LAUSR

BACKGROUND It is known that the microenvironmental cytokine IFN-γ provides a survival advantage for 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 profile in CLL cells by using western blotting, RT-qPCR and high-throughput RNA sequencing (RNA-seq). RESULTS We found that IFN-γ not only activated the pro-survival STAT3, but also activated the AKT and ERK 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 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 demonstrates 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. This article is protected by copyright. All rights reserved.