Variegated RHOA mutations in adult T-cell leukemia/lymphoma

Yasunobu Nagata, Kenji Kontani, Terukazu Enami, Keisuke Kataoka, Ryohei Ishii, Yasushi Totoki, Tatsuki R. Kataoka, Masahiro Hirata, Kazuhiro Aoki, Kazumi Nakano, Akira Kitanaka, Mamiko Sakata-Yanagimoto, Sachiko Egami, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Yusuke Shiozawa, Tetsuichi Yoshizato, Hiromichi Suzuki, Ayana KonKenichi Yoshida, Yusuke Sato, Aiko Sato-Otsubo, Masashi Sanada, Wataru Munakata, Hiromi Nakamura, Natsuko Hama, Satoru Miyano, Osamu Nureki, Tatsuhiro Shibata, Hironori Haga, Kazuya Shimoda, Toshiaki Katada, Shigeru Chiba, Toshiki Watanabe, Seishi Ogawa

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

AdultT-cell leukemia/lymphoma(ATLL) isadistinct formofperipheral T-cell lymphomawith poor prognosis, which is caused by the human T-lymphotropic virus type 1 (HTLV-1). In contrast to theunequivocal importanceofHTLV-1infectioninthepathogenesisofATLL, the role of acquired mutations in HTLV-1 infected T cells has not been fully elucidated, with a handful of genes known to be recurrentlymutated. In this study,we identifieduniqueRHOA 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 werewidely 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. TheGly17Val mutant did not bind GTP/GDP and act as a dominant negativemolecule, whereas othermutants (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.

Original languageEnglish
Pages (from-to)596-604
Number of pages9
JournalBlood
Volume127
Issue number5
DOIs
Publication statusPublished - 2016 Feb 4
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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