Clonal deleterious mutations in the IκBα gene in the malignant cells in Hodgkin's lymphoma

Members of the nuclear factor (NF)-kappa B family of transcription factors play a crucial role in cellular activation, immune responses, and oncogenesis. In most cells, they are kept inactive in the cytosol by complex formation with members of the inhibitor of NF-kappa B (I kappa B) family, whose degradation activates NF-KB in response to diverse stimuli. In Hodgkin's lymphoma (HL), high constitutive nuclear activity of NF-kappa B is characteristic of the malignant Hodgkin and Reed-Sternberg (H/RS) cells, which occur at low number in a background of nonneoplastic inflammatory cells. In single H/RS cells micromanipulated from histological sections of HL, we detect clonal deleterious somatic mutations in the I kappa B alpha gene in two of three Epstein-Barr virus (EBV)negative cases but not in two EBV-positive cases tin which a viral oncogene may account for NF-kappa B activation). There was no evidence for I kappa B alpha mutations in two non-HL entities or in normal germinal center B cells. This study establishes deleterious I kappa B alpha mutations as the first re current genetic defect found in H/RS cells, indicating a role of I kappa B alpha defects in the pathogenesis of HL and implying that I kappa B alpha is a tumor suppressor gene.