Loss of the B-lineage-specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma.
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.
Schwering
Ines
I
Institute for Genetics and the Department of Internal Medicine I, University of Cologne, Germany. ines.schwering@medizin.uni-koeln.de
Bräuninger
Andreas
A
Klein
Ulf
U
Jungnickel
Berit
B
Tinguely
Marianne
M
Diehl
Volker
V
Hansmann
Martin-Leo
ML
Dalla-Favera
Riccardo
R
Rajewsky
Klaus
K
Küppers
Ralf
R
D001402:B-Lymphocytes / Q000737:chemistry / Q000473:pathology*; D015415:Biomarkers; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008198:Lymph Nodes / Q000737:chemistry; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D051757:PAX5 Transcription Factor; D012333:RNA, Messenger / Q000032:analysis; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D016539:Reed-Sternberg Cells / Q000737:chemistry / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured
D015415:Biomarkers; D004268:DNA-Binding Proteins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D014157:Transcription Factors