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Inhibition of Syk protein tyrosine kinase induces apoptosis and blocks proliferation in T-cell non-Hodgkin's lymphoma cell lines

Leukemia volume 24, pages 229–232 (2010)Cite this article

Peripheral T-cell lymphomas (PTCLs) are among the most aggressive of all lymphomas and are associated with a poor prognosis compared with aggressive B-cell lymphomas. Therefore, novel targeted therapies are needed. Syk is a protein tyrosine kinase involved in B-cell receptor signaling in both normal and malignant B cells.1 Syk activation in B-cell lymphomas is associated with cell growth and survival, and an orally available Syk inhibitor is currently being tested for B-cell lymphomas in a phase I/II clinical trial, with encouraging results.2 Normal T lymphocytes lack Syk expression and use a Syk homolog, Zap-70, in receptor signaling. However, we recently showed that Syk protein is aberrantly expressed in the majority of PTCLs.3 The functional role of Syk in PTCL is currently unknown. Herein, we show that silencing Syk induces apoptosis and blocks proliferation in PTCL cells. These findings suggest that Syk represents a novel therapeutic target for patients with PTCL.

As siRNA-based inhibition of therapeutic targets is difficult to achieve clinically, we determined whether a Syk inhibitor currently in clinical trial, R406,2 would recapitulate the functional effects of Syk siRNA in PTCL cells. As expected, R406 led to dephosphorylation of Syk in both SU-DHL-1 and SR-786 (Figure 2d). Furthermore, R406 significantly inhibited cell proliferation in a dose-dependent manner (Figure 2e), and induced cell death in both lines (Figure 2f). The approximately 30% reduction in cell viability observed was comparable to that observed (range 20–70%) in the diffuse large B-cell lymphoma lines tested (for example, DHL6, Ly3). These effects were not because of inhibition of the Syk homolog, Zap-70, as SU-DHL-1 lacks Zap-70 expression (data not shown). R406 treatment of NPM-ALK+ (and Syk−) Karpas 299 cells failed to inhibit phosphorylation of AKT and ERK 1/2 or inhibit the expression of CD274, all of which are downstream of NPM-ALK (data not shown). In addition, R406 failed to downregulate CD274 in SR-786 or SU-DHL-1 cells. Therefore, the effects observed with R406 treatment are unlikely because of the inhibition of NPM-ALK.

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Acknowledgements

This research was supported in part by the Public Health Service Grant number P50 CA097274 from the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (UI/MC Lymphoma SPORE) and the National Cancer Institute.

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  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    R A Wilcox, A Novak & S M Ansell

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    D X Sun, A Dogan & A L Feldman

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Correspondence to A L Feldman.

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Wilcox, R., Sun, D., Novak, A. et al. Inhibition of Syk protein tyrosine kinase induces apoptosis and blocks proliferation in T-cell non-Hodgkin's lymphoma cell lines. Leukemia 24, 229–232 (2010). https://doi.org/10.1038/leu.2009.198

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