Peripheral T-cell lymphomas (PTCLs) are heterogeneous malignancies that are types of non-Hodgkin lymphomas; patients with this disease have poor prognoses. The IL-2-inducible T-cell kinase-spleen tyrosine kinase (ITK-SYK) fusion gene, the first recurrent chromosome translocation in PTCL‑not otherwise specified (NOS), can drive cellular transformation and the development of T-cell lymphoma in mouse models. The aim of the current study was to investigate the signal transduction pathways downstream of ITK-SYK. The authors constructed a lentiviral vector to overexpress the ITK-SYK fusion gene in Jurkat cells. By using Signal-Net and cluster analyses of microarray data, the authors identified the tyrosine-protein kinase JAK (JAK)3/STAT5 signalling pathway as a downstream pathway of ITK-SYK, activation of which mediates the effects of ITK-SYK on tumourigenesis. JAK3-selective inhibitor tofacitinib abrogated the phosphorylation of downstream signalling molecule STAT5, supressed cell growth, induced cell apoptosis and arrested the cell cycle at the G1/S phase in ITK-SYK+ Jurkat cells. In a xenograft mouse model, tumour growth was significantly delayed by tofacitinib. Since JAK3 associates with interleukin-2 receptor subunit γ (IL2RG) only, siRNA‑specific knockdown of IL2RG showed the same effect as tofacitinib treatment in vitro. These results first demonstrated that the activation of the IL2RG/JAK3/STAT5 signalling pathway contributed greatly to the oncogenic progress regulated by ITK-SYK, supporting further investigation of JAK3 inhibitors for the treatment of PTCLs carrying the ITK-SYK fusion gene.
CITATION STYLE
Zhang, L. L., Pan, H. X., Wang, Y. X., Guo, T., & Liu, L. (2019). Genome profiling revealed the activation of IL2RG/JAK3/STAT5 in peripheral T‑cell lymphoma expressing the ITK‑SYK fusion gene. International Journal of Oncology, 55(5), 1077–1089. https://doi.org/10.3892/ijo.2019.4882
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