A model for NPM-ALK oncogenicity. In t(2:5)(p23:q35) cells, NPM-ALK enhances transcription of target genes (1) through known signaling pathways, including PLCγ, PI3K, and STAT3/5 activation. Some of these up-regulated genes encode ARE-containing mRNAs whose stability involves AU-BPs. In addition, NPM-ALK enhances mRNA stability (2) by inducing hyperphosphorylation of AUF1. Depending on whether AUF1 is a stabilizing or a destabilizing factor, its posttranslational modification respectively either increases (A) or decreases (B) its affinity/binding for its target mRNAs, in either case leading to their increased stability. Decreased affinity of a destabilizing protein might favor the binding of a stabilizing AU-BP, such as HuR, thus contributing to increased stability of ARE-containing mRNAs. The phosphorylated AUF1 form might also be trapped together with NPM-ALK in cytoplasmic granules (B), allowing access of stabilizing HuR to ARE-mRNAs. In conclusion, enhancing transcription and increasing stability of mRNAs encoding for proteins which are key players of cell proliferation are 2 facets of NPM-ALK activity which both contribute to its oncogenicity.