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

Blood. 2015 Jan 1;125(1):124-32. doi: 10.1182/blood-2014-08-594507. Epub 2014 Oct 30.


Anaplastic large cell lymphoma (ALCL) is a distinct entity of T-cell lymphoma that can be divided into 2 subtypes based on the presence of translocations involving the ALK gene (ALK(+) and ALK(-) ALCL). The interferon regulatory factor 4 (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 after IRF4 knockdown demonstrated a significant downregulation of a variety of known MYC target genes. Furthermore, our analyses 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 and pharmacologic inhibition of MYC signaling were toxic to ALCL cell lines. Collectively, our results demonstrate that ALCLs are dependent on IRF4 and MYC signaling and that MYC may represent a promising target for future therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interferon Regulatory Factors / metabolism*
  • Lymphoma / metabolism
  • Lymphoma, Large-Cell, Anaplastic / genetics*
  • Lymphoma, Large-Cell, Anaplastic / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Interference
  • Retroviridae / metabolism
  • Signal Transduction


  • Interferon Regulatory Factors
  • Proto-Oncogene Proteins c-myc
  • interferon regulatory factor-4