BAX 作为 C-MYC 的介质使急性淋巴细胞白血病对 TLR9 激动剂敏感。
BAX as the mediator of C-MYC sensitizes acute lymphoblastic leukemia to TLR9 agonists.
机构信息
Cancer Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, 130021, China.
Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, China.
出版信息
J Transl Med. 2023 Feb 10;21(1):108. doi: 10.1186/s12967-023-03969-z.
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.
背景
尽管 B 细胞急性淋巴细胞白血病 (B-ALL) 的复发仍然是一个问题，但目前的一线治疗已经显著改善了 B-ALL 的预后。Toll 样受体 9 (TLR9) 激动剂作为免疫佐剂具有良好的安全性和效率。除了其免疫调节作用外，TLR9 激动剂对表达 TLR9 的癌细胞的直接作用也不容忽视。然而，TLR9 激动剂对 B-ALL 的直接作用尚不清楚。
方法
我们讨论了 TLR9 表达与 B-ALL 临床特征的关系，并探讨了 CpG 685 是否在不抑制正常 B 细胞功能的情况下对 B-ALL 具有直接凋亡作用。通过 Western blot、共免疫沉淀、免疫荧光共定位和染色质免疫沉淀，我们探讨了 CpG 685 诱导 B-ALL 细胞凋亡的作用机制。通过探讨 CpG 685 对 B-ALL 的作用机制，探讨了 CpG 685 治疗 B-ALL 疗效的预测生物标志物。这些效果在小鼠模型和临床样本中也得到了证实。
结果
B-ALL 患者中 TLR9 的高表达显示出良好的预后。C-MYC 诱导的 BAX 激活是 CpG 寡核苷酸对 B-ALL 作用的关键。C-MYC 过表达促进 P53 稳定，增强 Bcl-2 相关 X 蛋白 (BAX) 激活，并介导 BAX 基因的转录。此外，CpG 685 与 BCR-ABL 激酶抑制剂伊马替尼联合治疗可通过促进 BAX 激活和克服 BCR-ABL1 独立的 PI3K/AKT 激活来逆转 CpG 685 或伊马替尼单独耐药。
结论
TLR9 不仅是一个预后标志物，也是 B-ALL 治疗的潜在靶点。CpG 685 单药治疗可能适用于 C-MYC 过表达且无 BAX 缺失的 Ph B-ALL 患者。CpG 685 也可作为治疗 Ph B-ALL 的有效联合治疗药物。
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