Angioimmunoblastic T-cell lymphoma-like lymphadenopathy in mice transgenic for human with p.Gly17Val mutation.

A missense mutation in encoding p.Gly17 Val has been reported to occur frequently in angioimmunoblastic T-cell lymphoma (AITL). Here, we describe a murine model which expresses the human mutant gene product in a T-cell specific manner and develops AITL-like symptoms. Most transgenic mice feature with latency one or two enlarged lymph nodes characterized by aberrant lymph node architecture, extensive lymphocytic infiltration, extrafollicular meshwork of follicular dendritic cells (FDC) and arborized endothelial venules. Importantly, we provide evidence for expansion of PD-1+ follicular helper T (Tfh) cells which are the neoplastic cells of AITL. In addition, we saw proliferation of B-cells leading to hypergammaglobulinemia and the presence of dominant T cell clonal populations. Transplantation of lymph node cells to immunocompromised mice partly recreated lymphadenopathy after a long latency and with low penetrance suggesting that cells have undergone partial transformation to a premalignant state. Transcriptomic profiling revealed that the gene expression pattern within affected lymph nodes of the mice closely resembles that of AITL patients with the identical p.Gly17 Val mutation. The murine model should, therefore, be useful in dissecting pathogenesis of AITL at the molecular level particularly for the cases with the p.Gly17Val mutation.