The fusion oncogene VAV1‐MYO1F triggers aberrant T‐cell receptor signaling in vivo and drives peripheral T‐cell lymphoma in mice

VAV1‐MYO1F is a recently identified gain‐of‐function fusion protein of the proto‐oncogene Vav guanine nucleotide exchange factor 1 (VAV1) that is recurrently detected in T‐cell non‐Hodgkin's lymphoma (T‐NHL) patients. However, the pathophysiological functions of VAV1‐MYO1F in lymphomagenesis are insufficiently defined. Therefore, we generated transgenic mouse models to conditionally express VAV1‐MYO1F in T‐cells in vivo. We demonstrate that VAV1‐MYO1F triggers cell autonomous activation of T‐cell signaling with an activation of the ERK, JNK, and AKT pathways. VAV1‐MYO1F expression induces a T‐cell activation phenotype with high surface expression of CD25, ICOS, CD44, PD‐1, and decreased CD62L as well as aberrant T‐cell differentiation, proliferation, and neoplastic transformation. Consequently, the VAV1‐MYO1F expressing T‐cells induce a malignant T lymphoproliferative disease with 100% penetrance in vivo that mimics key aspects of human peripheral T‐cell lymphoma. These results demonstrate that the human T‐cell oncogene VAV1‐MYO1F is sufficient to trigger oncogenic T‐cell signaling and neoplastic transformation, and moreover, it provides a new clinically relevant mouse model to explore the pathogenesis of and treatment concepts for human T‐cell lymphoma.