Modeling Angioimmunoblastic T-cell lymphoma in mouse based on its genetic lesions
Project/Area Number |
18K16077
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 54010:Hematology and medical oncology-related
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Research Institution | University of Tsukuba |
Principal Investigator |
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Project Period (FY) |
2018-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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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)
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Keywords | AITL / 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.
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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.
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Report
(3 results)
Research Products
(7 results)
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[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.
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Journal Title
Cancer Res. 2020.
Volume: -
Issue: 9
Pages: 1875-1884
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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
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Journal Title
International Journal of Hematology
Volume: 108
Issue: 4
Pages: 447-451
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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