2019 Fiscal Year Final Research Report
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 |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | University of Tsukuba |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Keywords | AITL / dasatinib / RHOA / TET2 / VAV1 |
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| 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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| Free Research Field |
Hematology-Oncology
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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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