An oncogenic axis of STAT-mediated BATF3 upregulation causing MYC activity in classical Hodgkin lymphoma and anaplastic large cell lymphoma

Leukemia. 2018 Jan;32(1):92-101. doi: 10.1038/leu.2017.203. Epub 2017 Jun 29.


Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of activator protein-1 (AP-1) transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3), is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30+ lymphomas, namely cHL (21/30) and primary mediastinal B-cell lymphoma (8/9), but also CD30+ diffuse large B-cell lymphoma (15/20) frequently express BATF3 protein. Mass spectrometry and co-immunoprecipitation established interactions of BATF3 with JUN and JUNB in cHL and ALCL lines. BATF3 knockdown using short hairpin RNAs was toxic for cHL and ALCL lines, reducing their proliferation and survival. We identified MYC as a critical BATF3 target and confirmed binding of BATF3 to the MYC promoter. JAK/STAT signaling regulated BATF3 expression, as chemical JAK2 inhibition reduced and interleukin 13 stimulation induced BATF3 expression in cHL lines. Chromatin immunoprecipitation substantiated a direct regulation of BATF3 by STAT proteins in cHL and ALCL lines. In conclusion, we identified STAT-mediated BATF3 expression that is essential for lymphoma cell survival and promoted MYC activity in cHL and ALCL, hence we recognized a new oncogenic axis in these lymphomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / genetics*
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Survival
  • Gene Expression Regulation, Neoplastic / genetics
  • Hodgkin Disease / genetics*
  • Hodgkin Disease / pathology
  • Humans
  • Janus Kinase 2 / genetics
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Lymphoma, Large-Cell, Anaplastic / genetics*
  • Lymphoma, Large-Cell, Anaplastic / pathology
  • Oncogenes / genetics
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-myc / genetics*
  • RNA, Small Interfering / genetics
  • STAT Transcription Factors / genetics*
  • Signal Transduction / genetics
  • Transcription Factor AP-1 / genetics
  • Transcriptional Activation / genetics
  • Up-Regulation / genetics*


  • Basic-Leucine Zipper Transcription Factors
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • STAT Transcription Factors
  • Transcription Factor AP-1
  • Janus Kinase 2