The NPM-ALK oncoprotein abrogates CD30 signaling and constitutive NF-κB activation in anaplastic large cell lymphoma

AbstractNPM-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-κB activation, which is absent in ALCL cells. Here we show that NPM-ALK impedes CD30 signaling and NF-κB 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-κB activation and can also induce an ALCL phenotype, distinguishing ALCL cells from H-RS cells of T cell origin