Development of T-cell lymphomas in Emu-IEX-1 mice

Inhibition of apoptosis or abnormal cell survival can result in tumorigenesis by facilitating the insurgence of various mutations. Immediate-early response gene X-1 (IEX-1), protects T cells from apoptosis induced by the ligation of Fas or the T-cell receptor (TCR)/CD3 complex in Emu-IEX-1 mice that direct the gene expression in both T and B cell lineages under the control of the Emu enhancer. Consistent with a biased effect of IEX-1 towards T cells, Emu-IEX-1 mice selectively developed T-cell lymphomas in the spleen, when they aged, which may be associated with increased levels of IEX-1 phosphorylation in T cells compared to B cells. The lymphomas were single positive (CD4+CD8-, CD4-CD8+), double positive (CD4+CD8+), or double negative (CD4-CD8-) T cells. They resulted from aberrantly clonal expansions of T cells expressing a specific TCR, as suggested by the TCR repertoire analysis using a panel of monoclonal antibodies recognizing TCR Vbeta chain, as well as by TCR beta gene rearrangements. The study provides, for the first time, unambiguous evidence of the oncogenic potential of IEX-1 in a cell-specific manner. The animal model may help our understanding of peripheral T-cell lymphoma development.