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Prepublished online as a Blood First Edition Paper on September 26, 2002; DOI 10.1182/blood-2002-03-0839.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1505-1512
NEOPLASIA
Loss of the B-lineage-specific gene expression program in
Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma
Ines Schwering,
Andreas Bräuninger,
Ulf Klein,
Berit Jungnickel,
Marianne Tinguely,
Volker Diehl,
Martin-Leo Hansmann,
Riccardo Dalla-Favera,
Klaus Rajewsky, and
Ralf Küppers
From the Institute for Genetics and the Department of
Internal Medicine I, University of Cologne, Germany;
Department of Pathology, University of Frankfurt, Frankfurt/Main,
Germany; and the Institute of Cancer Genetics, Columbia
University, New York, NY.
Hodgkin and Reed-Sternberg (HRS) cells represent the malignant
cells in classical Hodgkin lymphoma (HL). Because their immunophenotype cannot be attributed to any normal cell of the hematopoietic lineage, the origin of HRS cells has been controversially discussed, but molecular studies established their derivation from germinal center B
cells. In this study, gene expression profiles generated by serial
analysis of gene expression (SAGE) and DNA chip microarrays from HL
cell lines were compared with those of normal B-cell subsets, focusing
here on the expression of B-lineage markers. This analysis revealed decreased mRNA levels for nearly all established
B-lineage-specific genes. For 9 of these genes, lack of protein
expression was histochemically confirmed. Down-regulation of genes
affected multiple components of signaling pathways active in B cells,
including B-cell receptor (BCR) signaling. Because several genes
down-regulated in HRS cells are positively regulated by the
transcriptional activator Pax-5, which is expressed in most HRS cells,
we studied HL cell lines for mutations in the Pax-5
gene. However, no mutations were found. We propose that the
lost B-lineage identity in HRS cells may explain their survival without
BCR expression and reflect a fundamental defect in maintaining the
B-cell differentiation state in HRS cells, which is likely caused by a
novel, yet unknown, pathogenic mechanism.
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