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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article looks at a study which evaluate the effects of MEK inhibitors (MEKi) on chronic lymphocytic leukaemia (CLL) to explore novel therapeutic opportunities for B-cell malignancies. It mentions combination of MEKi and phosphoinositide 3-kinase (PI3K) inhibitors antagonized this effect and induced cell death and viability of SIG-M5, an acute myeloid leukaemia cell line with a BRAF mutation. It also mentions interleukin 4 (IL4) to mimic the microenvironment of proliferation.