NPM-ALK signals through the T-cell receptor (TCR), IL-2-type cytokine, and STAT3 pathways. Aberrant NPM-ALK kinase activity hijacks key cell signaling pathways physiologically activated by TCR and IL-2 signaling pathways. Epigenetic silencing of the tumor suppressor genes SHP-1, STAT5a, and IL-2Rg by STAT3-activated DNA methyltransferases (DNMTs) inhibits the downregulation of NPM-ALK. Dashed lines reflect loss of expression and function as a result of epigenetic gene silencing. Transcriptional targets directly downstream of these signaling pathways include key transcription factors and other cell cycle and apoptosis regulators that normally promote growth and survival but lead to oncogenesis in ALK+ ALCL. Other direct transcriptional targets include histologic markers (CD30, CD274), immunosuppressive cytokines (IL10, TGFβ), and angiogenic factors (HIF1α). Phosphoproteomic analysis has revealed that in addition to modulating important signaling pathways, NPM-ALK alters key metabolic pathways through phosphorylation, such as that of the rate-limiting enzyme pyruvate kinase, whose phosphorylation inactivates the enzyme promoting a shift from aerobic to anaerobic glycolysis.