Interferon gamma regulates a complex pro-survival signal network in chronic lymphocytic leukemia

Eur J Haematol. 2023 Apr;110(4):435-443. doi: 10.1111/ejh.13921. Epub 2023 Jan 12.


Background: It is known that the microenvironmental cytokine interferon gamma (IFN-γ) provides a survival advantage for chronic lymphocytic leukemia (CLL) cells. However, the mechanisms involved in this effect have not been properly investigated.

Methods: Herein, we conducted a comprehensive screening of the effects of IFN-γ on signaling pathways and gene expression profiles in CLL cells by using western blotting, real-time quantitative reverse transcription (RT-qPCR) and high-throughput RNA sequencing (RNA-seq).

Results: We found that IFN-γ not only activated the pro-survival signal transducer and activator of transcription 3 (STAT3), but also activated the protein kinase B and extracellular signal-regulated kinase signaling pathways. RNA-seq analysis showed that IFN-γ stimulation changed the expression profiles of more than 500 genes, with 391 being up-regulated and 123 down-regulated. These genes are involved in numerous biological processes, including anti-apoptosis, cell migration, and proliferation. IFN-γ significantly up-regulated the expression of CD38, BCL6, CXCL9, BCL2A1, SCOS3, IL-10, HGF, EGFR, THBS-1, FN1, and MUC1, which encode proteins potentially associated with disease progression, worse prognosis or poor response to treatment. Blocking janus kinases1/2 (JAK1/2) or STAT3 signal by specific inhibitors affected the expression of most genes, suggesting a pivotal role of the JAK1/2-STAT3 pathway in IFN-γ pro-survival effects in CLL.

Conclusions: Our data demonstrate that IFN-γ regulates a complex pro-survival signal network in CLL through JAK1/2-STAT3, which provides a rational explanation for IFN-γ promoting CLL cells survival and drug resistance.

Keywords: CLL; IFN-γ; JAK1/2-STAT3 pathway; pro-survival.

MeSH terms

  • Cytokines / metabolism
  • Humans
  • Interferon-gamma* / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell* / metabolism
  • STAT3 Transcription Factor / metabolism
  • STAT3 Transcription Factor / pharmacology
  • Signal Transduction


  • Cytokines
  • Interferon-gamma
  • STAT3 Transcription Factor