期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 53, 期 3, 页码 -出版社
WILEY
DOI: 10.1002/eji.202250147
关键词
Human fusion oncogene; Immunology; Peripheral T-cell lymphoma; VAV1-MYO1F
类别
VAV1-MYO1F is a newly identified fusion protein that is frequently detected in T-cell non-Hodgkin's lymphoma (T-NHL) patients. The pathophysiological functions of VAV1-MYO1F in lymphomagenesis are not well defined. In this study, transgenic mouse models were generated to conditionally express VAV1-MYO1F in T-cells. The results demonstrate that VAV1-MYO1F triggers cell autonomous activation of T-cell signaling and induces aberrant T-cell differentiation, proliferation, and neoplastic transformation.
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.
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