Activating mutations in the Vav guanine nucleotide exchange factor 1 (VAV1) gene are reported in various subtypes of mature T-cell neoplasms (TCN). However, oncogenic activities associated with VAV1 mutations in TCN remain unclear. To define them, we established transgenic mice expressing VAV1 mutants cloned from human TCN. Although we observed no tumors in these mice for up to a year, tumors did develop in comparably-aged mice on a p53-null background (p53-/- VAV1-Tg), and p53-/- VAV1-Tg mice died with shorter latencies than did p53-null (p53-/-) mice. Notably, various TCN with tendency of maturation developed in p53-/- VAV1-Tg mice, while p53-/- mice exhibited only immature TCN. Mature TCN in p53-/- VAV1-Tg mice mimicked human peripheral T-cell lymphoma (PTCL)-GATA3 and exhibited features of type2 T helper (TH2) cells. Phenotypes seen following transplantation of either p53-/- VAV1 or p53-/- tumor cells into nude mice were comparable, indicating cell-autonomous tumor-initiating capacity. Whole transcriptome analysis (WTA) showed enrichment of multiple Myc-related pathways in TCN from p53-/- VAV1-Tg mice relative to p53-/- or wild-type T cells. Remarkably, amplification of Myc locus were found recurrently in TCN of p53-/- VAV1-Tg mice. Finally, treatment of nude mice transplanted with p53-/- VAV1-Tg tumor cells with JQ1, a bromodomain inhibitor, which targets the Myc pathway, prolonged survival of mice. We conclude that VAV1 mutations function in malignant transformation of T cells in vivo and that VAV1-mutant expressing mice could provide an efficient tool for screening new therapeutic targets in TCN harboring these mutations. We conclude that VAV1 mutations function in malignant transformation of T cells in vivo and that VAV1-mutant expressing mice could provide an efficient tool for screening new therapeutic targets in TCN harboring these mutations.