The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma

Abstract

Peripheral T cell lymphomas (PTCLs) are highly aggressive malignancies with poor prognosis. Their molecular pathogenesis is not well understood and small animal models for the disease are lacking. Recently, the chromosomal translocation t(5;9)(q33;q22) generating the interleukin-2 (IL-2)–inducible T cell kinase (ITK)–spleen tyrosine kinase (SYK) fusion tyrosine kinase was identified as a recurrent event in PTCL. We show that ITK-SYK associates constitutively with lipid rafts in T cells and triggers antigen-independent phosphorylation of T cell receptor (TCR)–proximal proteins. These events lead to activation of downstream pathways and acute cellular outcomes that correspond to regular TCR ligation, including up-regulation of CD69 or production of IL-2 in vitro or deletion of thymocytes and activation of peripheral T cells in vivo. Ultimately, conditional expression of patient-derived ITK-SYK in mice induces highly malignant PTCLs with 100% penetrance that resemble the human disease. Our work demonstrates that constitutively enforced antigen receptor signaling can, in principle, act as a powerful oncogenic driver. Moreover, we establish a robust clinically relevant and genetically tractable model of human PTCL.

T-cell Receptor Signaling Activates an ITK/NF-κB/GATA-3 axis in T-cell Lymphomas Facilitating Resistance to Chemotherapy

“…In the current study, antibody-mediated cross-linking of the TCR was utilized, and in contrast to “tonic” signaling, more closely resembles TCR activation by high-affinity antigenic peptides leading to “active” TCR signaling. Recurrent genomic alterations in the TCL, including the loss of negative feedback mechanisms or gain of positive regulators, may lower the threshold for TCR activation, and thus potentiate low affinity interactions with peptide/MHC normally associated with “tonic” signaling(47–52). While previous observational studies demonstrating biased usage of specific TCR-Vβ chains implicate the TCR in disease pathogenesis(40, 41), most TCL are not associated with T-cell mediated autoimmunity or chronic infections.…”

A three‐signal model of T‐cell lymphoma pathogenesis

“…This translocation, observed in ≈20% of PTCL, NOS(25), fuses the pleckstrin homology and Tec homology domains of ITK with the SYK kinase domain, producing a catalytically active fusion protein that phosphorylates SLP-76, LAT, PLC-γ1, and endogenous (wildtype) SYK. The ITK-SYK fusion initiates a signaling cascade that mimics TCR-mediated signaling(26, 27), but is not dependent upon SRC family kinases for its activation(26). Optimal signaling requires the downstream adaptor SLP-76 and SYK (or ZAP-70); however, the requirement for endogenous SYK was independent from its kinase activity.…”

“…Optimal signaling requires the downstream adaptor SLP-76 and SYK (or ZAP-70); however, the requirement for endogenous SYK was independent from its kinase activity. This novel fusion is oncogenic, as its transgenic expression in mice leads to a lymphoproliferative disorder resembling human PTCL(27–29). While SYK is more highly expressed in B cells when compared with conventional T cells, it is highly expressed in the majority (>90%) of PTCLs (30), including those lacking an ITK-SYK fusion.…”

SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia

“…SYK -targeting shRNA induced AML cell differentiation in vitro , and SYK inhibition was shown to have anti-leukemia activity in AML mouse models. SYK is a cytoplasmic tyrosine kinase critical in normal B-cell development and hematopoietic signaling (Mocsai et al, 2010) recently found to be aberrantly activated through translocations in T-cell lymphoma ( ITK-SYK ) (Pechloff et al, 2010) and myelodysplastic syndrome (MDS) ( TEL-SYK ) (Kuno et al, 2001). Thus far, however, next-generation sequencing efforts have failed to identify frequent mutational events in SYK in AML, or in B-cell malignancies, where SYK dependency has also been demonstrated.…”