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(American Journal of Pathology. 2002;161:875-883.)
© 2002 American Society for Investigative Pathology

Regular Articles

The Nucleophosmin-Anaplastic Lymphoma Kinase Fusion Protein Induces c-Myc Expression in Pediatric Anaplastic Large Cell Lymphomas

Elizabeth A. Raetz*{dagger}, Sherrie L. Perkins{ddagger}, Marlee A. Carlson*, Kevin P. Schooler{ddagger}, William L. Carroll*{dagger}§ and David M. Virshup*{dagger}§

From the Center for Children at the Huntsman Cancer Institute;* the Department of Pediatrics,{dagger} Division of Pediatric Hematology-Oncology; and the Departments of Pathology{ddagger} and Oncological Sciences,§ University of Utah, Salt Lake City, Utah

The majority of pediatric anaplastic large cell lymphomas (ALCLs) carry the t(2;5)(p23;q35) chromosomal translocation that juxtaposes the dimerization domain of nucleophosmin with anaplastic lymphoma kinase (ALK). The nucleophosmin-ALK fusion induces constitutive, ligand-independent activation of the ALK tyrosine kinase leading to aberrant activation of cellular signaling pathways. To study the early consequences of ectopic ALK activation, a GyrB-ALK fusion was constructed that allowed regulated dimerization with the addition of coumermycin. Expression of the fusion protein caused a coumermycin-dependent increase in cellular tyrosine phosphorylation and c-Myc immunoreactivity, which was paralleled by a rise in c-myc RNA. To assess the clinical relevance of this observation, c-Myc expression was determined in pediatric ALK-positive and -negative lymphomas. Co-expression of c-Myc and ALK was seen in tumor cells in 15 of 15 (100%) ALK-positive ALCL samples, whereas no expression of either ALK or c-Myc was seen in six of six cases of ALK-negative T-cell lymphoma. C-Myc may be a downstream target of ALK signaling and its expression a defining characteristic of ALK-positive ALCLs.




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