Abstract 2543: Akt and Myc cooperate to promote cell proliferation in Lck-Dlx5 T-cell lymphomas

Abstract

Abstract Constitutive activation of AKT is a frequent occurrence in the development of human T-cell acute lymphocytic leukemia/lymphoma (T-ALL), due largely to inactivation of PTEN. Up regulation of MYC is also commonly observed in T-ALL. We previously demonstrated that transgenic expression of a constitutively active form of Akt2 alone is sufficient to initiate T-cell lymphoma in mice, and that tumor formation typically requires up regulation of c-Myc or Dlx5 caused by specific chromosomal rearrangements. Here we report that transgenic overexpression of Dlx5 specifically in the mouse thymus can also drive T-cell lymphomagenesis. Tumors from these mice were characterized by loss of Pten expression and trisomy 15. Proliferation of these lymphoma cells was highly sensitive to the Akt pathway inhibitors BEZ235 and RAD001 as well as to the Myc inhibitor JQ1. Additionally, BEZ235 was found to cooperate with JQ1 to induce a more profound effect on cell cycle arrest and apoptosis. Moreover, BEZ235 potentiated vincristine-induced apoptosis when cells were treated with both drugs simultaneously, whereas pretreatment with BEZ235 antagonized the cell-killing effect of vincristine. These findings suggest that combination therapies with AKT and MYC inhibitors hold promise for the treatment of T-ALL in the clinic. Citation Format: Yinfei Tan, Eleonora Sementino, Joseph Testa. Akt and Myc cooperate to promote cell proliferation in Lck-Dlx5 T-cell lymphomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2543. doi:10.1158/1538-7445.AM2015-2543