Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling

Küppers, Ralf
Klein, Ulf
Schwering, Ines
Distler, Verena
Bräuninger, Andreas
Cattoretti, Giorgio
Tu, Yuhai
Stolovitzky, Gustavo A.
Califano, Andrea
Hansmann, Martin-Leo
Dalla-Favera, Riccardo

¹Institute for Genetics, and
²Department of Internal Medicine I, University of Cologne, Cologne, Germany
³Institute for Cancer Genetics, Columbia University, New York, New York, USA
⁴Department of Pathology, University of Frankfurt, Frankfurt/Main, Germany
⁵IBM T.J. Watson Research Center, Yorktown Heights, New York, New York, USA
⁶First Genetic Trust Inc., Lyndhurst, New Jersey, USA

Received for publication August 9, 2002, and accepted in revised form December 17, 2002.

Address correspondence to: Ralf Küppers, University of Cologne, Department of Internal Medicine I, LFI E4 R706, Joseph-Stelzmannstrasse 9, D-50931 Cologne, Germany. Phone: 49 221 478 4490; Fax: 49 221 478 6383; E-mail: [email protected].

Ralf Küppers, Ulf Klein, and Ines Schwering contributed equally to this work.

Conflict of interest: The authors have declared that no conflict of interest exists.

Nonstandard abbreviations used: Hodgkin lymphoma (HL); Hodgkin and Reed/Sternberg (HRS); germinal center (GC); lymphocyte predominant (LP); B cell non Hodgkin lymphoma (B-NHL); diffuse large cell lymphoma (DLCL); Burkitt lymphoma (BL); follicular lymphoma (FL); B cell chronic lymphocytic leukemia (B-CLL); lymphoblastoid cell lines (LCL).

Journal of Clinical Investigation 111(4):p 529-537, February 2003.

Hodgkin lymphoma (HL) is a malignancy of unknown pathogenesis. The malignant Hodgkin and Reed/Sternberg (HRS) cells derive from germinal center B cells (or rarely, T cells) but have a heterogeneous and largely uncharacterized phenotype. Using microarrays, we compared the gene expression profile of four HL cell lines with profiles of the main B cell subsets and B cell non-HLs to find out whether HRS cells, despite their described heterogeneity, show a distinct gene expression, to study their relationship to other normal and malignant B cells, and to identify genes aberrantly or overexpressed by HRS cells. The HL lines indeed clustered as a distinct entity, irrespective of their B or T cell derivation, and their gene expression was most similar to that of EBV-transformed B cells and cell lines derived from diffuse large cell lymphomas showing features of in vitro-activated B cells. Twenty-seven genes, most of which were previously unknown to be expressed by HRS cells, showed aberrant expression specifically in these cells, e.g., the transcription factors GATA-3, ABF1, EAR3, and Nrf3. For five genes, expression in primary HRS cells was confirmed. The newly identified HL-specific genes may play important roles in the pathogenesis of HL, potentially represent novel diagnostic markers, and can be considered for therapeutic targeting.