Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) is a distinct entity of T-cell lymphoma that can be divided into two subtypes based on the presence of translocations involving the ALK gene (ALK+ and ALK- ALCL). The transcription factor IRF4 is known to be highly expressed in both ALK+ and ALK- ALCLs. However, the role of IRF4 in the pathogenesis of these lymphomas remains unclear. Here we show that ALCLs of both subtypes are addicted to IRF4 signaling, as knockdown of IRF4 by RNA interference was toxic to ALCL cell lines in vitro and in ALCL xenograft mouse models in vivo. Gene expression profiling following IRF4 knockdown demonstrated a significant downregulation of a variety of known MYC target genes. Our analyses furthermore revealed that MYC is a primary target of IRF4, identifying a novel regulatory mechanism of MYC expression and its target gene network in ALCL. MYC itself is essential for ALCL survival, as both knockdown of MYC as well as pharmacologic inhibition of MYC signaling was toxic to ALCL cell lines. Collectively, our results demonstrate that ALCLs are dependent on IRF4 and MYC signaling and that MYC might represent a promising target for future therapies.