title: Variegated RHOA mutations in adult T-cell leukemia/lymphoma.
abstract: Adult T-cell leukemia/lymphoma (ATLL) is a distinct form of peripheral T-cell lymphoma with poor prognosis, which is caused by the human T-lymphotropic virus type 1 (HTLV-1). In contrast to the unequivocal importance of HTLV-1 infection in the pathogenesis of ATLL, the role of acquired mutations in HTLV-1 infected T cells has not been fully elucidated, with a handful of genes known to be recurrently mutated. In this study, we identified unique RHOA mutations in ATLL through whole genome sequencing of an index case, followed by deep sequencing of 203 ATLL samples. RHOA mutations showed distinct distribution and function from those found in other cancers. Involving 15% (30/203) of ATLL cases, RHOA mutations were widely distributed across the entire coding sequence but almost invariably located at the guanosine triphosphate (GTP)-binding pocket, with Cys16Arg being most frequently observed. Unexpectedly, depending on mutation types and positions, these RHOA mutants showed different or even opposite functional consequences in terms of GTP/guanosine diphosphate (GDP)-binding kinetics, regulation of actin fibers, and transcriptional activation. The Gly17Val mutant did not bind GTP/GDP and act as a dominant negative molecule, whereas other mutants (Cys16Arg and Ala161Pro) showed fast GTP/GDP cycling with enhanced transcriptional activation. These findings suggest that both loss- and gain-of-RHOA functions could be involved in ATLL leukemogenesis. In summary, our study not only provides a novel insight into the molecular pathogenesis of ATLL but also highlights a unique role of variegation of heterologous RHOA mutations in human cancers.
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan;
authors.forename: Kenji
authors.initials: K
authors.lastname: Kontani
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan;
authors.forename: Terukazu
authors.initials: T
authors.lastname: Enami
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan;
authors.forename: Ryohei
authors.initials: R
authors.lastname: Ishii
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan;
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Totoki
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan;
authors.forename: Tatsuki R
authors.initials: TR
authors.lastname: Kataoka
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan;
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Aoki
authors.affiliation: Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan;
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; and.
authors.forename: Akira
authors.initials: A
authors.lastname: Kitanaka
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan;
authors.forename: Mamiko
authors.initials: M
authors.lastname: Sakata-Yanagimoto
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan;
authors.forename: Sachiko
authors.initials: S
authors.lastname: Egami
authors.affiliation: Laboratory of DNA Information Analysis, and.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information Analysis, and.
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: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Tetsuichi
authors.initials: T
authors.lastname: Yoshizato
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Ayana
authors.initials: A
authors.lastname: Kon
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, 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, Kyoto, Japan;
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: 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: 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: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan;
authors.forename: Wataru
authors.initials: W
authors.lastname: Munakata
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan;
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan;
authors.forename: Natsuko
authors.initials: N
authors.lastname: Hama
authors.affiliation: Laboratory of DNA Information Analysis, and 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 Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan;
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan;
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan;
authors.forename: Hironori
authors.initials: H
authors.lastname: Haga
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; and.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan;
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Katada
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan;
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
authors.affiliation: Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan;
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001665:Binding Sites; D004252:DNA Mutational Analysis; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D020742:rhoA GTP-Binding Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C066737:RHOA protein, human; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D020742:rhoA GTP-Binding Protein