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Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma

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

Key Points

  • Glycogen Synthase 3 (GSK3) is overexpressed in and functionally exploited by lymphoma cells.

  • New GSK3 inhibitor 9-ING-41 induces apoptosis and cell cycle arrest at prophase by targeting centrosomes and microtubule bound GSK3β.

Abstract

Targeting the B-cell receptor and PI3K/mTOR signaling pathways has shown meaningful but incomplete anti-tumor activity in lymphoma. Glycogen Synthase 3 (GSK3) kinase α and β are two homologous and functionally overlapping serine/threonine kinases that phosphorylate multiple protein substrates in several of key signaling pathways. To date, no agents targeting GSK3 have been approved for lymphoma therapy. We show that lymphoma cells abundantly express GSK3α and GSK3β compared to normal B- and T-lymphocytes at both mRNA and protein levels. By use of 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-Seq data on 234 DLBCL patients, we found higher expression of either GSK3α or GSK3β correlate well with shorter overall survival. These data provide rationale for testing GSK3 inhibitors in lymphoma patient trials.

  • Submitted September 13, 2018.
  • Revision received May 7, 2019.
  • Accepted May 7, 2019.