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

Abstract

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.

Pivotal factors associated with the immunosuppressive tumor microenvironment and melanoma metastasis

“… 22 , 23 , 24 , 25 Comparable results are observed with Non‐Hodgkin's lymphoma, in which activation of IL2Rγ—JAK3—STAT5 signaling pathway significantly promotes cancer progression while knockdown of IL2Rγ garners the same effect as Tofacitinib, a JAK inhibitor that effectively inhibits the activity of JAK1 and JAK3. 26 , 27 Actually, Julianna Volkó et al found the assembly of IL2R may occur and exert its function in the cytoplasm, which is a probable factor in immunotherapy resistance, 28 as IL2Rβ and IL2Rγ could form ligand‐independent homodimerization and stimulate mutant JAK3‐STAT pathway. 29 However, there still exist no reports on whether IL2RG is abnormally expressed and what influence ectopic IL2RG expression levels may exert in melanoma.…”

Janus Kinase Signaling: Oncogenic Criminal of Lymphoid Cancers

“…In PTCL, as mentioned above, the JAK3/STAT5 signaling program was identified to be downstream of ITK/SYK via Signal Net and cluster analyses of microarray data. JAK3 selective inhibitor tofacitinib abrogated the phosphorylation of STAT5, suppressed cell growth, induced cell apoptosis and arrested the cell cycle at the G1/S phase [5]. As JAK3-activating mutation was frequent in NKTCL pathogenesis, the pan-JAK inhibitor Tofacitinib efficiently reduced phosphorylated STAT5 and cell viability in JAK3-mutant and wild-type NKTCL cell lines and mouse xenografts [19,24].…”

“…A double kinase fusion ITK-SYK was identified in PTLC, which drove cellular transformation and progression of this malignancy. Additionally, through microarray data analysis, JAK3/STAT5 activation was discovered as a downstream effect of ITK-SYK aberrance, and pharmacological inhibition of JAK3 abrogated STAT5 phosphorylation, suppressed cell survival and induced G1/S phase arrest [5].…”

“…In this article, we review activating mutations and fusions of JAKs that enhance JAK/STAT phosphorylation and lead to overexpression of STAT target oncogenes in a couple of lymphoid cancerous contexts, canonical JAK/STAT signaling and the nuclear role of JAKs that non-canonically bind to RNA polymerase II and phosphorylate histones [2] or chromatin modifiers [3,4]. We also summarize the effectiveness of JAK-targeting monotherapy and combinational therapy in curing lymphoid cancers, which induce programmed cell death and cell cycle arrest [5].…”

Mutations Affecting Genes in the Proximal T-Cell Receptor Signaling Pathway in Peripheral T-Cell Lymphoma

“…Most of the cases with ITK-SYK were later confirmed as Tfh like-PTCL [ 55 ]. ITK-SYK proteins were demonstrated in Jurkat cells to activate the IL2RG/JAK3/STAT5 signaling pathway, which was associated with the abundant secretion of IL-2 and IL-21 [ 56 ]. In a mouse model of ITK-SYK induced T-cell lymphoma, ITK-SYK was found to enhance the expression of PD-1 that subsequently attenuated the AKT and PKC activities in premalignant ITK-SYK expressing cells [ 57 ].…”