Format

Send to

Choose Destination
Blood. 2019 May 17. pii: blood.2018874560. doi: 10.1182/blood.2018874560. [Epub ahead of print]

Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma.

Author information

1
Hematology, Mayo Clinic, United States.
2
Hematology Research, Mayo Clinic, United States.
3
Internal Medicine, Mayo Clinic, Rochester, MN, United States.
4
Mayo Clinic, United States.
5
Division of Hematology, Mayo Clinic College of Medicine, United States.
6
Division of Hematology and Internal Medicine, Mayo Clinic, United States.
7
College of Medicine, University of Iowa, United States.
8
Immunology, Mayo Clinic College of Medicine, United States.
9
Department of Molecular Medicine, Mayo Clinic, United States.
10
DT, Developmental Therapeutics Consortium, United States.
11
Actuate Therapeutics Inc, United States.
12
Department of Hematology, Mayo Clinic, United States witzig.thomas@mayo.edu.

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.

PMID:
31101621
DOI:
10.1182/blood.2018874560

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center