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

A missense mutation in RHOA encoding p.Gly17Val has been reported to occur frequently in angioimmunoblastic T-cell lymphoma (AITL). Here, we describe a murine model which expresses the human RHOA 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. We also provide evidence for presence of dominant T cell clonal populations and expansion of B-cells leading to hypergammaglobulinemia. Transcriptomic profiling revealed that the gene expression pattern within affected lymph nodes of the mice most closely resembles that of AITL patients with the identical p.Gly17Val mutation. The murine model should therefore be useful in dissecting pathogenesis of AITL at the molecular level and in preclinical trials of various therapeutic agents, particularly for the cases with the highly prevalent p.Gly17Val mutation. 9 lymph nodes, including 4 tumor samples (enlarged lymph nodes from RHOA p.Gly17Val transgenic mice), 3 control samples (lymph nodes from litter mates), and 2 seemingly normal (i.e. not enlarged) lymph nodes from RHOA p.Gly17Val transgenic mice CD4+lymphocytes from RHOA transgenic mice and from litter mates.