The Oncogenic Fusionprotein NPM-ALK Cooperates with Bcl2 To Induce T-Cell Lymphomas in Mice.

The NPM-ALK fusion oncogene arising from the t(2;5) translocation has been shown to transform lymphoid cells in culture and induce tumors in mice. In a previous report, we have demonstrated that expression of NPM-ALK in a murine retroviral infection/transplantation model leads to histiocytic and plasmacytoid tumors in mice. In the earlier model, we did not find any signs of a T-cell malignancy in the transplanted animals, although control animals transplanted with an empty vector expressing EGFP demonstrated successful targeting of the T-cell compartment. To further delineate the effects of NPM-ALK expression in T-cells in cell culture, we infected a human T-cell line (Jurkat) with NPM-ALK. Interestingly, NPM-ALK expressing cells demonstrated an increased rate of apoptosis, whereas control infected cells showed normal growth without significant cell death. Bcl2 levels were reduced in the NPM-ALK expressing cells and exogenous Bcl2 expression could partially rescue NPM-ALK induced cell death. We therefore investigated the effect of increased Bcl2 expression in vivo by infection of either C57B6 wild type or vav-Bcl2 transgenic mice derived BM cells with NPM-ALK and subsequent transplantation into lethally irradiated recipient mice. Whereas the control mice mostly developed the previously described histiocytic malignancy without significant T-cell involvement, all mice receiving NPM-ALK and Bcl2 coexpressing cells displayed a thymus derived T-cell lymphoma with infiltration of the thymus, lymphnodes, spleen and to a lesser extent also the bone marrow, where the histiocytic phenoype predominated. The malignant T-cells expressed Thy1.2, CD4 and NPM-ALK, but were mostly TdT negative. Our results implicate that Bcl2 cooperates with NPM-ALK in the induction of T-cell lymphomas, suggesting that NPM-ALK may require additional hits to suppress apoptosis and induce full transformation in T-cells.