Abstract Activating mutations in the Vav guanine nucleotide exchange factor 1 (VAV1) gene are reported in various subtypes of mature T-cell neoplasms (TCNs). However, oncogenic activities associated with VAV1 mutations in TCNs remain unclear. To define them, we established transgenic mice expressing VAV1 mutants cloned from human TCNs. 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 TCNs with tendency of maturation developed in p53−/−VAV1-Tg mice, whereas p53−/− mice exhibited only immature TCNs. Mature TCNs in p53−/−VAV1-Tg mice mimicked a subtype of human peripheral T-cell lymphoma (PTCL-GATA3) and exhibited features of type 2 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 showed enrichment of multiple Myc-related pathways in TCNs from p53−/−VAV1-Tg mice relative to p53−/− or wild-type T cells. Remarkably, amplification of the Myc locus was found recurrently in TCNs of p53−/−VAV1-Tg mice. Finally, treatment of nude mice transplanted with p53−/−VAV1-Tg tumor cells with JQ1, a bromodomain inhibitor that 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 TCNs harboring these mutations.