The Journal of Experimental Medicine
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Published online 26 August 2002 doi:10.1084/jem.20020062
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© Rockefeller University Press, 0022-1007/2002/9/605/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 5, September 2, 2002 605-617
Nuclear Factor {kappa}B–dependent Gene Expression Profiling of Hodgkin's Disease Tumor Cells, Pathogenetic Significance, and Link to Constitutive Signal Transducer and Activator of Transcription 5a Activity

Michael Hinz1, Petra Lemke1, Ioannis Anagnostopoulos2, Christine Hacker1, Daniel Krappmann1, Stephan Mathas1,3, Bernd Dörken1,3, Martin Zenke1, Harald Stein2 and Claus Scheidereit1

1 Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany
2 Institute for Pathology, Universitätsklinikum Benjamin Franklin, Free University, 12200 Berlin, Germany
3 Robert-Rössle-Klinik, Universitätsklinikum Charité, Humboldt University of Berlin, 13125 Berlin, Germany

Address correspondence to C. Scheidereit, Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany. Phone: 49-30-9406-3816; Fax: 49-30-9406-3866; E-mail: scheidereit{at}mdc-berlin.de

Constitutive nuclear nuclear factor (NF)-{kappa}B activity is observed in a variety of hematopoietic and solid tumors. Given the distinctive role of constitutive NF-{kappa}B for Hodgkin and Reed-Sternberg (HRS) cell viability, we performed molecular profiling in two Hodgkin's disease (HD) cell lines to identify NF-{kappa}B target genes. We recognized 45 genes whose expression in both cell lines was regulated by NF-{kappa}B. The NF-{kappa}B–dependent gene profile comprises chemokines, cytokines, receptors, apoptotic regulators, intracellular signaling molecules, and transcription factors, the majority of which maintain a marker-like expression in HRS cells. Remarkably, we found 17 novel NF-{kappa}B target genes. Using chromatin immunoprecipitation we demonstrate that NF-{kappa}B is recruited directly to the promoters of several target genes, including signal transducer and activator of transcription (STAT)5a, interleukin-13, and CC chemokine receptor 7. Intriguingly, NF-{kappa}B positively regulates STAT5a expression and signaling pathways in HRS cells, and promotes its persistent activation. In fact, STAT5a overexpression was found in most tumor cells of tested patients with classical HD, indicating a critical role for HD. The gene profile underscores a central role of NF-{kappa}B in the pathogenesis of HD and potentially of other tumors with constitutive NF-{kappa}B activation.

Key Words: oncogene • tumor suppressor • survival • chromatin • microarray


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