title: STX11 functions as a novel tumor suppressor gene in peripheral T-cell lymphomas.
abstract: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Their molecular pathogenesis has not been entirely elucidated. We previously showed that 6q24 is one of the most frequently deleted regions in primary thyroid T-cell lymphoma. In this study, we extended the analysis to other subtypes of PTCL and performed functional assays to identify the causative genes of PTCL that are located on 6q24. Genomic loss of 6q24 was observed in 14 of 232 (6%) PTCL cases. The genomic loss regions identified at 6q24 always involved only two known genes, STX11 and UTRN. The expression of STX11, but not UTRN, was substantially lower in PTCL than in normal T-cells. STX11 sequence analysis revealed mutations in two cases (one clinical sample and one T-cell line). We further analyzed the function of STX11 in 14 cell lines belonging to different lineages. STX11 expression only suppressed the proliferation of T-cell lines bearing genomic alterations at the STX11 locus. Interestingly, expression of a novel STX11 mutant (p.Arg78Cys) did not exert suppressive effects on the induced cell lines, suggesting that this mutant is a loss-of-function mutation. In addition, STX11-altered PTCL not otherwise specified cases were characterized by the presence of hemophagocytic syndrome (67% vs 8%, P = 0.04). They also tended to have a poor prognosis compared with those without STX11 alteration. These results suggest that STX11 plays an important role in the pathogenesis of PTCL and they may contribute to the future development of new drugs for the treatment of PTCL.
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.|Department of Cancer Genetics, Nagoya University Graduate School of Medicine at Aichi Cancer Center Research Institute, Nagoya, Japan.|Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Noriaki
authors.identifier: http://orcid.org/0000-0001-7001-0106
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Tsuzuki
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Kennosuke
authors.initials: K
authors.lastname: Karube
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.|Department of Pathology and Laboratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Takahara
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Suguro
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Nishikori
authors.affiliation: Multi-institutional Clinical Trial Support Center, National Cancer Center, Tokyo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Shimoyama
authors.affiliation: Department of Hematology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Tsukasaki
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.|Department of Cancer Genetics, Nagoya University Graduate School of Medicine at Aichi Cancer Center Research Institute, Nagoya, Japan.|Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Seto
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D057895:Haploinsufficiency / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D016411:Lymphoma, T-Cell, Peripheral / Q000378:metabolism* / Q000473:pathology; D061986:MCF-7 Cells; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion / Q000235:genetics*; D013601:T-Lymphocytes / Q000473:pathology; D049411:Utrophin / Q000235:genetics
chemical_list: D050765:Qa-SNARE Proteins; C541732:STX11 protein, human; C483599:UTRN protein, human; D049411:Utrophin
keywords: Functional analyses; STX11; genomic loss of 6q24; peripheral T-cell lymphomas; tumor suppressor gene