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Inhibition of acylglycerol kinase sensitizes DLBCL to venetoclax via upregulation of FOXO1-mediated BCL-2 expression

Lookup NU author(s): Dr Arian Laurence



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022 Ivyspring International Publisher. All rights reserved.Background: Despite of the paradigm change on the treatments of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) by venetoclax, it has been less successful in the treatment of diffuse large B-cell lymphoma (DLBCL). Here, we explored whether acylglycerol kinase regulates the sensitivity of DLBCLs to venetoclax and its mechanism in both cell lines and preclinical animal models. Methods: The expression of AGK and sensitivity to venetoclax of seven DLBCL cell lines were determined. Upon knockdown and overexpression of AGK by lentivirus in DLBCL cells, the venetoclax-induced apoptosis and PTEN-FOXO1-BCL-2 signaling axis were evaluated in vitro. The efficacy of venetoclax and PTEN-FOXO1-BCL-2 signaling axis were evaluated in immunodeficient NCG mice that were implanted with control or shAGK stably transduced SU-DHL4 cells. The expressions of AGK, BCL-2 and FOXO1 were evaluated in tumor tissues of DLBCL patients. Results: AGK expression was inversely correlated with sensitivity of DLBCL to venetoclax. Inhibition of AGK rendered the DLBCL cells more sensitive to venetoclax. Mechanistically, AGK phosphorylated and inactivated PTEN, which led to AKT activation and reduced FOXO1 nuclear translocation. Inhibition of AGK also led to enhanced efficacy of venetoclax for suppression of DLBCL tumor growth in vivo, which was dependent on FOXO1. In human DLBCL tumor tissues, the expression of AGK inversely correlated with BCL-2 expression, as well as the amounts of nuclear FOXO1. Conclusions: Our data demonstrated that AGK regulates venetoclax response in DLBCL via PTEN-FOXO1-BCL-2 signaling axis. Targeting AGK may enhance the efficacy of venetoclax for the treatment of DLBCL patients.

Publication metadata

Author(s): Ning N, Zhang S, Wu Q, Li X, Kuang D, Duan Y, Xia M, Liu H, Weng J, Ba H, Tang Z, Cheng X, Mei H, Huang L, Ao Q, Wang G, Hu Y, Laurence A, Wang J, Wang G, Yang X-P

Publication type: Article

Publication status: Published

Journal: Theranostics

Year: 2022

Volume: 12

Issue: 13

Pages: 5537-5550

Online publication date: 18/07/2022

Acceptance date: 18/05/2022

Date deposited: 15/08/2022

ISSN (electronic): 1838-7640

Publisher: Ivyspring International Publisher


DOI: 10.7150/thno.72786

PubMed id: 35910796


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