Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis

The pathogenesis of nodular lymphocyte -predominant Hodgkin lymphoma (NLPHL) and its relationship to other lymphomas are largely unknown. This is partly because of the technical challenge of analyzing its rare neoplastic lymphocytic and histiocytic (L & H) cells, which are dispersed in an abundant nonneoplastic cellular microenvironment. We performed a genome-wide expression study of microdissected L & H lymphoma cells in comparison to normal and other malignant B cells that indicated a relationship of L & H cells to and/or that they originate from germinal center B cells at the transition to memory B cells. L & H cells show a surprisingly high similarity to the tumor cells of T cell -rich B cell lymphoma and classical Hodgkin lymphoma, a partial loss of their B cell phenotype, and deregulation of many apoptosis regulators and putative oncogenes. Importantly, L & H cells are characterized by constitutive nuclear factor kappa B activity and aberrant extracellular signal-regulated kinase signaling. Thus, these findings shed new light on the nature of L & H cells, reveal several novel pathogenetic mechanisms in NLPHL, and may help in differential diagnosis and lead to novel therapeutic strategies.