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

Xiaoya Shao1,2, Xueqiong Meng1, Haiping Yang3

  • 1School of Basic Medical Science, Henan University of Science and Technology, Luoyang, China.

Leukemia & Lymphoma
|October 12, 2022
PubMed

Insights

Cytokine IFN-γ from dysfunctional T cells boosts resistance to BCL-2 inhibitor ABT-199 in chronic lymphocytic leukemia (CLL). Blocking the JAK1/2-STAT3 pathway with inhibitors enhances ABT-199 efficacy against CLL cells.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Chronic lymphocytic leukemia (CLL) treatment improved with BCL-2 inhibitors like ABT-199.
  • Acquired resistance to ABT-199 is a significant cause of CLL progression.
  • Understanding resistance mechanisms is crucial for developing more effective therapies.

Purpose of the Study:

  • To investigate the role of cytokine Interferon-gamma (IFN-γ) in mediating ABT-199 resistance in CLL.
  • To identify the signaling pathways involved in IFN-γ-induced resistance.
  • To evaluate combination therapies targeting resistance mechanisms.

Main Methods:

  • Exposure of CLL cells to IFN-γ and ABT-199.
  • Assessment of anti-apoptotic protein expression (BCL-2, MCL-1, BCL-xL).
  • Inhibition of JAK1/2-STAT3 signaling pathway and evaluation of its effect on resistance.
  • Combination treatment with ABT-199 and JAK1/2 or STAT3 inhibitors.

Main Results:

  • IFN-γ stimulation significantly increased CLL cell resistance to ABT-199.
  • IFN-γ up-regulated the expression of anti-apoptotic proteins BCL-2, MCL-1, and BCL-xL.
  • Inhibition of the JAK1/2-STAT3 pathway diminished IFN-γ-induced expression of these proteins.
  • Combination therapy with ABT-199 and JAK1/2 or STAT3 inhibitors enhanced malignant B cell death.

Conclusions:

  • IFN-γ contributes to ABT-199 resistance in CLL by up-regulating BCL-2, MCL-1, and BCL-xL via the JAK1/2-STAT3 pathway.
  • Blocking this pathway increases the effectiveness of ABT-199 in inducing CLL cell apoptosis.
  • Targeting the JAK1/2-STAT3 pathway presents a potential therapeutic strategy to overcome ABT-199 resistance in CLL.
Keywords:
ABT-199CLLIFN-γcombinationresistance

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