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

Abstract

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.

Keywords:

• CLL
• IFN-γ
• ABT-199
• resistance
• combination

Author contributions

XS was responsible for design of the work, acquired the majority of the data and drafted the manuscript. XM, PY and XW contributed to data acquisition. LQ, GS, XX and HZ contributed to resource acquisition and data analysis. YC and SM contributed to the conception of the project, interpretation of the data and writing of the manuscript. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

YC was supported of Henan University of Science and Technology by University funding #13480048. XM was funded of Henan University of Science and Technology by University funding #13480052. Work in SM’s laboratory was supported by the M.C. Andreu Memorial Fund.