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Overexpression of Syk Tyrosine Kinase in Peripheral T-Cell Lymphomas

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Overexpression of Syk Tyrosine Kinase in Peripheral T-Cell Lymphomas Leukemia (2008) 22, 1139–1143 & 2008 Nature Publishing Group All rights reserved 0887-6924/08 $30.00 www.nature.com/leu ORIGINAL ARTICLE Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas AL Feldman1, DX Sun1, ME Law1, AJ Novak2, AD Attygalle3, EC Thorland1, SR Fink1, JA Vrana1, BL Caron1, WG Morice1, ED Remstein1, KL Grogg1, PJ Kurtin1, WR Macon1 and A Dogan1 1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; 2Department of Hematology, Mayo Clinic, Rochester, MN, USA and 3Department of Histopathology, Royal Marsden Hospital, London, UK Peripheral T-cell lymphomas (PTCLs) are fatal in the majority of Materials and methods patients and novel treatments, such as protein tyrosine kinase (PTK) inhibition, are needed. The recent finding of SYK/ITK translocations in rare PTCLs led us to examine the expression Cases of Syk PTK in 141 PTCLs. Syk was positive by immuno- We studied specimens from 141 patients with PTCL diagnosed 15 histochemistry (IHC) in 133 PTCLs (94%), whereas normal by WHO criteria. There were 86 men and 55 women of a T cells were negative. Western blot on frozen tissue (n ¼ 6) mean age of 59 years (range, 5–88 years). The study was and flow cytometry on cell suspensions (n ¼ 4) correlated with approved by the Institutional Review Board and the Biospeci- IHC results in paraffin. Additionally, western blot demonstrated mens Committee of Mayo Clinic. All patients provided informed that Syk-positive PTCLs show tyrosine (525/526) phosphory- lation, known to be required for Syk activation. Fluorescence consent for the use of their tissues for research purposes. in situ hybridization showed no SYK/ITK translocation in 86 cases. Overexpression of Syk, phosphorylation of its Y525/526 residues and the availability of orally available Syk inhibitors suggest that Syk merits further evaluation as a Immunohistochemistry candidate target for pharmacologic PTK inhibition in patients Paraffin tissue microarrays were constructed as described with PTCL. previously.16 In cases with insufficient tissue, whole-tissue Leukemia (2008) 22, 1139–1143; doi:10.1038/leu.2008.77; sections were analyzed. Slides were pretreated in 1 mM EDTA published online 10 April 2008 buffer at pH 8.0 for 30 min at 98 1C (PT Module; Lab Vision, Keywords: peripheral T-cell lymphoma; Syk; tyrosine kinase; Fremont, CA, USA) and then stained for Syk with a rabbit phosphorylation polyclonal antibody (C-20, 1:50; Santa Cruz Biotechnology, Santa Cruz, CA, USA). Dual Link Envision þ /DAB þ (Dako, Carpinteria, CA, USA) was used for detection. Tumors were considered positive for Syk when 430% of the neoplastic cells demonstrated Syk staining. Slides were visualized through an Introduction Olympus BX51 microscope (Olympus, Melville, NY, USA) and photographed with an Olympus DP71 camera using Olympus Peripheral T-cell lymphomas (PTCLs) remain a major DP manager image acquisition software. treatment problem among all lymphomas because of their high mortality rate and the minimal effectiveness of conven- tional chemotherapy.1 Novel therapeutic strategies, such as inhibiting protein tyrosine kinases (PTKs), might improve Western blotting the outlook toward the treatment of patients with PTCL. Protein lysates prepared from frozen tissue sections of six PTCLs Recently, a t(5;9)(q33;q22) translocation2 was reported in a and from the B-cell lymphoma cell line, Raji, were separated by subgroup of PTCL with follicular involvement,3 resulting polyacrylamide gel (Bio-Rad, Hercules, CA, USA) electrophor- in overexpression of the SYK gene under the control of the esis, transferred to PVDF membranes (Bio-Rad) and incubated ITK promoter. SYK encodes a cytoplasmic PTK, which is for 1 h with primary antibodies as follows: Syk (1:500; N-19, important in proliferation and prosurvival signaling4–7 and is Santa Cruz), phospho-Syk (Tyr525/526, 1:1000; no. 2711, Cell expressed in a variety of hematopoietic cells, including Signaling Technology, Danvers, MA, USA) and actin (1:1000; normal B lymphocytes8 and most B-cell lymphomas.5,9–12 C-11, Santa Cruz). Normal peripheral T cells, however, generally lack Syk protein expression.13 In the current work, we demonstrate that Syk is overexpressed Flow cytometric immunophenotyping in the majority of PTCLs, despite the absence of SYK/ITK Flow cytometric immunophenotyping was performed on translocations in most cases. As one orally available Syk 17 thawed, washed cells as described previously. Briefly, cells inhibitor14 is already in clinical trial for B-cell lymphomas, were stained with fluorochrome-conjugated antibodies (Becton Syk merits further evaluation as a possible therapeutic target in Dickinson/Pharmingen, San Jose, CA, USA) to CD3 (peridinin patients with PTCL as well. chlorophyll protein), CD5 (phycoerythrin) and CD19 (PE-Cy7). Stained cells were washed, fixed and permeabilized (Caltag Fix Correspondence: Dr AL Feldman, Department of Laboratory Medicine and Perm; Caltag/Invitrogen, Eugene, OR, USA) and then and Pathology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, stained with anti-Syk (fluorescein isothiocyanate). Cells were USA. E-mail: [email protected] analyzed on a FACSCanto instrument (Becton Dickinson) Received 3 January 2008; revised 11 February 2008; accepted 29 and data were analyzed using FACSDiva Software (Becton February 2008; published online 10 April 2008 Dickinson). Syk expression in PTCLs AL Feldman et al 1140 Fluorescence in situ hybridization evaluated cases using D-FISH probes for SYK and ITK. Despite Interphase fluorescence in situ hybridization (FISH) was appropriate fusion signals in control tissue with the translocation performed on tissue microarray or whole-tissue sections as (not shown), no evidence of t(5;9)(q33;q22) was identified in 86 described previously,16 using dual fusion (D-FISH) Spectrum- informative study cases of PTCL (84 of which were positive for Orange- and SpectrumGreen-labeled DNA probes that hybri- Syk by IHC). These 86 cases included 23 AITLs, 38 PTCL-Us, 13 dize to regions spanning the SYK and ITK breakpoints involved ALCLs and 12 other cases, a distribution similar to that in the in the t(5;9)(q33;q22) translocation. A minimum of 50 cells were overall study set. Additional copies of SYK (3–6 signals) were scored per case. Control material carrying the translocation was identified in only four cases, including two ALK-negative ALCLs kindly provided by Dr B Streubel (Vienna, Austria). (both Syk protein-positive by IHC) and two PTCL-Us (one Syk- positive and one Syk-negative). The FISH probes used did not allow distinction between gene amplification and polysomy as Results and discussion the cause for additional SYK signals. None of the cases studied had the characteristic features of PTCLs with follicular involve- We evaluated Syk expression in reactive and neoplastic T cells ment described by de Leval et al.,3 which were seen in 3/5 by immunohistochemistry (IHC) using a polyclonal antibody previously reported cases with SYK/ITK translocation.2 Based on against the C terminus of Syk. Although T cells in reactive tonsil, our findings, translocations or additional copies of SYK do not lymph node and spleen were negative (Figure 1a), IHC appear to be the mechanisms leading to Syk protein over- demonstrated cytoplasmic Syk expression in 133/141 (93%) expression in most Syk-positive PTCLs. PTCLs studied. These included 35/35 (100%) AITLs (angioim- Syk has been suggested as a potential therapeutic target for munoblastic T-cell lymphomas; Figure 1b), 62/66 (94%) PTCL- PTCL by Mahadevan et al.,19 but previous data on Syk Us (PTCLs, unspecified; Figure 1c), 6/6 (100%) anaplastic expression in T-cell lymphomas are limited and somewhat lymphoma kinase (ALK)-positive anaplastic large-cell lympho- conflicting. A small study found Syk in only 2/19 PTCLs by IHC, mas (ALCLs), 11/12 (92%) systemic ALK-negative ALCLs (Figures including 1/8 PTCL-U and 1/1 mycosis fungoid (weak staining).10 1d and e), 3/3 (100%) cutaneous ALCLs, 4/4 (100%) mycosis The higher positivity rate found by us might be due to fungoides (nodal involvement), 1/2 (50%) enteropathy-asso- differences in the antibodies used, or due to unknown ciated T-cell lymphoma, 4/5 (80%) extranodal NK/T-cell differences in the patient populations studied. Syk expression lymphomas, nasal type (NKTLs) 4/5 (80%) hepatosplenic T-cell and Syk kinase activity have been reported to be decreased in lymphomas (Figure 1f), 2/2 (100%) subcutaneous panniculitis- lysates of cutaneous T-cell lymphoma cells isolated from like T-cell lymphomas and 1/1 (100%) T-prolymphocytic peripheral blood (n ¼ 4),18 a source not evaluated in our study. leukemia. All eight Syk-negative cases were extranodal, inclu- This difference in site might account for our finding that Syk was ding ALK-negative ALCLs (Figure 1d), enteropathy-associated expressed in 4/4 cases of lymph node involvement by mycosis T-cell lymphomas, hepatosplenic T-cell lymphomas (Figure 1e), fungoides. Other previous studies have shown Syk overexpres- NKTLs and PTCL-Us (four cases). Seven of these had a cytotoxic sion in SYK-translocated cases,2 Syk upregulation in adult T-cell phenotype by IHC. leukemia/lymphoma cell lines20 and a relative increase in SYK Because Syk expression was found in a greater proportion of expression in ALK-positive ALCLs.21 PTCLs than previously reported,10 we corroborated the IHC Several comments regarding the interpretation of our findings results using western blotting. Reactive splenic lymphocytes are warranted. First, IHC of reactive lymphoid tissue showed were sorted by flow cytometry into B-cell, ab T-cell and gd Syk-positive cells to outnumber CD20-positive cells in the T-cell populations. B-cell lysates demonstrated a 72 kDa band paracortex (Figure 1a). Most lymphocytes appeared negative for corresponding to Syk, whereas T-cell lysates were negative Syk. By morphology and distribution, many of the positive cells (Figure 2a).
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