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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.

Genome profiling revealed the activation of IL2RG/JAK3/STAT5 in peripheral T‑cell lymphoma expressing the ITK‑SYK fusion gene