Downregulation of STAT3 in EBV-positive Hodgkin lymphoma

ABSTRACT: STAT3 encodes an oncogenic transcription factor which is activated via various signalling pathways or Epstein Barr virus (EBV)-infection. The tumor cells of Hodgkin lymphoma (HL) are derived from germinal center B-cells and transformed by chromosomal rearrangements, aberrant signal transduction, downregulation of transcription factors mediating B-cell differentiation, and EBV-infection. HL cell lines represent useful models to investigate the molecular pathology and deduced treatment options in this malignancy. Using cell line L-540, we have recently shown that constitutively activated STAT3 drives aberrant expression of hematopoietic NKL homeobox gene HLX. Here, we analyzed HL cell line AM-HLH which is EBV-positive but nevertheless HLX negative. Consistently, AM-HLH expressed decreased levels of STAT3 proteins which were additionally inactivated and located in the cytoplasm. Combined genomic and gene expression profiling data revealed amplified and overexpressed candidates involved in opposed regulation of STAT3 and EBV. Subsequent analyses demonstrated that IRF4 and NFATC inhibited STAT3 expression. However, treatment with IL6 or IL27 activated STAT3, elevated expression of HLX and MIR155, and inhibited IRF4. MIR155 (STAT3 target gene) and BCL11A and SPIB (target genes of HLX) are described as suppressors and activators of EBV and showed reduced and elevated expression levels in AM-HLH, respectively. Taken together, this cell line deals with two conflicting oncogenic drivers, namely JAK2-STAT3-signalling and EBV-infection but is sensitive to cytokine signalling, mediating a switch between these aberrant pathways. Thus, AM-HLH represents an interesting cell line model to study the pathogenic roles of STAT3 and EBV and their therapeutic implications in HL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE204717 | GEO | 2022/12/31

REPOSITORIES: GEO