Development of T-cell lymphomas in Eμ-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 Eμ-IEX-1 mice that direct the gene expression in both T and B cell lineages under the control of the Eμ enhancer. Consistent with a biased effect of IEX-1 towards T cells, Eμ-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 Vβ chain, as well as by TCR β 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.