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The anaplastic lymphoma kinase (ALK) gene fuses to the nucleophosmin (NPM) gene as a result of a (2;5) translocation associated with a subtype of human lymphoma (initially designated anaplastic large cell lymphoma [ALCL] or Ki-1/CD30–positive lymphoma). The immunocytochemical detection of NPM-ALK (and proteins encoded by other ALK fusion genes) has allowed the definition of a tumor entity, “ALK-positive lymphoma” (which shows only partial overlap with pathologists' diagnosis of ALCL), to be defined and is invaluable in distinguishing this disease from ALK-negative large cell lymphomas. Eight variant ALK fusion proteins have been identified. Some are expressed only in ALCL, some are found only in the nonhematopoietic neoplasm inflammatory myofibroblastic tumor (IMT), and some are present in both types of malignancy. The ALK gene is silent in adult tissues except for restricted sites within the nervous system (consequently, patients with ALK-positive lymphoma produce antibodies to the ALK protein) but is expressed in some neuroblastomas and rhabdomyosarcomas. Biochemical studies suggest an anti-apoptotic function of NPM-ALK, and this may contribute to oncogenesis. Although ALK-positive lymphomas have a generally good prognosis, new therapeutic regimens are still needed for patients whose disease is refractory to conventional treatment.