癌症研究
车站3
鲁索利替尼
信号转导
细胞凋亡
JAK-STAT信号通路
威尼斯人
细胞因子
生物
化学
免疫学
慢性淋巴细胞白血病
白血病
细胞生物学
酪氨酸激酶
骨髓
生物化学
骨髓纤维化
作者
Xiaoya Shao,Xueqiong Meng,Haiping Yang,Xinxin Wang,Qin Ling,Guomin Shen,Xiaoping Xi,Huijuan Zhao,Salvador Macip,Yixiang Chen
标识
DOI:10.1080/10428194.2022.2131408
摘要
Although clinical outcomes of CLL have improved with the use of BCL-2 inhibitor, ABT-199, acquired resistance eventually occurs in many cases, which leads to CLL disease progression. Thus, understanding the mechanisms that mediate this relapse is important to design improved therapies. Herein, we report that cytokine IFN-γ, secreted by dysfunctional T cells, enhanced CLL cells resistance to ABT-199. IFN-γ stimulation significantly increased the expression of BCL-2, MCL-1 and BCL-xL. Blocking JAK1/2-STAT3 signaling pathway impaired the expression of these anti-apoptotic proteins after IFN-γ stimulation. The combination of ABT-199 with JAK1/2 inhibitor Ruxolitinib or STAT3 inhibitors Stattic and C188-9 increased malignant B cell death. In summary, we show that IFN-γ enhanced CLL cells resistance to ABT-199 at least in part by up-regulating BCL-2, MCL-1 and BCL-xL expression via JAK1/2-STAT3 pathway, and thus blocking this pathway with inhibitors increased ABT-199 efficiency to induce CLL cell apoptosis, suggesting a potential therapeutically relevant combination to overcome ABT-199 resistance.
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