title: Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice.
abstract: TET2 (Ten Eleven Translocation 2) is a dioxygenase that converts methylcytosine (mC) to hydroxymethylcytosine (hmC). TET2 loss-of-function mutations are highly frequent in subtypes of T-cell lymphoma that harbor follicular helper T (Tfh)-cell-like features, such as angioimmunoblastic T-cell lymphoma (30-83%) or peripheral T-cell lymphoma, not otherwise specified (10-49%), as well as myeloid malignancies. Here, we show that middle-aged Tet2 knockdown (Tet2(gt/gt)) mice exhibit Tfh-like cell overproduction in the spleen compared with control mice. The Tet2 knockdown mice eventually develop T-cell lymphoma with Tfh-like features after a long latency (median 67 weeks). Transcriptome analysis revealed that these lymphoma cells had Tfh-like gene expression patterns when compared with splenic CD4-positive cells of wild-type mice. The lymphoma cells showed lower hmC densities around the transcription start site (TSS) and higher mC densities at the regions of the TSS, gene body and CpG islands. These epigenetic changes, seen in Tet2 insufficiency-triggered lymphoma, possibly contributed to predated outgrowth of Tfh-like cells and subsequent lymphomagenesis. The mouse model described here suggests that TET2 mutations play a major role in the development of T-cell lymphoma with Tfh-like features in humans.
authors.affiliation: 1] Department of Hematology, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan [2] Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Muto
authors.affiliation: 1] Department of Hematology, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan [2] Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki, Japan [3] Faculty of Medicine, Department of Hematology, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sakata-Yanagimoto
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Nagae
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shiozawa
authors.affiliation: Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Miyake
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Enami
authors.affiliation: Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kamada
authors.affiliation: 1] Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki, Japan [2] Faculty of Medicine, Department of Hematology, University of Tsukuba, Tsukuba, Ibaraki, Japan [3] Life Science center, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Molecular Biological Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Department of Clinical Laboratory, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nanmoku
authors.affiliation: 1] Department of Hematology, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan [2] Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki, Japan [3] Faculty of Medicine, Department of Hematology, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Obara
authors.affiliation: 1] Department of Hematology, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan [2] Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki, Japan [3] Faculty of Medicine, Department of Hematology, University of Tsukuba, Tsukuba, Ibaraki, Japan [4] Department of Clinical Laboratory, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Suzukawa
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Nakamura
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: 1] Department of Hematology, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan [2] Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki, Japan [3] Faculty of Medicine, Department of Hematology, University of Tsukuba, Tsukuba, Ibaraki, Japan [4] Life Science center, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Chiba
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D049308:Dioxygenases; D055785:Gene Knockdown Techniques; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C551914:Tet2 protein, mouse