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IFN-γ promotes CLL cells survival by regulating complex signal networks.docx (853.47 kB)

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

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journal contribution
posted on 2024-02-22, 12:08 authored by Y Chen, X Shao, H Yang, L Ren, Y Cui, W Zhang, S Macip, X Meng

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.

Funding

Henan University of Science and Technology funding #13480048 and #13480052

the Key Project of Science and Technology in Henan Province #222102310300 and 22A310014

the M.C. Andreu Memorial Fund

History

Alternative title

IFN-γ promotes CLL cells survival by regulating a complex signal network

Author affiliation

College of Life Sciences/Molecular & Cell Biology

Version

  • AM (Accepted Manuscript)

Published in

European Journal of Haematology

Volume

110

Issue

4

Pagination

435 - 443

Publisher

Wiley

issn

0902-4441

eissn

1600-0609

Copyright date

2022

Available date

2024-02-22

Spatial coverage

England

Language

eng

Deposited by

Professor Salvador Macip Maresma

Deposit date

2024-02-12

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