Integrated approach toward angioimmunoblastic T-cell lymphoma - elucidation of molecular mechanism and development of diagnostics and therapeutics

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H02660
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Tsukuba
• Principal Investigator: Chiba Shigeru 筑波大学, 医学医療系, 教授 (60212049)
• Research Collaborator: Kato Takayasu ; Nguyen Bich Tran ; Hattori Keichiro ; Fujisawa Manabu ; Fukumoto Kota ; Tanzima Nuhat Sharna
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 血管免疫芽球性T細胞リンパ腫 / RHOA / TET2 / VAV1 / 治療標的

Outline of Final Research Achievements

We screened a protein that specifically bound to a previously identified angioimmunoblastic T-cell lymphoma (AITL)-specific RHOA(G17V) mutant, and identified VAV1, a signaling protein. By the binding, VAV1 tyrosine phosphorylation was enhanced and T cell receptor downstream signaling was strengthened. We then showed that dasatinib, a commercially available tyrosine kinase inhibitor, suppressed VAV1 phosphorylation and T cell receptor downstream signals. We also observed that Tet2 gene disruption and RHOA(G17V) expression, mimicking the AITL genome, developed AITL-like T-cell lymphoma in mice, and this tumor responded to dasatinib. The survival of the tumor-bearing recipient mice was prolonged by dasatinib administration.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

研究代表者らが世界的に高い競争力をもつ血管免疫芽球性T細胞リンパ腫(AITL)について、病態解明と診断・治療法開発を目指した。遺伝子変異の同定に基づいて申請した診断法特許が2018年に成立し検査会社が商品化した。一方、変異蛋白質に特異的に結合する蛋白質の同定を手がかりに、この蛋白質をリン酸化する酵素が治療標的になることを見出し、マウスで作製したAITLモデルを用いて、市販されているチロシンキナーゼ阻害剤が有効であることを示した。この成果に基づいて臨床試験を計画している。期待通りの結果が得られれば、既存薬の適応拡大に繋がり、AITLの新規治療薬として大きな意義をもつ。