BAX as the mediator of C-MYC sensitizes acute lymphoblastic leukemia to TLR9 agonists

Ling Bai; Lei Zhou; Wei Han; Jingtao Chen; Xiaoyi Gu; Zheng Hu; Yongguang Yang; Wei Li; Xiaoying Zhang; Chao Niu; Yongchong Chen; Hui Li; Jiuwei Cui

doi:10.1186/s12967-023-03969-z

BAX as the mediator of C-MYC sensitizes acute lymphoblastic leukemia to TLR9 agonists

J Transl Med. 2023 Feb 10;21(1):108. doi: 10.1186/s12967-023-03969-z.

Authors

Ling Bai¹, Lei Zhou¹, Wei Han¹, Jingtao Chen², Xiaoyi Gu^{1

2

3}, Zheng Hu^{2

3}, Yongguang Yang^{2

3}, Wei Li¹, Xiaoying Zhang¹, Chao Niu¹, Yongchong Chen¹, Hui Li¹, Jiuwei Cui⁴

Affiliations

¹ Cancer Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, 130021, China.
² Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, China.
³ International Center of Future Science, Jilin University, Changchun, 130021, China.
⁴ Cancer Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, 130021, China. cuijw@jlu.edu.cn.

Abstract

Background: The prognosis of B-cell acute lymphoblastic leukemia (B-ALL) has improved significantly with current first-line therapy, although the recurrence of B-ALL is still a problem. Toll-like receptor 9 (TLR9) agonists have shown good safety and efficiency as immune adjuvants. Apart from their immune regulatory effect, the direct effect of TLR9 agonists on cancer cells with TLR9 expression cannot be ignored. However, the direct effect of TLR9 agonists on B-ALL remains unknown.

Methods: We discussed the relationship between TLR9 expression and the clinical characteristics of B-ALL and explored whether CpG 685 exerts direct apoptotic effect on B-ALL without inhibiting normal B-cell function. By using western blot, co-immunoprecipitation, immunofluorescence co-localization, and chromatin immunoprecipitation, we explored the mechanism of the apoptosis-inducing effect of CpG 685 in treating B-ALL cells. By exploring the mechanism of CpG 685 on B-ALL, the predictive biomarkers of the efficacy of CpG 685 in treating B-ALL were explored. These efficiencies were also confirmed in mouse model as well as clinical samples.

Results: High expression of TLR9 in B-ALL patients showed good prognosis. C-MYC-induced BAX activation was the key to the effect of CpG oligodeoxynucleotides against B-ALL. C-MYC overexpression promoted P53 stabilization, enhanced Bcl-2 associated X-protein (BAX) activation, and mediated transcription of the BAX gene. Moreover, combination therapy using CpG 685 and imatinib, a BCR-ABL kinase inhibitor, could reverse resistance to CpG 685 or imatinib alone by promoting BAX activation and overcoming BCR-ABL1-independent PI3K/AKT activation.

Conclusion: TLR9 is not only a prognostic biomarker but also a potential target for B-ALL therapy. CpG 685 monotherapy might be applicable to Ph^- B-ALL patients with C-MYC overexpression and without BAX deletion. CpG 685 may also serve as an effective combinational therapy against Ph⁺ B-ALL.

Keywords: Apoptosis; B-cell acute lymphoblastic leukemia; BAX; CpG oligodeoxynucleotide; Toll-like receptor 9.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Imatinib Mesylate / pharmacology
Imatinib Mesylate / therapeutic use
Mice
Oligodeoxyribonucleotides / pharmacology
Oligodeoxyribonucleotides / therapeutic use
Phosphatidylinositol 3-Kinases
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
Toll-Like Receptor 9* / agonists
Toll-Like Receptor 9* / genetics
Toll-Like Receptor 9* / metabolism
bcl-2-Associated X Protein / metabolism

Substances

bcl-2-Associated X Protein
Imatinib Mesylate
Toll-Like Receptor 9
Phosphatidylinositol 3-Kinases
Oligodeoxyribonucleotides
Tlr9 protein, mouse