| 研究実績の概要 |
Background: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive T-cell neoplasm (TCN). Genetic analysis has identified RHOAG17V and TET2 loss-of-function mutations in 70% of AITL patients. In the other hand, VAV1 mutations have been found in 8% of non RHOA-mutated patients.
Methods: Mice expressing RHOAG17V and VAV1 mutants (VAV1Tg) under CD2 promoter were generated. RHOAG17V mice were crossed with MxCreTet2f/f mice and pIpC was given to obtain Tet2 deficiency and RHOAG17V mutant (Tet2-/-RHOAG17V) mice. VAV1Tg mice were crossed with p53-/- mice to get p53 deficiency and VAV1 mutant (p53-/- VAV1Tg) mice.
Results: Tet2-/-RHOAG17V mice spontaneously developed AITL-like lymphomas due to deregulated T-cell receptor signaling pathway. Using these mice, we found that dasatinib, a multikinase inhibitor, was effective in the treatment of AITL. Meanwhile, VAV1Tg mice did not develop any tumors after one year follow-up. However, p53-/- VAV1Tg mice developed TCN including immature and mature tumors while p53-/- mice developed only immature tumors. The mature tumors in p53-/- VAV1Tg mice mimicked human peripheral T-cell lymphomas. Enrichment of Myc-related pathways and somatic copy number alterations of Myc locus were found in these tumors. JQ1, a bromodomain inhibitor targeting the Myc pathway, was effective in treatment of TCN in p53-/- VAV1 mice.
Conclusion: The combination of RHOAG17V mutant and Tet2 deficiency or the one of VAV1 mutants and p53 deficiency led to the development of TCN in mice. These mouse models may be useful to examine novel treatment strategies for TCN.
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