Aberrant SYK Expression As a Potential Therapeutic Target in T/NK Cell Neoplasms

Background:

During T cell development spleen tyrosine kinase (SYK) is highly expressed at pre-TCR signaling stages, and gradually becomes undetectable at the mature stage. We have previously reported aberrant expression of SYK in peripheral T-cell lymphoma (PTCL). Additionally, ITK-SYK fusion protein detected in a subset of PTCL, mimics a constitutively active TCR signal and drives oncogenesis in mouse models of PTCL. Multiple SYK inhibitors are currently under active investigation in clinical trials for patients with B cell lymphoma and acute myeloid leukemia, and show promising results. Multiparameter flow cytometry can quantitate protein levels at single cell resolution in immunophenotypically defined neoplastic populations. In this study, we employ multiparameter flow cytometry to quantitate the SYK expression in T and NK cell malignancies and to guide the clinical trial design and as potential tool to evaluate the therapeutic responses.

Methods:

Patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), T-cell large granular lymphocyte leukemia (T-LGL), HTLV-1+ adult T-cell leukemia/lymphoma (ATLL), T-cell prolymphocytic leukemia (T-PLL), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), mixed phenotype acute leukemia (MPAL) and natural killer cell large granular lymphocyte leukemia (NK-LGL) were included.

Abnormal samples included the peripheral blood (46 cases), bone marrow aspirates (10 cases) or tissue (9 cases) from 65 patients diagnosed with T or NK cell malignancies, including AITL (8 cases), ATLL (5 cases), ALCL (2 cases), CTCL (25 cases), PTCL-NOS (5 cases), T-PLL (7 cases), T-LGL (7 cases), NK-LGL (1 case), MEITL (1 case), MAPL (3 cases) and T-ALL (1 case).

Normal controls included peripheral blood from healthy donors (15 cases), or patient derived- peripheral blood (6 cases), bone marrow aspirates (13 cases) and lymph node (16 cases) with diagnostic normal immunophenotype.

Results:

SYK was highly expressed in all the B and most NK cells from peripheral blood, bone marrow and lymph node of normal controls and there was no difference in the percentage of positive cells or intensity of staining in different specimen types.

In normal T cell subsets SYK was expressed in a small proportion of T cells and at very low level. Only 3.9% (95% CI: 3.3% - 6.3%) of the CD4+ T cells from peripheral blood, 2.6% (1.5% - 6.6%) from bone marrow, and 1.9% (1.4% - 5.8%) from lymph node were positive for SYK. Similar to CD4+ T cells, SYK was expressed in 5.4% (95% CI: 4.3% - 7.8%) of the CD8+ T cells from peripheral blood. These data suggest SYK expression is nearly undetectable in the normal mature T cells which are part of adaptive immunity. In contrast, lymphoid cells of innate immunity such as NK cells express high levels of SYK.

Similar to normal T-cell subsets, the neoplastic T-cells of most PTCL believed to originate from cells of adaptive immunity (AITL, ATLL, ALCL, CTCL, PTCL-NOS and T-PLL) showed low levels of SYK expression (median: 5.8%; 95% CI: 5.8% -10.4%) with rare exceptions (Figure 1). In contrast, the T and NK cell neoplasms of innate immunity origin (NK-LGL, MEITL) and immature precursor T-cell origin (MPAL and T-ALL) showed high levels of SYK expression (median 91.1%, 95% CI as 97.1% - 99.6%). SYK expression in T-LGL was more modest and variable (median 43.6%, 95% CI as 43.6% - 78.0% (Figure 1).

Conclusion: SYK is highly expressed in the neoplastic lymphoid cells of innate immunity such as NK-LGL, MEITL and T-LGL cases, and immature hematopoietic neoplasms with T-cell differentiation. The expression of SYK in neoplastic cells from patients with mature T cell lymphoma of adaptive immunity remains low. Given the significant physiological role of SYK in innate immunity, SYK expression in NK/T-cell neoplasms is likely to have an oncogenic role, suggesting that SYK might be a good therapy target for these tumors.

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