Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IκBα

The NF-kappa B/Rel family of transcription factors regulates wide variety of genes whose products play a fundamental role in inflammatory and immune responses. The implication of NF-kappa B/Rel proteins and their I kappa B regulatory subunits in the control of cellular growth and oncogenesis, was suggested by the induction of fatal lymphomas in birds by the v-rel oncoprotein, and the rearrangement and amplification of several genes encoding the NF-kappa B/Rel/I kappa B signal transduction factors in human malignancies, primarily of lymphoid origin. Hodgkin's disease (HD) is a lymphoma characterized by a low frequency of malignant Hodgkin and Reed-Sternberg (H/RS) cells in a reactive background of nonneoplastic cells. The peculiar activated phenotype of Hodgkin and Reed-Sternberg cells and their pattern of cytokine secretion are believed to be a consequence of constitutive activation of the NF-kappa B transcription factor. Here, we report the detection of mutations of the 1k Ba gene, in two HD-derived cell lines and in two out of eight biopsy samples from patients with relapsed Hodgkin's disease. The presence of defective I kappa B alpha is thus likely to explain the constitutive activation of NF-kappa B in these cells and suggests that I kappa B alpha is a tumour suppressor controlling the oncogenic activation of NF-kappa B in Hodgkin and Reed-Sternberg cells.