Fuses ITK to SYK in Unspecified Peripheral T-Cell Lymphoma

Novel t(5;9)(q33;q22) fuses ITK to SYK in unspeciﬁed peripheral T-cell lymphoma

B Streubel1, U Vinatzer2, M Willheim3, M Raderer4 and A Chott1

1Department of Pathology, Medical University of Vienna, Vienna, Austria; 2Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria; 3Department of Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria and 4Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria

Among peripheral T-cell lymphomas (PTCL), the heterogeneous according to the WHO classification. With the notable category of unspecified PTCL represents the most common exception of the t(2;5) and its variants in ALCL, however, no subtype. Nevertheless, recurrent chromosomal translocations recurrent chromosomal translocation has been reported to occur are unknown in this aggressive type of lymphoma. Here we 7–11 describe a novel t(5;9)(q33;q22) in unspecified PTCL. Molecular in PTCLs. This study describes the genetic and molecular analyses delineated the breakpoints to ITK and SYK resulting in features of a novel recurrent t(5;9) in a minority of U-PTCLs a previously undescribed expression of the Syk tyrosine kinase which, at least in part, share some histopathologic peculiarities. by Itk. ITK–SYK transcripts were detected in five of 30 (17%) unspecified PTCL, but not in cases of angioimmunoblastic T-cell lymphoma (n ¼ 9) and anaplastic lymphoma kinase- Materials and methods negative anaplastic large-cell lymphoma (n ¼ 7). In all five translocation-positive cases, the breakpoints were identical fusing the N-terminal pleckstrin homology domain and proline- Cases rich region of ITK to the tyrosine kinase domain of SYK. Three The study group comprised 46 PTCLs, which were classified of the five t(5;9)(q33;q22) þ unspecified PTCL shared a very according to the WHO classification into U-PTCLs (n ¼ 30), similar histological pattern with predominant involvement of AILT (n ¼ 9), and ALCL, anaplastic lymphoma kinase (ALK) lymphoid follicles and the same CD3 þ CD5 þ CD4 þ bcl- negative (n ¼ 7). Among the 30 U-PTCLs, eight cases were 6 þ CD10 þ immunophenotype. These results demonstrate the histologically consistent with PTCL with follicular involvement presence of a recurrent t(5;9)(q33;q22) in a subset of unspeci- 12 fied PTCL, which may represent a novel distinct subgroup of according to de Leval et al. and one additional case PTCL. represented a PTCL with perifollicular growth pattern according Leukemia (2006) 20, 313–318. doi:10.1038/sj.leu.2404045; to Ru¨diger et al.13 All samples used for the analysis were derived published online 8 December 2005 from the primary site of disease presentation. The presence of Keywords: lymphoma; T cell; chromosomal translocation; ITK; SYK tumor cells was evaluated in each tissue block on hematoxylin- and eosin-stained slides cut before and after the sections used for fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR). Introduction Immunohistochemistry In T-cell non-Hodgkin’s lymphoma, the WHO classification has Immunohistochemistry (IHC) on paraffin sections was per- defined a number of distinctive entities, which correspond to 14 formed in all cases as described elsewhere. The antibody recognizable subtypes of T-cell neoplasia.1 Among peripheral T- panel included bF1, CD3, CD2, CD5, CD7, CD4, CD8, TIA-1, cell lymphomas (PTCL) with primary nodal presentation, CD20, CD21, CD10, bcl-6 and MIB-1. In addition, the five angioimmunoblastic T-cell lymphoma (AILT) and anaplastic t(5;9)(q33;q22) þ cases, 11 t(5;9)(q33;q22)À T-cell lymphomas large-cell lymphoma (ALCL) are regarded as well-defined and five reactive lymph nodes were immunostained using entities. The various remaining PTCLs, which have been listed antibodies raised against the amino- and carboxy-terminal in the Kiel classification according to cell size and morphologic portions of Syk, respectively (Santa Cruz Biotechnology, Santa patterns, such as lymphoepithelioid or T-zone lymphoma,2 are Cruz, Ca, USA), and against phosphorylated (Thr180/Tyr182) grouped together as unspecified (U-) PTCLs, because patho- p38 MAP kinase, phosphorylated (Thr202/Tyr204) p44/42 MAP logists were not able to distinguish them reproducibly. These kinase and NF-kB p105/p50 (Cell Signaling, Beverly, MA, USA) tumors account for approximately half of the PTCLs in Western according to the manufacturer’s recommendations. countries.3–5 Clinically, most patients present with advanced stage and the disease belongs to the category of the most 4 aggressive non-Hodgkin’s lymphomas. Unspecified PTCLs are Cytogenetics and FISH usually derived from activated CD4 þ T-cells, although a 6 In all cases, except the index case in which fresh tissue was minority may instead express CD8 and cytotoxic proteins. available, formalin-fixed paraffin-embedded tissue was used. The identification of recurrent chromosomal rearrangements In the index case, cytogenetic analysis was performed by has been helpful in recognizing and defining lymphoma entities G-banding of a freshly obtained lymph node. FISH with whole chromosome painting probes for chromosomes 5 and 9 and a Correspondence: Dr B Streubel, Department of Pathology, Medical gene-specific probe for RARA was carried out on metaphases University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, (Vysis, Downer’s Grove, IL, USA). To identify the breakpoints on Austria. E-mail: [email protected] the derivative chromosomes 5 and 9, 14 bacterial artificial Received 21 July 2005; revised 9 September 2005; accepted 11 clones (BACs) were selected of chromosomes 9 and 11 BACs of October 2005; published online 8 December 2005 chromosome 5 from the www.ensembl.org. BAC probes were ITK/SYK rearrangement in PTCL B Streubel et al 314 directly labelled with SpectrumOrange- and SpectrumGreen- each sample and relative expression numbers calculated using dUTP using nick translation (Vysis). Forty-six PTCLs were the DDCT method. studied with clones RP11-563G12 and RP11-1091N2 for ITK rearrangement, RP11-31B18 and RP11-47O12 for SYK rearrangement and RP11-956N15 and CTB4E7 for ITK–SYK transloca- Results tion. For interphase FISH, 300 cells were analyzed. The cutoff value for the diagnosis of each set of probes was the mean Cytogenetic analysis and molecular cloning reveal a percentage of cells with a false-positive signal constellation plus novel t(5;9)(q33;q22) with rearrangement of ITK and 3 s.d. as assessed with the use of tissue specimens obtained from SYK in a case of U-PTCL 10 reactive lymph nodes. G-banding analysis in a case of U-PTCL revealed a t(5;9) (q33;q22) as the primary chromosomal abnormality. Duplica- tion of 17q was observed in a subclone. The karyotype was Rapid amplification of cDNA ends described as: 46,XX,t(5;9)(q33;q22)[2]/46,XX,t(5;9)(q33;q22), The 50- and 30-rapid amplification of cDNA end (RACE)-ready dup(17)(q21q24)[12]/46,XX[18]. FISH with whole chromosome cDNAs were prepared from 1 mg of the patients total RNA, painting probes for chromosomes 5 and 9 confirmed the followed by RACE and nested-RACE using the Clontech reciprocal translocation (Figure 1a), a duplication of RARA SMARTt RACE cDNA Amplification Kit according to the was observed on the derivative chromosome 17. To identify manufacturer’s instructions. Gene-specific primers for 50- and the partner genes targeted by the t(5;9)(q33;q22), FISH studies 30-RACE were 50-CAGTGGCCAGGGATCAGTCTCATGG and were performed on metaphases with sets of BACs for chromo- 50-ACAGAAAGTCCTCCCCTGCCCAAGG, nested primers for 50 somal bands 5q33 and 9q22, respectively. FISH analysis and 30 nested-RACE were 50-ACAGGTGCGGGAGCGGT mapped the breakpoint on 5q33 between RP11-563G12 TAGTTCAC and 50-TATGCGAGGCCGAGTCCTGGATGC, re- and RP11-1091N2 (Figure 1b), with RP11-956N15 spanning spectively. The 50- and 30-nested-RACE PCR products were the breakpoint. The breakpoint on 9q22 was flanked by directly sequenced using an ABI Prism 310 (PE Applied RP11-31B18 and RP11-47O12 (Figure 1c) and covered by Biosystems, Foster City, CA, USA). Sequences were compared CTB4E7. The clones spanning the breakpoints contained the ITK with the Genbank database using BLAST program (http:// gene on chromosome 5 and the SYK gene on chromosome www.ncbi.nlm.nih.gov/BLAST). 9, indicating that ITK and SYK were rearranged by the t(5;9)(q33;q22) (Figure 1d).

Detection of ITK–SYK fusion transcripts by RT-PCR RNA was isolated from archival formalin-fixed, paraffin- ITK–SYK is the relevant fusion transcript To identify putative ITK–SYK and SYK–ITK fusion genes, RACE embedded lymphoma tissue and cDNA synthesized as de- 15 was performed. Sequence analysis of PCR products revealed a scribed previously. PCR detection of the ITK-SYK fusion transcript was performed with a single set of primers (ITK-fwd: 50-GTGCCCAATATGATCCAACC; SYK-rev: 50-TGCAAGTTCTG GCTCATACG). All PCR products were gel purified (QIAquick Gel Extraction Kit, Qiagen, West Sussex, UK) and sequenced. ACTB was amplified in parallel as an internal positive control.

Real-time quantitative RT-PCR for SYK Frozen tumor samples of the index case and of six U-PTCLs were homogenized and total RNA extracted. In addition, RNA of fluorescent-activated cell-sorted (FACS) T-cell sub-populations of three healthy volunteers served as controls. Peripheral blood mononuclear cells were isolated from heparinized blood by Ficoll–diatrizoate centrifugation. A total of 1 Â 107 cells was stained with anti-CD3 FITC and anti-CD8 PE mAb (BD Biosciences, San Jose, CA, USA). Cells were sorted on a FACSVantage SE fluorescence-activated cell sorter (BD Bios- ciences) based on their expression of CD3 plus CD8 (CD8 þ T- cells) or CD3 without CD8 (corresponding to CD4 þ T-cells). Purity of sorted T-cell sub-populations was 495%. Real-time quantitative RT-PCR (QRT-PCR) analysis was s Figure 1 FISH for the detection of t(5;9)(q33;q22) involving ITK and performed on the ABI Prism 7000 sequence detection system SYK.(a) Green signal for chromosome 9 is observed on the der(5) and 15 (Applied Biosystems) as described previously. Gene expres- red signal for chromosome 5 on the der(9), confirming the t(5;9). (b) sion assays (Assay-on-DemandTM) suitable for this system were The dual break apart probe for ITK demonstrates the rearrangement of carried out according to the manufacturer’s instructions the ITK locus showing the green signal on the der(5) and the orange (Applied Biosystems). For each data point, duplicate samples signal on the der(9), whereas the normal chromosome 5 carries the were analyzed in parallel. Duplicate assays of serial dilutions of colocalization signal. (c) The dual break apart probe for SYK demonstrates the rearrangement of the SYK locus showing the green a cDNA standard (Ramos cDNA) were included in each signal on the der(9) and the orange signal on the der(5). experiment. Transcript levels were normalized for those of (d) Colocalized fusion signals on the der(5) and der(9) confirm GAPDH to account for variability in the amount of cDNA in ITK–SYK rearrangement.

Leukemia ITK/SYK rearrangement in PTCL B Streubel et al 315 chimeric ITK–SYK transcript containing N-terminal ITK unspecified PTCLs (n ¼ 22), AILT (n ¼ 9), and ALCL, ALK (1–577 bp; GenBank, NM_005546) fused in-frame with negative (n ¼ 7). FISH probes flanking and covering ITK C-terminal SYK cDNA (breakpoint 1063 bp; GenBank, and SYK, as described for the index patient, were used NM_003177). At the protein level, the first 165 amino acids of to screen for the ITK–SYK translocation. Apart from the ITK are fused to the carboxy-terminal tyrosine kinase domain of index case, ITK–SYK translocation was detected in four SYK (Figure 2). Primers derived from the ITK and SYK cDNA further cases. Variant translocations of ITK or SYK were sequences were then used to confirm the RACE results directly not found. Including the index case, ITK–SYK translocation by RT-PCR. In contrast to the consensus ITK–SYK transcript, the was detected in 3/8 PTCLs with follicular involvement, SYK–ITK transcript showed an interstitial deletion of SYK at in the single case showing perifollicular involvement 993 bp resulting in a premature stop codon. This finding highly and in one of the 21 unspecified PTCLs with diffuse growth suggested that ITK–SYK was the relevant transcript derived from pattern. The nine AILTs and the seven ALK-negative ALCLs the t(5;9)(q33;q22). were all negative. To confirm the FISH results and to identify the breakpoints, RT-PCR was performed in a series of 18 U-PTCLs comprising the ITK–SYK is predominately found in a peculiar histologic nine cases with the ‘follicular pattern’ and nine cases of diffuse subtype of U-PTCLs lymph node involvement. Sequencing of the PCR products We were next interested to determine whether the ITK–SYK demonstrated that the chimeric ITK–SYK transcripts had the translocation occurs recurrently in PTCLs. Histologically, the identical breakpoints (as described for the index case) in all five U-PTCL case carrying the t(5;9)(q33;q22) showed a largely cases with t(5;9)(q33;q22). In summary, ITK–SYK rearrangement preserved lymph node architecture in which medium-sized and was observed most often among the PTCLs with follicular large atypical lymphoid cells with clear cytoplasm had replaced involvement (three of eight cases, 38%) and occurred overall in the germinal center B cells with at least partial preservation of five of 30 or 17% of the U-PTCL cases investigated. Immuno- the follicular dendritic cell networks. Immunophenotypically, phenotypic and clinical data of these patients are listed in Tables the lymphoma cells were CD3 þ CD2 þ CD5 þ CD4 þ bcl- 1 and 2. 6 þ CD10 þ (Figure 3 and Table 1). This histology, which is in contrast to the diffuse infiltration usually seen in U-PTCLs, has been recognized by de Leval et al.12 and termed ‘PTCL t(5;9)(q33;q22) leads to the expression of ITK–SYK with follicular involvement and a CD4 þ /bcl-6 þ phenotype’. As a result of the t(5;9)(q33;q22), the expression of the ITK–SYK Assuming that the probability of detecting the ITK–SYK fusion gene is driven by the promoter of its 50 partner ITK. ITK is translocation is highest in cases with similar histology, we known to be expressed in T cells and therefore expression of the searched our archive for such cases and retrieved seven ITK–SYK fusion gene could be expected. We performed QRT- PTCL that met the histologic criteria, and an additional PCR and IHC for C-terminal Syk, which was part of the chimeric case with curious perifollicular lymphoma involvement, as ITK–SYK fusion gene. QRT-PCR demonstrated varying mRNA described by Ru¨diger et al.13 Overall, 46 PTCLs were studied for expressions of SYK with highest levels in the index case with rearrangements of ITK and SYK additionally comprising ‘typical’ ITK–SYK rearrangement and a further U-PTCL (Figure 4a). In the

Figure 2 RACE identiﬁes ITK–SYK fusion. Sequence analysis of a 2.4 kb PCR product reveals in-frame fusion of N-terminal ITK to C-terminal SYK. The individual domains of Itk are indicated PH (pleckstrin homology), TH (proline-rich Tec homology), SH3 (Src homology), SH2 (Src homology), TK (tyrosine kinase) and of Syk N- and C-terminal SH2 (Src homology), and TK (tyrosine kinase).

Leukemia ITK/SYK rearrangement in PTCL B Streubel et al 316

Figure 3 Histologic and immunophenotypic ﬁndings in an U-PTCL with follicular involvement and ITK–SYK rearrangement. (a) Low-power view of the lymph node, showing a distinct nodular pattern. (b) The nodules are composed of medium- to large-sized lymphoid cells with abundant clear cytoplasm. (c and d) The nodules contain networks of CD21 þ follicular dendritic cells. (e) Inﬁltrating lymphoid cells are positive for CD5 and (f) many of which coexpress bcl-6.

Table 1 Immunophenotype of neoplastic T-cells in U-PTCL with follicular patterna

Case no. t(5;9) bF1 CD3 CD2 CD7 CD5 CD4 CD8 CD10 Bcl-6 Ki-67 (%) TCRg

1+À ++À ++À + + 55 ND 2+ND++À ++À + + 35 RR 3+À +ND+++À + + 50 RR 4 ÀÀ+NDÀ ++ÀÀ À 70 RR 5 À ND+++++À + À 25 RR 6 À ND + ND ND + ÀÀ À +45RR 7 À ++ +À ++À + À 60 RR 8 ÀÀ++À ++À + À 70 ND 9+NDÀ + À + ÀÀ À À 60 RR ND ¼ not done; RR ¼ monoclonal rearrangement of T-cell receptor g-chain gene. aCase nos. 1–8 histologically corresponding to PTCL with follicular involvement according to de Leval et al.12; case no. 9 corresponding to PTCL with distinct perifollicular growth pattern according to Ru¨ diger et al.13

Table 2 Clinical data of patients with U-PTCL with follicular pattern

Case no. Age (years)/sex Stage Clinical course Status

1a 57/F III 6 Â CHOP, radiation Alive+10 mos (CR) 2a 51/M IV 6 Â CHOP – CR, relapse after 10 mos – autologous BMT – CR Alive+45 mos (CR) 3a 55/M I 6 Â CHOP, radiation Alive+17 mos (CR) 4 84/F III No treatment Lost to follow-up 5 71/F III CHOP14, PD after four courses Alive+9 mos 6 45/F III 6 Â CHOP, relapse – autologous BMT, relapse – PD Dead after 21 mos 7 73/F IVS 8 Â CHOP Alive+9 mos (PR) 8 54/M IIIS No treatment Lost to follow-up 9a 61/F III 6 Â CHOP, PR, relapse, PD after 17 mos Dead after 22 mos at(5;9)(q33;q22)+ case.

latter case, over-representation (ﬁve copies) of SYK, but no gain cases were negative for an antibody against the N-terminal Syk, of chromosome 9 (two copies for centromere 9), was observed which was not part of the ITK–SYK fusion transcript (Figure 4c). by FISH analysis. IHC using an antibody against C-terminal SYK We therefore concluded that the ITK–SYK fusion transcript was showed cytoplasmic Syk staining in 4/5 t(5;9)(q33;q22) þ cases expressed on mRNA and protein level in t(5;9)(q33;q22) þ (Figure 4b). In contrast, t(5;9)(q33;q22) þ tumor cells of all ﬁve tumor cells.

Leukemia ITK/SYK rearrangement in PTCL B Streubel et al 317 region upstream of the SH3 domain of ITK are fused to C-terminal SYK. In contrast to ITK, a translocation of SYK has been observed in hematopoietic neoplasia. An atypical myelodysplastic syndrome with t(9;12)(q22;p12) resulted in a TEL–SYK fusion gene with constitutive activation of SYK.22 TEL was initially identified in chronic myelomonocytic leukemia with t(5;12)(q33;p13) and TEL–PDGFRb fusion resulting in the activation of the tyrosine kinase activation of PDGFRb.23 The same mechanism of constitutive tyrosine kinase activation was observed in the TEL–SYK fusion gene. The TEL–Syk fusion protein was located in the cytoplasm and possibly activated PI3-K/Akt, MAPK and STAT5.24 As a consequence of the t(5;9)(q33;q22), we demonstrated activation of the Syk tyrosine kinase by Itk. Similarly to the TEL–Syk fusion protein, a cytoplasmic Itk–Syk fusion protein was observed in our cases. This is also in concordance with the observation that Itk is expressed in the cytoplasm.25 Syk is a non-receptor protein kinase that serves as a key regulator of multiple biochemical signal transduction events and Figure 4 Analysis of C-terminal SSYK expression by real-time has high homology to ZAP70 protein tyrosine kinase.26 Syk is quantitative RT-PCR and immunohistochemistry. (a) Highest levels of expressed in a wide variety of hematopoietic cells, but only in SYK expression are detected in U-PTCL case with t(5;9)(q22;q33) and 27 in a translocation-negative case with five copies of SYK.(b) Tumor low levels in peripheral T-cells. Treatment of human Jurkat T- cells show cytoplasmic staining for C-terminal Syk. (c) Tumor cells are cells with the proapoptotic and inflammatory cytokine TNF negative for N-terminal Syk. In (b and c) small reactive lymphoid cells activates Syk, which consequently plays an essential role in stain for C-Syk and N-Syk, respectively. TNF-induced activation of JNK, p38 MAPK, p44/p42 MAPK, NF- kB and apoptosis.28 We tested tissue sections of our t(5;9)(q33;q22) þ PTCLs with specific antibodies for p38 MAPK, p44/p42 MAPK and NF-kB. Nuclei of tumor cells were negative Discussion in all cases, indicating that p38 MAPK, p44/p42 MAPK and NF- kB were not activated in the t(5;9)(q33;q22) þ PTCLs. Mutations So far, no recurrent chromosomal translocations have been in the SYK active site, which could be an explanation for the reported to occur in U-PTCLs. We have identified a novel inactivity of the usual targets of Syk, were excluded in the t(5;9)(q33;q22) as the primary cytogenetic alteration in a case of t(5;9)(q33;q22) þ index case (data not shown). an U-PTCL and upon screening a series of such cases detected Chromosomal translocations represent the biologic hallmark this aberration in a total of five cases, four of which in several B-cell lymphomas, such as the t(14;18)(q32;q21) in demonstrated a follicular or perifollicular growth pattern follicular lymphoma or the t(11;14)(q13;q32) in mantle cell indicating a tropism of the lymphoma cells to lymphoid follicles. lymphoma, whereas the t(2;5)(p23;q35) and its variants so far The t(5;9)(q33;q22) resulted in an ITK–SYK fusion transcript with has been the sole example to occur in T-cell neoplasia, that is, in identical breakpoints in all cases. The chimeric transcript was ALCL. As each of these lymphomas share histological and expressed in the tumor cells on mRNA and protein level. immunophenotypical features (with various extent), it was not Translocations of ITK have not been reported so far. Itk surprising to detect some unifying properties among the belongs to a group of five related kinases comprising the Tec t(5;9)(q33;q22) þ U-PTCL. Most strikingly, four of the five family.16 The Tec family kinases are defined by a common translocation-positive lymphomas showed a high propensity to structure that includes a tyrosine kinase catalytic domain the follicular environment resulting in a follicular pattern of occupying the C-terminal half of the protein, preceded by the involvement, and three of them displayed a bcl-6 þ CD10 þ Src homology (SH2 and SH3) protein interaction domains.17 helper T-cell immunophenotype. Owing to the low number of Although similar in structure to the Src family kinases, the Tec cases investigated, we cannot exclude that the t(5;9)(q33;q22) kinases lack the C-terminal regulatory tyrosine and the N- may also occur in other lymphoma subtypes, such as AILT, terminal myristoylation signals that characterize the Src family. which is also characterized by a bcl-6 þ CD10 þ T-cell Instead, the Tec kinases possess a proline-rich region (TH phenotype.29 Nevertheless, the identification and characteriza- domain) just upstream of the SH3 domain, which may help tion of a novel t(5;9)(q33;q22) indicates an important role of Itk regulate the Tec kinases via an interaction with their SH3 and Syk in a subset of PTCLs. Larger series of U-PTCLs with a domain.18 Additionally, Itk has an N-terminal pleckstrin follicular pattern have to be evaluated for the presence of the homology (PH) domain that facilitates its interaction with t(5;9)(q33;q22) to determine whether there are clinical differ- membrane-bound phosphatidylinositol(3,4,5)P3, a product of ences between translocation-positive and -negative cases. phosphatidylinositol-3-kinase. Significant understanding of Itk biology was developed by the generation of knockout mice, which showed that CD4 þ T-cell development, including References reduced differentiation of T-cells into the Th2 lineage, was impaired and that TCR–CD3 signaling events, interleukin-2 1 Jaffe ES, Harris NL, Stein H, Vardiman JW (eds). World Health production and T-cell proliferation were diminished.19–21 The Organization Classification of Tumours. Pathology and Genetics: multiple roles of Itk in T-cell development and T-cell-mediated Tumours of Haemopoietic and Lymphoid Tissues. 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