Potential role of hypoxia in early stages of Hodgkin lymphoma pathogenesis

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 NF kappa B 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.