Molecular biology of Hodgkin's lymphoma.

Hodgkin's lymphoma (HL) is characterized by typical mononucleated Hodgkin and multinucleated Reed-Sternberg cells, which occur at low frequency in a mixed cellular infiltrate in the tumor tissue. Because of the rarity of these cells and their unusual immunophenotype, which is strikingly different from those of all normal hematopoietic cell types, the origin of these cells and their clonality have long been unclear. Single-cell studies of rearranged immunoglobulin genes showed that Hodgkin and Reed-Sternberg (HRS) cells represent clonal tumor-cell populations derived from germinal center B cells. In classical HL, the detection of obviously crippling immunoglobulin gene mutations in a fraction of the cases suggests that HRS cells may derive from germinal center B cells that have lost the capacity to be positively selected by antigen and that normally would have undergone apoptosis. In rare cases, HRS cells represent transformed T lymphocytes. The transforming events involved in malignant transformation of HRS cells are still largely unknown. Constitutive activation of the transcription factor NFkappaB, which can, for example, be induced through Epstein-Barr virus transformation of HRS cells or destructive somatic mutations of the inhibitor of NFkappaB, is likely to be a key event in HL pathogenesis. Significant progress has been made in our understanding of the cellular interactions in HL tissues, which are mainly mediated by a large variety of cytokines and chemokines.