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

doi:10.1182/blood.2018874560

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Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma

Journal article

Open access

Peer reviewed

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, …

Blood, Vol.134(4), pp.363-373

07/25/2019

DOI: 10.1182/blood.2018874560

PMCID: PMC6659256

PMID: 31101621

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url

https://doi.org/10.1182/blood.2018874560View

Published (Version of record) Open Access

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.

Gene Expression

Animals

Biomarkers, Tumor

Cell Cycle Checkpoints - drug effects

Cell Cycle Checkpoints - genetics

Cell Line, Tumor

Cell Proliferation - genetics

Cell Survival - genetics

Disease Models, Animal

Gene Targeting - methods

Glycogen Synthase Kinase 3 - antagonists & inhibitors

Glycogen Synthase Kinase 3 - genetics

Glycogen Synthase Kinase 3 - metabolism

Glycogen Synthase Kinase 3 beta - genetics

Glycogen Synthase Kinase 3 beta - metabolism

Humans

Indoles - pharmacology

Lymphoma - diagnosis

Lymphoma - etiology

Lymphoma - mortality

Lymphoma - therapy

Maleimides - pharmacology

Mice

Mice, Transgenic

Mitosis - drug effects

Mitosis - genetics

Molecular Targeted Therapy - adverse effects

Molecular Targeted Therapy - methods

Spindle Apparatus - drug effects

Treatment Outcome

Xenograft Model Antitumor Assays

Details

Title: Subtitle: Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma
Creators: Xiaosheng Wu - Mayo Clinic
Mary Stenson - Mayo Clinic
Jithma Abeykoon - Mayo Clinic
Kevin Nowakowski - Mayo Clinic
Lianwen Zhang - Mayo Clinic
Joshua Lawson - Mayo Clinic
Linda Wellik - Mayo Clinic
Ying Li - Mayo Clinic
Jordan Krull - Mayo Clinic
Kerstin Wenzl - Mayo Clinic
Anne J Novak - Mayo Clinic
Stephen M Ansell - Mayo Clinic
Gail A Bishop - University of Iowa
Daniel D Billadeau - Mayo Clinic
Kah Whye Peng - Mayo Clinic
Francis Giles
Daniel M Schmitt
Thomas E Witzig - Mayo Clinic
Resource Type: Journal article
Publication Details: Blood, Vol.134(4), pp.363-373
DOI: 10.1182/blood.2018874560
PMID: 31101621
PMCID: PMC6659256
NLM abbreviation: Blood
ISSN: 0006-4971
eISSN: 1528-0020
Grant note: P30 ES005605 / NIEHS NIH HHS P20 CA102701 / NCI NIH HHS T32 AI007425 / NIAID NIH HHS P30 CA086862 / NCI NIH HHS P50 CA102701 / NCI NIH HHS P50 CA097274 / NCI NIH HHS
Language: English
Date published: 07/25/2019
Academic Unit: Microbiology and Immunology; President; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984297434002771

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