Molecular single-cell analysis of Hodgkin- and Reed-Sternberg cells harboring unmutated immunoglobulin variable region genes

Hodgkin- and Reed-Sternberg (H/RS) cells in classical Hodgkin's disease of the B lineage are the clonal progeny of antigen-experienced B cells harbori ng highly mutated immunoglobulin variable (V) region genes. Based on the de tection of obviously destructive somatic mutations in a fraction of cases, we speculated that H/RS cells may be derived from a pre-apoptotic germinal center B cell. Seemingly contradicting this speculation, we present here th e first case of classical Hodgkin's disease with H/RS cells harboring unmut ated, potentially functional V region genes, which may indicate the derivat ion of the H/RS done from a naive B cell. However, germinal center founder cells, which have not yet acquired somatic mutations, already have the intr insic propensity to die by apoptosis. Thus, the rare occurrence of H/RS cel ls with unmutated V genes is expected if the H/RS cells are derived from th e pool of pre-apoptotic germinal center B cells.