Mechanisms of aberrant GATA3 expression in classical Hodgkin lymphoma and its consequences for the cytokine profile of Hodgkin and Reed/Sternberg cells.
The transcription factor network in Hodgkin lymphoma (HL) represents a unique composition of proteins found in no other hematopoietic cell. Among these factors, an aberrant expression of the T-cell transcription factor GATA3 is observed in B cell-derived Hodgkin and Reed/Sternberg (HRS) tumor cells. Herein, we elucidate the regulation and function of this factor in HL. We demonstrate binding of NFκB and Notch-1, 2 factors with deregulated activity in HL to GATA3 promoter elements. Interference with NFκB and Notch-1 activity led to decreased GATA3 expression, indicating a dependency of deregulated GATA3 expression on these transcription factors. Down-regulation of GATA3 in HL cell lines demonstrated its role in the regulation of IL-5, IL-13, STAT4, and other genes. A correlation between GATA3 and IL-13 expression was confirmed for HRS cells in HL tissues. Thus, GATA3 shapes the cytokine expression and signaling that is typical of HL. Conclusively, aberrant GATA3 expression in HRS cells is stimulated by the deregulated constitutive activity of NFκB and Notch-1, indicating a complex network of deregulated transcription factors in these cells. GATA3 activity significantly contributes to the typical cytokine secretion of and signaling in HRS cells, which presumably plays an essential role in HL pathogenesis.
Stanelle
Jens
J
Institute of Cell Biology, University of Duisburg-Essen Medical School, Essen, Germany.
Döring
Claudia
C
Hansmann
Martin-Leo
ML
Küppers
Ralf
R
D017209:Apoptosis; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D050990:GATA3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D016539:Reed-Sternberg Cells / Q000276:immunology*; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
D016207:Cytokines; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D018793:Interleukin-13; D019409:Interleukin-15; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human