Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming

摘要: Anaplastic lymphoma kinase (ALK), physiologically expressed only by nervous system cells, displays a remarkable capacity to transform CD4(+) T lymphocytes and other types of nonneural cells. In this study, we report that activity nucleophosmin (NPM)/ALK chimeric protein, the dominant form ALK in cell lymphomas (TCLs), closely resembles activation induced IL-2, key cytokine supporting growth survival normal lymphocytes. Direct comparison gene expression ALK(+) TCL cells treated with an inhibitor IL-2-dependent ALK(-) stimulated revealed very similar, albeit inverse, gene-regulation pattern. Depending on analysis method, up 67% affected genes were modulated common NPM/ALK IL-2. Based patterns, Jak/STAT- IL-2-signaling pathways topped list identified as both IL-2 NPM/ALK. The dependence five selected genes-CD25 (IL-2Rα), Egr-1, Fosl-1, SOCS3, Irf-4-was confirmed at protein level. IL-2-stimulated CD25, Irf-4 activated predominantly STAT5 STAT3 transcription factors, whereas Egr-1 Fosl-1 was MEK-ERK pathway. Finally, found not associated previously either or ALK, contributes proliferation. These findings indicate transforms target lymphocytes, least part, using pre-existing, signaling pathways.