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Brief Definitive Report

Clonal Deleterious Mutations in the Ib Gene in the Malignant Cells in Hodgkin's Lymphoma

^a Institute for Genetics, University of Cologne, 50931 Cologne, Germany
^b Department of Internal Medicine I, University of Cologne, 50931 Cologne, Germany
^c Department of Pathology, University of Frankfurt, 60596 Frankfurt, Germany
University of Cologne, Department of Internal Medicine I, Joseph-Stelzmannstr. 9, LFI E4 R706, 50931 Cologne, Germany.49-221-478-638349-221-478-4490

rkuppers{at}mac.genetik.uni-koeln.de

Members of the nuclear factor (NF)-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-B (IB) family, whose degradation activates NF-B in response to diverse stimuli. In Hodgkin's lymphoma (HL), high constitutive nuclear activity of NF-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 IB gene in two of three Epstein-Barr virus (EBV)-negative cases but not in two EBV-positive cases (in which a viral oncogene may account for NF-B activation). There was no evidence for IB mutations in two non-HL entities or in normal germinal center B cells. This study establishes deleterious IB mutations as the first recurrent genetic defect found in H/RS cells, indicating a role of IB defects in the pathogenesis of HL and implying that IB is a tumor suppressor gene.

Key Words: Hodgkin's lymphoma • IB • nuclear factor B • tumor suppressor gene • Reed-Sternberg cell

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