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STX11 Functions As a Novel Tumor Suppressor Gene in Peripheral T& STX11 functions as a novel tumor suppressor gene in peripheral T-cell lymphomas Noriaki Yoshida,1,2,3 Shinobu Tsuzuki,1 Kennosuke Karube,1,8 Taishi Takahara,1,4 Miyuki Suguro,1 Hiroaki Miyoshi,3 Momoko Nishikori,5 Masanori Shimoyama,6 Kunihiro Tsukasaki,7 Koichi Ohshima3 and Masao Seto1,2,3 1Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya; 2Department of Cancer Genetics, Nagoya University Graduate School of Medicine at Aichi Cancer Center Research Institute, Nagoya; 3Department of Pathology, Kurume University School of Medicine, Kurume; 4Department of Pathology and Laboratory Medicine, Nagoya University Graduate School of Medicine, Nagoya; 5Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto; 6Multi-institutional Clinical Trial Support Center, National Cancer Center, Tokyo; 7Department of Hematology, National Cancer Center Hospital East, Kashiwa, Japan; Key words Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin Functional analyses, genomic loss of 6q24, peripheral T- lymphomas with poor prognosis. Their molecular pathogenesis has not been cell lymphomas, STX11, tumor suppressor gene entirely elucidated. We previously showed that 6q24 is one of the most fre- Correspondence quently deleted regions in primary thyroid T-cell lymphoma. In this study, we Masao Seto, Department of Pathology, Kurume University extended the analysis to other subtypes of PTCL and performed functional assays School of Medicine, 67 Asahimachi, Kurume, Fukuoka to identify the causative genes of PTCL that are located on 6q24. Genomic loss of 830-0011, Japan. 6q24 was observed in 14 of 232 (6%) PTCL cases. The genomic loss regions identi- Tel: +81-942-35-3311 (Ext. 3181); +81-942-31-7547 (Direct); fied at 6q24 always involved only two known genes, STX11 and UTRN. The Fax: +81-942-31-0342; E-mail: [email protected] expression of STX11, but not UTRN, was substantially lower in PTCL than in nor- mal T-cells. STX11 sequence analysis revealed mutations in two cases (one clinical 8Present address: Cell Biology and Pathology, University sample and one T-cell line). We further analyzed the function of STX11 in 14 cell of the Ryukyus Graduate School of Medicine, Uehara 207, lines belonging to different lineages. STX11 expression only suppressed the pro- Nishihara-cho, Okinawa, 903-0215, Japan liferation of T-cell lines bearing genomic alterations at the STX11 locus. Interest- Funding Information ingly, expression of a novel STX11 mutant (p.Arg78Cys) did not exert suppressive Grants-in-Aid from the Ministry of Health, Labor, and effects on the induced cell lines, suggesting that this mutant is a loss-of-function Welfare of Japan; the Ministry of Education, Culture, STX11 Sports, Science, and Technology of Japan; the Japan Soci- mutation. In addition, -altered PTCL not otherwise specified cases were ety for the Promotion of Science; and Takeda Science characterized by the presence of hemophagocytic syndrome (67% vs 8%, Foundation. P=0.04). They also tended to have a poor prognosis compared with those with- out STX11 alteration. These results suggest that STX11 plays an important role in Received May 10, 2015; Revised July 7, 2015; Accepted July 9, 2015 the pathogenesis of PTCL and they may contribute to the future development of new drugs for the treatment of PTCL. Cancer Sci (2015) doi: 10.1111/cas.12742 eripheral T-cell lymphomas (PTCL) are tumors derived genes in the pathophysiology of PTTL. STX11 is a member of P from mature T-cells. They are relatively rare and account the t-SNAP receptor (t-SNARE) family. A biallelic germline for approximately 10% of non-Hodgkin Lymphomas.(1) A mutation in STX11 is known to cause familial hemophagocytic recent epidemiological study demonstrated that the incidence lymphohistiocytosis type 4 (FHL type 4).(18) Although of PTCL is increasing in Japan and the USA.(2) PTCL are degranulation of cytotoxic T-cells (CTL) and natural killer known to be clinically, histopathologically and genetically (NK) cells is impaired by STX11 deficiency, the precise molec- heterogeneous.(3,4) Recently, studies employing unbiased and ular function of STX11 is largely unknown.(19–21) The inci- genome-wide methods showed that the genetic alterations were dence of T-cell lymphomas in patients with FHL type 4 has involved in the pathophysiology of PTCL.(5–16) Because of the not been reported.(18,22,23) Moreover, Stx11 knockout mice are heterogeneity of the diseases, additional genomic alterations normal in development and differentiation of T-cells.(19,21) are predicted to contribute to the pathophysiology of PTCL. UTRN encodes utrophin, a component of cytoskeleton. Therefore, the molecular pathogenesis of PTCL has not been Because nonsense and frameshift mutations in UTRN have fully elucidated. been reported in a small number of cancers, UTRN is regarded We previously analyzed the genomic alterations associated as a tumor suppressor gene.(24) However, alterations of UTRN with primary T-cell lymphoma of the thyroid (primary thyroid have not been described in malignant lymphomas such as T-cell lymphoma [PTTL]).(17) In that study, we observed that PTCL. 67% of PTTL cases showed genomic loss at 6q24.2. The mini- In this study, we demonstrated for the first time that STX11 mal common region (MCR) lost in those cases contained functions as an important tumor suppressor gene in PTCL by STX11 and ⁄ or UTRN, suggesting the involvement of these using gene expression and functional analyses. In addition, we © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd Cancer Sci | 2015 on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Original Article Tumor suppressor STX11 in PTCL www.wileyonlinelibrary.com/journal/cas identified a loss-of-function mutation of STX11 that is associ- Table 1. Frequency of STX11 loss in non-Hodgkin’s lymphoma ated with T-cell lymphoma. Histological subgroup n (%) ⁄ Materials and Methods PTTL 4 6 (67) PTCL-NOS 4 ⁄ 51 (8) Samples and cell lines. The Institute Review Board of the ATL 3 ⁄ 62 (5) Aichi Cancer Center approved all the samples and medical Acute type 3 ⁄ 35 (9) records used in our study. Most patients with PTCL-NOS and Chronic type 0 ⁄ 27 (0) PTTL were treated with anthracycline-based chemotherapy, as AITL† 0 ⁄ 39 (0) (6,17) previously reported. Clinicopathological findings were ALCL‡ 3 ⁄ 74 (3) (6,25) reexamined from the results of previous our studies. CD4- PTCL 14 ⁄ 232 (6) positive cells were used as controls in this study and were NK-cell lymphoma 7 ⁄ 35 (20) (26) purified as previously reported. DLBCL 28 ⁄ 118 (24) Six T-cell neoplasm cell lines (ST1, KOB, Su9T01, KOB, Mantle cell lymphoma 3 ⁄ 21 (14) Hut102, Hut78 and Jurkat) were used in this study. In addition Follicular lymphoma 8 ⁄ 80 (10) to the six T-cell lines, an NK cell line (NKL), four B-cell lines Burkitt lymphoma 2 ⁄ 26 (8) (Reh, SUDHL6, Raji and Jeko1), a myeloid cell line (K562) MALT lymphoma 1 ⁄ 31 (3) and three epithelial cell lines (293T, MCF7 and HeLa) were Total 63 ⁄ 543 (12) also analyzed. Cell lines were cultured as previously (27,28) †This was determined using the published result reported by Thorns reported. The cell lines used in the present study are sum- et al.(35) ‡This was determined using the published result reported by marized in Supplementary Table S1. Salaverria et al.(36) AITL, angioimmunoblastic lymphoma; ALCL, Array comparative genomic hybridization analysis. Focusing anaplastic large cell lymphoma; ATL, adult T-cell leukemia ⁄ lymphoma; on chromosome 6q loss, we reexamined our previous compara- DLBCL, diffuse large B-cell lymphoma; MALT lymphoma, mucosa-asso- tive genomic hybridization (CGH) data on 430 cases of non- ciated lymphoid tissue lymphoma; PTCL, peripheral T-cell lymohomas; (17) PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; PTTL, Hodgkin’s lymphoma. These data comprised six PTTL, 51 primary thyroid T-cell lymphoma. PTCL-NOS,(6) 62 adult T-cell leukemia ⁄ lymphoma (ATL; 35 and 27 cases of the acute- and chronic-type cases, respec- tively),(16) 35 NK-cell lymphoma,(27) 118 diffuse large B-cell (29,30) (31) lymphoma (DLBCL), 80 follicular lymphoma, 26 Bur- University), a modified version of R commander software.(38) (32) (33) kitt lymphoma 21 mantle cell lymphoma and 31 Detailed methods can be found in Supplementary Data S1. mucosa-associated lymphoid tissue lymphoma(34) cases. In addition, we evaluated the genomic loss of 6q using previous results of the genomic alterations in 39 angioimmunoblastic T- Results (35) cell lymphoma (AITL) and 74 anaplastic large cell lym- Recurrent genomic loss of 6q24.2 found in subtypes of non- (36) phoma (ALCL) cases. Platforms of array CGH used in Hodgkin’s lymphoma. We investigated the genomic loss these analyses and the accession numbers for the database are frequency of 6q24 in various subtypes of non-Hodgkin lym- described in Supplementary Table S2. phoma. Heterozygous loss of 6q24 was observed in 6% Gene expression analysis. We evaluated the expression levels (n = 232) of PTCL cases (Table 1), whereas homozygous of STX11 and UTRN using published data (GSE6338 and loss of this region was not observed in our analysis. The (5,37) GSE19069). Using quantitative real-time RT-PCR, we loss of 6q24 occurred most frequently in the TTCL cases measured the gene expression levels of STX11 in 29 cases of (67%, n = 6). This genomic deficiency was also frequently PTCL-NOS, four cases of PTTL, and six T-cell lines, for observed in DLBCL and NK-cell lymphomas (24% and which adequate RNA was available. 20%, respectively), and the genes located near the 6q24 Mutation analysis of STX11.
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