ISHL10 Abstract T006

The AP-1 transcription factor BATF3 regulates MYC expression and is required for tumor cell survival in classical Hodgkin Lymphoma and anaplastic large cell lymphoma

The malignant cells in classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) are characterized by deregulated transcription factor activity of several signaling pathways including constitutive active JAK/STAT and AP-1. Our group and others have performed gene expression profiling (GEP) of cHL and ALCL and identified BATF3, a member of the AP-1 transcription factor family, as one of the most up-regulated genes in cHL and ALCL cells. In the present study, up-regulated expression of BATF3 was confirmed at mRNA and protein level in cHL and ALCL cells. To assess BATF3 function, small hairpin (sh)RNA vectors against BATF3 were generated to downregulate BATF3 in lymphoma cell lines. Transduction experiments demonstrate that downregulation of BATF3 leads to reduced cell proliferation and induced apoptosis in cHL and ALCL cell lines. To identify BATF3-regulated targets in BATF3-knockdown cells, GEP was performed. GEP after BATF3 knockdown demonstrated a significant downregulation of known MYC target genes and immunoblot analysis confirmed downregulation of MYC in shBATF3-transduced cells. Chromatin-immunoprecipitation (ChIP) experiments demonstrated that BATF3 regulates MYC expression by binding to an AP-1 element present in the MYC promoter. To examine whether BATF3 activity was connected to the constitutive JAK/STAT activation in cHL and ALCL, we treated cHL and ALCL cell lines with the JAK2 inhibitor TG101348 and found decreased levels of BATF3 protein, suggesting that BATF3 is regulated by STAT factors. Additionally, activation of JAK/STAT signaling by interleukin stimulation induced BATF3 expression in cHL and ALCL cell lines. ChIP experiments validated STAT binding to the BATF3 promoter, indicating that STATs directly regulate BATF3 expression. In conclusion, we recognized a new oncogenic axis in cHL and ALCL and revealed a complex transcription factor network in which BATF3 links STAT signaling to MYC expression.