HTLV-1 hijacks T-cell differentiation/function by deregulatingHelios gene expression

2012 Fiscal Year Final Research Report

• Project/Area Number: 23659484
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: WATANABE Toshiki 東京大学, 大学院・新領域創成科学研究科, 教授 (30182934)
• Co-Investigator(Kenkyū-buntansha): NAKANO Kazumi 東京大学, 大学院・新領域創成科学研究科, 助教 (60549591)
• Project Period (FY): 2011 – 2012
• Keywords: CD4 陽性 T 細胞 / HTLV-1 Tax / Helios / スプライス変異 / ドミナントネガティブ

Research Abstract

Adult T-cell leukemia is a T-cell neoplasm caused by HTLV-1 infection. In the present study, we found drastic deregulation of Helios expression in ATL cells. Helios is an Ikaros-family transcription factor and a pivotal regulator of T-cell differentiation and activation. Detailed investigations in transcript variants of Helios in PBMCs from ATL patients clarified that the majority of ATL patients demonstrated abnormal splicing patterns of Helios mRNAs, while four cases did not express Helios mRNA at the detectable level. We identified ATL-specific short Helios transcripts and further confirmed that resultant isoforms not only functioned dominant-negatively, but also reduced apoptotic sensitivity and increased proliferation of the cells, probably through activation of S1P pathway, which is deeplyimplicated to cell-motility and proliferation.

Research Products

• [Journal Article] Adult T-cell leukemia cells are characterized by abnormalities of Helios expression that promotes T-cell growth (2013)
  • Author(s): Asanuma S, Yamagishi M, Kawanami K, Nakano K, Sato-Otsubo A, Muto S, Sanada M, Yamochi T, Kobayashi S, Utsunomiya A, Iwanaga M, Yamaguchi K, Uchimaru K, Ogawa S, Watanabe T
  • Journal Title: Cancer Sci Volume: 104(5) Pages: 32
  • DOI: doi:10.1111/cas.12181
  • Peer Reviewed
• [Presentation] Aberrrantly spliced Helios variants in ATL cells induce T cellproliferation (2012)
  • Author(s): Asanuma S, Nakano K, Yamagishi M, Ogawa S, Yamaguchi K, Utsunomiya A, Watanabe T
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 20121019-1021
• [Presentation] 新規ATL型HeliosはIkaros転写因子ファミリーの機能を阻害し、T細胞の増殖を促進する (2011)
  • Author(s): 浅沼里実,川波克明,山岸誠,中野和民,山口一成,宇都宮與,渡邉俊樹
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20111213-16
• [Presentation] 新規ATL型HeliosはIkaros転写因子ファミリーの機能を阻害し、T細胞の増殖を促進する (2011)
  • Author(s): 浅沼里実、川波克明、山岸誠、中野和民、山口一成、宇都宮與、渡邉俊樹
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 20111003-05
• [Presentation] Novel Helios variants found in ATL cells hamper functions of Ikaros family proteins and induce T cell proliferation (2011)
  • Author(s): Asanuma S, Kawanami K, Yamagishi M, Nakano K, Yamaguchi K, Utsunomiya A, Watanabe T
  • Organizer: The XXV Symposium of the International Association for Comparative Research on Leukemia and Related Diseases
  • Place of Presentation: Yayoi Auditorium of Univ.Tokyo
  • Year and Date: 20110915-17
• [Presentation] Over-expression of dominant-negative Helios isoforms in adult T-cell leukemia (ATL) cells (2011)
  • Author(s): Asanuma S, Kawanami K, Nakano K,Yamagishi M, Yamaguchi K, Utsunomiya A, Watanabe T
  • Organizer: The 15^th International Conference on Human Retrovirology: HTLV and Related Viruses
  • Place of Presentation: Lueven, Belgium
  • Year and Date: 20110605-08