IFN-γ enhances CLL cell resistance to ABT-199 by regulating MCL-1 and BCL-2 expression via the JAK-STAT3 signaling pathway

• Published in: Leukemia & lymphoma Vol. 64; no. 1; pp. 71 - 78
• Main Authors: Shao, Xiaoya, Meng, Xueqiong, Yang, Haiping, Wang, Xinxin, Qin, Ling, Shen, Guomin, Xi, Xiaoping, Zhao, Huijuan, Macip, Salvador, Chen, Yixiang
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.01.2023
• Subjects: ABT-199; Apoptosis; Biphenyl Compounds - pharmacology; Cell Line, Tumor; CLL; combination; Drug Resistance, Neoplasm; Humans; IFN-γ; Interferon-gamma - metabolism; Interferon-gamma - pharmacology; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Neoplasm Recurrence, Local; Nitrophenols - pharmacology; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; resistance; Signal Transduction; STAT3 Transcription Factor - metabolism; CLL; IFN-γ; ABT-199; resistance; combination
• ISSN: 1042-8194; 1029-2403
• DOI: 10.1080/10428194.2022.2131408

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.