Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma

Xiaosheng Wu, Mary Stenson, Jithma Abeykoon, Kevin Nowakowski, Lianwen Zhang, Joshua Lawson, Linda Wellik, Ying Li, Jordan Krull, Kerstin Wenzl, Anne J. Novak, Stephen M. Ansell, Gail A. Bishop, Daniel D. Billadeau, Kah Whye Peng, Francis Giles, Daniel M. Schmitt, Thomas E. Witzig

Research output: Contribution to journalArticle

8 Scopus citations

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. GSK3b 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.

Original languageEnglish (US)
Pages (from-to)363-373
Number of pages11
JournalBlood
Volume134
Issue number4
DOIs
StatePublished - Jul 25 2019

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Wu, X., Stenson, M., Abeykoon, J., Nowakowski, K., Zhang, L., Lawson, J., Wellik, L., Li, Y., Krull, J., Wenzl, K., Novak, A. J., Ansell, S. M., Bishop, G. A., Billadeau, D. D., Peng, K. W., Giles, F., Schmitt, D. M., & Witzig, T. E. (2019). Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma. Blood, 134(4), 363-373. https://doi.org/10.1182/blood.2018874560