""""""""The anaplastic lymphoma kinase is a tyrosine kinase that is activated in human T-cells by a chromosomal translocation t(2;5) that fuses the catalytic domain of anaplastic lymphoma kinase (ALK) with a protein oligomerization domain of nucleophosmin (NPM), a nuclear protein. This fusion protein, NPM-ALK is the causative molecular lesion responsible for nearly 60% of cases of anaplastic large cell lymphoma in humans. Prior work in this laboratory has established that NPM-ALK can potently transform rat1a fibroblasts. Expression of NPM-ALK in human T-cells shows that it is a potent activator of signaling pathways that are important in T-cell activation. Work in the laboratory has established that NPM-ALK activates signaling pathways that are responsible for inducing the transcriptional activity of two distinct transcription factor families; c-rel, and ATF/CREB. The action of NPM-ALK is ras- dependent. Recent work shows that NPM-ALK can function at a position downstream of the activated T-cell receptor that can potentiate signaling induced by co-stimulation through the CD28 receptor. Moreover, the expression of NPM-ALK in human T-cells induces the transcriptional activation of multiple enhancers within the interleukin-2 promoter. These data suggest that NPM-ALK may play a major role in the transformation of human T-cells through the promotion of an interleukin-2 mediated autocrine growth-factor loop similar to that seen in the molecular pathogenesis of HTLV-I associated leukemia/lymphoma. Current efforts are focussed at identifying the precise molecular signaling pathways in human T-cells that are effected by NPM-ALK.""""""""
