title: Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma.
abstract: The pathogenesis of classical Hodgkin lymphoma (cHL), the most common lymphoma in the young, is still enigmatic, largely because its Hodgkin and Reed-Sternberg (HRS) tumor cells are rare in the involved lymph node and therefore difficult to analyze. Here, by overcoming this technical challenge and performing, for the first time, a genome-wide transcriptional analysis of microdissected HRS cells compared with other B-cell lymphomas, cHL lines, and normal B-cell subsets, we show that they differ extensively from the usually studied cHL cell lines, that the lost B-cell identity of cHLs is not linked to the acquisition of a plasma cell-like gene expression program, and that Epstein-Barr virus infection of HRS cells has a minor transcriptional influence on the established cHL clone. Moreover, although cHL appears a distinct lymphoma entity overall, HRS cells of its histologic subtypes diverged in their similarity to other related lymphomas. Unexpectedly, we identified 2 molecular subgroups of cHL associated with differential strengths of the transcription factor activity of the NOTCH1, MYC, and IRF4 proto-oncogenes. Finally, HRS cells display deregulated expression of several genes potentially highly relevant to lymphoma pathogenesis, including silencing of the apoptosis-inducer BIK and of INPP5D, an inhibitor of the PI3K-driven oncogenic pathway.
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, Essen, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Tiacci
authors.forename: Claudia
authors.initials: C
authors.lastname: Döring
authors.forename: Verena
authors.initials: V
authors.lastname: Brune
authors.forename: Carel J M
authors.initials: CJ
authors.lastname: van Noesel
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.forename: Gunhild
authors.initials: G
authors.lastname: Mechtersheimer
authors.forename: Brunangelo
authors.initials: B
authors.lastname: Falini
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
authors.forename: Martin-Leo
authors.initials: ML
authors.lastname: Hansmann
mesh_terms: D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D000072181:Inositol Polyphosphate 5-Phosphatases; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins; D020411:Oligonucleotide Array Sequence Analysis; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D016539:Reed-Sternberg Cells / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases