Abstract
NPM-ALK characterizes anaplastic large cell lymphoma (ALCL), as does the high expression of CD30, a feature shared with H-RS cells of classic Hodgkin's lymphoma. In H-RS cells, ligand-independent signaling by overexpressed CD30 drives constitutive NF-kappaB activation, which is absent in ALCL cells. Here we show that NPM-ALK impedes CD30 signaling and NF-kappaB activation, dependent on both ALK kinase activity and the N-terminal NPM domain. NPM-ALK transduction into H-RS cell lines abrogates recruitment and aggregation of TRAF proteins, inducing an ALCL-like morphology and phenotype. TRAF2 associates with NPM-ALK at a consensus binding motif located in the kinase domain. Thus, NPM-ALK abrogates CD30-driven NF-kappaB activation and can also induce an ALCL phenotype, distinguishing ALCL cells from H-RS cells of T cell origin.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Amino Acid Motifs
-
Cells, Cultured
-
Consensus Sequence
-
Cytoplasm / metabolism
-
Electrophoretic Mobility Shift Assay
-
Humans
-
I-kappa B Proteins / metabolism
-
Ki-1 Antigen / genetics
-
Ki-1 Antigen / metabolism*
-
Lymphoma, Large-Cell, Anaplastic / genetics
-
Lymphoma, Large-Cell, Anaplastic / metabolism*
-
Lymphoma, Large-Cell, Anaplastic / pathology
-
NF-kappa B / genetics
-
NF-kappa B / metabolism*
-
Oncogene Proteins, Fusion / genetics
-
Oncogene Proteins, Fusion / metabolism*
-
Phenotype
-
Phosphorylation
-
Protein Binding
-
Protein-Tyrosine Kinases / genetics
-
Protein-Tyrosine Kinases / metabolism*
-
Proteins / metabolism*
-
Signal Transduction
-
TNF Receptor-Associated Factor 2
-
Tyrosine / metabolism
Substances
-
I-kappa B Proteins
-
Ki-1 Antigen
-
NF-kappa B
-
Oncogene Proteins, Fusion
-
Proteins
-
TNF Receptor-Associated Factor 2
-
Tyrosine
-
p80(NPM-ALK) protein
-
Protein-Tyrosine Kinases