NPM-ALK promotes cell-cycle progression through activation of JNK/cJun signaling in NPM-ALK⁺ ALCL. ALCL frequently carries the chromosomal translocation t(2;5)(p23;q35), resulting in aberrant expression of NPM-ALK. NPM-ALK has been shown to be oncogenic through activation of a number of cell- signaling pathways. This study reveals another oncogenic pathway, JNK/cJun, that is constitutively activated by the NPM-ALK fusion kinase. The JNKs, members of the MAPK superfamily, have been shown to play a role in cell proliferation and transformation. Activation of JNK, through phosphorylation by 2 distinct MAPK kinases, MAPK kinase 4 and MAPK kinase 7, mediates phosphorylation of cJun, the best-characterized transcription factor of the AP-1 family. Phosphorylation of cJun by JNK is essential for stimulation of its transcriptional activity and its growth-promoting effects. The latter can be mediated through regulation of a number of cell-cycle- controlling genes including the cyclin-dependent kinase inhibitor p21, which operates at both the G1/S and G2/M checkpoints. Taken together, our data suggest that the NPM-ALK–induced activation of JNK/cJun signaling may lead to uncontrolled cell-cycle progression and cell proliferation, thus contributing to oncogenesis of NPM-ALK⁺ ALCL.