title: Somatic RHOA mutation in angioimmunoblastic T cell lymphoma.
abstract: Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma characterized by generalized lymphadenopathy and frequent autoimmune-like manifestations. Although frequent mutations in TET2, IDH2 and DNMT3A, which are common to various hematologic malignancies, have been identified in AITL, the molecular pathogenesis specific to this lymphoma subtype is unknown. Here we report somatic RHOA mutations encoding a p.Gly17Val alteration in 68% of AITL samples. Remarkably, all cases with the mutation encoding p.Gly17Val also had TET2 mutations. The RHOA mutation encoding p.Gly17Val was specifically identified in tumor cells, whereas TET2 mutations were found in both tumor cells and non-tumor hematopoietic cells. RHOA encodes a small GTPase that regulates diverse biological processes. We demonstrated that the Gly17Val RHOA mutant did not bind GTP and also inhibited wild-type RHOA function. Our findings suggest that impaired RHOA function in cooperation with preceding loss of TET2 function contributes to AITL-specific pathogenesis.
authors.affiliation: 1] Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. [2].
authors.forename: Mamiko
authors.initials: M
authors.lastname: Sakata-Yanagimoto
authors.affiliation: 1] Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. [2].
authors.forename: Terukazu
authors.initials: T
authors.lastname: Enami
authors.affiliation: 1] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [2] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. [3].
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Ishii
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Miyake
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Muto
authors.affiliation: Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsuyama
authors.affiliation: 1] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [2] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Sakata
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kamada
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Nakamoto-Matsubara
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Nguyen Bich
authors.initials: NB
authors.lastname: Tran
authors.affiliation: 1] Department of Hematology, Toranomon Hospital, Tokyo, Japan. [2] Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Izutsu
authors.affiliation: 1] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [2] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Pathology, Toranomon Hospital, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Ohta
authors.affiliation: Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Furuta
authors.affiliation: Department of Hematology, Tsuchiura Kyodo General Hospital, Tsuchiura, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Department of Hematology, Mito Medical Center, National Hospital Organization, Mito, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Komeno
authors.affiliation: Department of Hematology, Tsukuba Memorial Hospital, Tsukuba, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Hematology, JA Toride Medical Center, Toride, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Noguchi
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Noguchi
authors.affiliation: 1] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [2] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: 1] Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. [2] Department of Clinical Laboratory, University of Tsukuba Hospital, Tsukuba, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Suzukawa
authors.affiliation: Department of Clinical Laboratory, University of Tsukuba Hospital, Tsukuba, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nanmoku
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
authors.affiliation: 1] Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. [2] Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Pathology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Nakamura
authors.affiliation: 1] Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. [2] Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: 1] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [2] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. [3].
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: 1] Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. [2] Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan. [3].
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
mesh_terms: D000818:Animals; D001483:Base Sequence; D001973:Bromodeoxyuridine; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D059472:Exome / Q000235:genetics; D006801:Humans; D007119:Immunoblastic Lymphadenopathy / Q000235:genetics*; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D019169:Jurkat Cells; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D041681:NIH 3T3 Cells; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D011518:Proto-Oncogene Proteins; C066737:RHOA protein, human; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D020742:rhoA GTP-Binding Protein; D001973:Bromodeoxyuridine