title: BCL6 locus is hypermethylated in angioimmunoblastic T-cell lymphoma.
abstract: BCL6, a master transcription factor for differentiation of follicular helper T (TFH) cells, is highly expressed in angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphomas (PTCL) containing tumor cells with TFH features. TET2, encoding an epigenetic regulator, is frequently mutated in AITL/PTCL. We previously reported that Tet2 knockdown mice developed T-cell lymphomas with TFH features. Hypermethylation of the Bcl6 locus followed by BCL6 upregulation was thought to be the key event for lymphoma development in mice. The mechanisms by which BCL6 expression is upregulated in human AITL/PTCL, however, have not been elucidated. Here, we investigated the impact of TET2 mutations on methylation of BCL6 locus in human AITL/PTCL samples. Hypermethylation of the BCL6 locus was more frequent in PTCL samples than B-cell lymphoma samples (PTCL vs B-cell lymphomas: 9/42 vs 0/35). PTCL samples with TET2 mutations were more frequently hypermethylated than those without TET2 mutations (PTCL with TET2 mutations vs without mutations: 6/22 vs 0/17). BCL6 expression in hypermethylated samples was higher than that in low methylated samples. Deregulated BCL6 expression caused by hypermethylation and TET2 mutations may result in skewed TFH differentiation and eventually contribute to AITL/PTCL development in patients, as well as lymphoma development in Tet2 knockdown mice.
authors.affiliation: Department of Hematology, Comprehensive Human, Biosciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Nishizawa
authors.affiliation: Department of Hematology, Comprehensive Human, Biosciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan. sakatama-tky@umin.net.|Department of Hematology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan. sakatama-tky@umin.net.|Department of Hematology, University of Tsukuba Hospital, Amakubo, Tsukuba, Ibaraki, Japan. sakatama-tky@umin.net.
authors.forename: Mamiko
authors.initials: M
authors.lastname: Sakata-Yanagimoto
authors.affiliation: Department of Hematology, Comprehensive Human, Biosciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Hattori
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.|Department of Hematology, University of Tsukuba Hospital, Amakubo, Tsukuba, Ibaraki, Japan.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Muto
authors.affiliation: Department of Hematology, Comprehensive Human, Biosciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan.
authors.forename: Tran
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Hematology, Toranomon Hospital, Toranomon, Minato-ku, Tokyo, Japan.|Okinaka Memorial Institute for Medical Research, Toranomon, Minato-ku, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Izutsu
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Kyoto-shi, Sakyo-ku, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Kyoto-shi, Sakyo-ku, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Nakamura
authors.affiliation: Department of Hematology, Comprehensive Human, Biosciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan. schibatky@umin.net.|Department of Hematology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan. schibatky@umin.net.|Department of Hematology, University of Tsukuba Hospital, Amakubo, Tsukuba, Ibaraki, Japan. schibatky@umin.net.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
mesh_terms: D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D055785:Gene Knockdown Techniques; D006801:Humans; D007119:Immunoblastic Lymphadenopathy / Q000235:genetics* / Q000473:pathology; D016393:Lymphoma, B-Cell; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000473:pathology; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics*
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D049308:Dioxygenases; C541081:TET2 protein, human
keywords: Angioimmunoblastic T-cell lymphoma; BCL6 expression; Follicular helper T cells; Hypermethylation; TET2 mutation