The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/2000/1/395/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 2, January 17, 2000 395-402

Brief Definitive Report

Clonal Deleterious Mutations in the I{kappa}B{alpha} Gene in the Malignant Cells in Hodgkin's Lymphoma

Berit Jungnickela, Andrea Staratschek-Joxb, Andreas Bräuningerc, Tilmann Spiekerc, Jürgen Wolfb, Volker Diehlb, Martin-Leo Hansmannc, Klaus Rajewskya, and Ralf Küppersa,b
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

Correspondence to: Ralf Küppers, University of Cologne, Department of Internal Medicine I, Joseph-Stelzmannstr. 9, LFI E4 R706, 50931 Cologne, Germany. Tel:49-221-478-4490 Fax:49-221-478-6383 E-mail:rkuppers{at}mac.genetik.uni-koeln.de.

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-{kappa}B 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 (in 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 recurrent 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.

Key Words: Hodgkin's lymphoma, I{kappa}B{alpha}, nuclear factor {kappa}B, tumor suppressor gene, Reed-Sternberg cell


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