title: Potential role of hypoxia in early stages of Hodgkin lymphoma pathogenesis.
abstract: A unique feature of the germinal center B cell-derived Hodgkin and Reed/Sternberg cells of classical Hodgkin lymphoma is their lost B cell phenotype and the aberrant expression of factors of other hematopoietic cell types, including ID2 and NOTCH1. As cellular dedifferentiation and upregulation of ID2 and NOTCH1 are typical consequences of a hypoxic response, we wondered whether hypoxia may impose an HRS cell-like phenotype in B cells. Culturing normal B cells or cell lines of germinal center-type diffuse large B-cell lymphoma under hypoxic conditions caused partial downregulation of several B cell markers, ID2 upregulation, and increased NOTCH1 activity. The hypoxic cells acquired further features of Hodgkin and Reed/Sternberg cells, including increased JUN expression, and enhanced NFκB activity. The Hodgkin and Reed/Sternberg cell-expressed epigenetic regulators KDM4C and PCGF2, as well as the phosphatase DUSP1 were partially induced in hypoxic B cells. Inhibition of DUSP1 was toxic for classical Hodgkin lymphoma cell lines. Thus, hypoxia induces key Hodgkin and Reed/Sternberg cell characteristics in mature B cells. We speculate that hypoxic conditions in the germinal center may impose phenotypic changes in germinal center B cells, promoting their survival and initiating their differentiation towards a Hodgkin and Reed/Sternberg cell-like phenotype. These may then be stabilized by transforming events in the Hodgkin and Reed/Sternberg precursor cells.
authors.affiliation: Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen, Essen.
authors.forename: Frederik
authors.initials: F
authors.lastname: Wein
authors.affiliation: Institute of Physiology, University of Duisburg-Essen, Essen.
authors.forename: Teresa
authors.initials: T
authors.lastname: Otto
authors.affiliation: Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen, Essen.
authors.forename: Pascal
authors.initials: P
authors.lastname: Lambertz
authors.affiliation: Institute of Physiology, University of Duisburg-Essen, Essen.
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School, Frankfurt am Main, Germany.
authors.forename: Martin-Leo
authors.initials: ML
authors.lastname: Hansmann
authors.affiliation: Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen, Essen ralf.kueppers@uk-essen.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D044127:Epigenesis, Genetic; D015870:Gene Expression; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D006689:Hodgkin Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D010641:Phenotype
chemical_list: D015415:Biomarkers; D051793:Hypoxia-Inducible Factor 1; D036341:Intercellular Signaling Peptides and Proteins