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Modeling Angioimmunoblastic T-cell lymphoma in mouse based on its genetic lesions

Research Project

Project/Area Number 18K16077
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionUniversity of Tsukuba

Principal Investigator

NGUYEN BICH-TRAN  筑波大学, 医学医療系, 研究員 (10812901)

Project Period (FY) 2018-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
KeywordsAITL / dasatinib / RHOA / TET2 / VAV1 / PTCL / Dasatinib
Outline of Final Research Achievements

Genetic analysis has identified the co-exist of TET2 loss-of-function and RHOA mutations, and VAV1 mutations in Angioimmunoblastic T-cell lymphoma (AITL), an aggressive T-cell neoplasm (TCN). To clarify the AITL pathogenesis, we generated mouse models based on these genetic lesions. Mice expressing Tet2 deficiency and RHOA mutant (Tet2-/-RHOATg) and mice expressing p53 deficiency and VAV1 mutant (p53-/- VAV1Tg) were generated. Tet2-/-RHOATg mice developed AITL-like lymphomas due to deregulated T-cell receptor signaling pathway. We found that dasatinib, a multikinase inhibitor, was effective in the treatment of mouse AITL. p53-/- VAV1Tg mice developed TCN mimicked human peripheral T-cell lymphomas while p53-/- developed immature TCN. Enrichment of Myc-related pathways and somatic copy number alterations of Myc locus were found in these tumors. The combination of Tet2 deficiency and RHOA mutant or the one of p53 deficiency and VAV1 mutants led to the development of TCN in mice.

Academic Significance and Societal Importance of the Research Achievements

The roles of common genetic lesions in human T-cell lymphoma (TCN) were clarified. Using these mice for testing some potential drugs, we have found that dasatinib was effective in mouse TCN treatment. Our results may be useful for TCN treatment and improve the prognosis of this intractable disease.

Report

(3 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • Research Products

    (7 results)

All 2020 2019 2018

All Journal Article (2 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (5 results) (of which Int'l Joint Research: 4 results)

  • [Journal Article] Dasatinib is an effective treatment for angioimmunoblastic T-cell lymphoma.2020

    • Author(s)
      Nguyen TB, Sakata-Yanagimoto M, Fujisawa M, Tanzima Nuhat S, Miyoshi H, Nannya Y, Hashimoto K, Fukumoto K, Bernard OA, Kiyoki Y, Ishitsuka K, Momose H, Sukegawa S, Shinagawa A, Suyama T, Sato Y, Nishikii H, Obara N, Kusakabe M, Yanagimoto S, Ogawa S, Ohshima K, Chiba S.
    • Journal Title

      Cancer Res. 2020.

      Volume: - Issue: 9 Pages: 1875-1884

    • DOI

      10.1158/0008-5472.can-19-2787

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Blastic plasmacytoid dendritic cell neoplasm arising from clonal hematopoiesis2018

    • Author(s)
      Suma Sakurako、Sakata-Yanagimoto Mamiko、Nguyen Tran B.、Hattori Keiichiro、Sato Taiki、Noguchi Masayuki、Nannya Yasuhito、Ogawa Seishi、Watanabe Rei、Fujimoto Manabu、Nakamura Naoya、Kusakabe Manabu、Nishikii Hidekazu、Kato Takayasu、Chiba Shigeru
    • Journal Title

      International Journal of Hematology

      Volume: 108 Issue: 4 Pages: 447-451

    • DOI

      10.1007/s12185-018-2461-z

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Targeting T-cell Receptor signaling pathway as Angioimmunoblastic T-cell treatment2019

    • Author(s)
      Tran B. Nguyen
    • Organizer
      the 78th Annual Meeting of the Japanese Cancer Association, Japan
    • Related Report
      2019 Annual Research Report
  • [Presentation] VAV1 Mutations Contributes to the Development of T-Cell Malignancies in Mice2019

    • Author(s)
      Kota Fukumoto
    • Organizer
      the 61st ASH Annual Meeting and Exposition, USA
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Effectiveness of Dasatinib in an Angioimmunoblastic T-cell Lymphoma Mouse Model2018

    • Author(s)
      Nguyen Bich Tran
    • Organizer
      Japanese Association of Hematology International Symposium
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Effectiveness of Dasatinib in a T-cell Lymphoma Mouse Model2018

    • Author(s)
      Nguyen Bich Tran
    • Organizer
      Japanese Cancer Association Annual Meeting 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Effectiveness of Dasatinib in an Angioimmunoblastic T-cell Lymphoma Mouse Model2018

    • Author(s)
      Nguyen Bich Tran
    • Organizer
      Japanese Association of Hematology Annual Meeting 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2021-02-19  

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