Figure 6

Model of ALK and CD30 signaling. In ALCL, the NPM–ALK fusion protein governs CD30 expression by phosphorylating signal transducer and activator of transcription 3 (STAT3). NPM–ALK also regulates extracellular signal-regulated kinase 1 (ERK1)- and ERK2-mediated activation of JUNB protein. Phosphorylated STAT3 and activated AP1 complexes containing JUNB then cooperate to enhance CD30 transcription. NPM–ALK impedes CD30 signaling and NFκB activation by sequestering tumor necrosis factor receptor-associated factor 2 (TRAF2) away from CD30. This occurs via dimerization of NPM-ALK with wild-type (WT) NPM. CD30 engagement normally causes TRAF2 degradation. Engagement of CD30 on ALCL cells results in activation of both the canonical and alternative NFκB pathways, which causes apoptosis and p21-mediated cell-cycle arrest. A clinical trial is testing the use of anti-CD30 antibodies (red arrow) in ALCL109. Reprinted from Chiarle et al.⁷⁷