-cell lymphoma patients, we found that higher expression of GSK3α or GSK3β correlates well with shorter overall survival. These data provide rationale for testing GSK3 inhibitors in lymphoma patient trials.
- Subjects :
- 0301 basic medicine
Indoles
Lymphoma
Cell Survival
Immunology
Gene Expression
Mitosis
Mice, Transgenic
Mitotic prophase
Spindle Apparatus
Biology
Biochemistry
Maleimides
Glycogen Synthase Kinase 3
Mice
03 medical and health sciences
0302 clinical medicine
GSK-3
Cell Line, Tumor
Biomarkers, Tumor
medicine
Animals
Humans
Molecular Targeted Therapy
Cell Proliferation
Glycogen Synthase Kinase 3 beta
Kinase
Cell growth
Cell Cycle Checkpoints
Cell Biology
Hematology
medicine.disease
Xenograft Model Antitumor Assays
Disease Models, Animal
Treatment Outcome
030104 developmental biology
030220 oncology & carcinogenesis
Gene Targeting
Cancer research
Phosphorylation
Signal transduction
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 134
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....cc6e69bdf4c17966737cddf8100f3e54