Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma.
Members of the nuclear factor (NF)-kappaB 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-kappaB (IkappaB) family, whose degradation activates NF-kappaB in response to diverse stimuli. In Hodgkin's lymphoma (HL), high constitutive nuclear activity of NF-kappaB 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 IkappaBalpha 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-kappaB activation). There was no evidence for IkappaBalpha mutations in two non-HL entities or in normal germinal center B cells. This study establishes deleterious IkappaBalpha mutations as the first recurrent genetic defect found in H/RS cells, indicating a role of IkappaBalpha defects in the pathogenesis of HL and implying that IkappaBalpha is a tumor suppressor gene.
Jungnickel
B
B
Institute for Genetics, University of Cologne, 50931 Cologne, Germany.
Staratschek-Jox
A
A
Bräuninger
A
A
Spieker
T
T
Wolf
J
J
Diehl
V
V
Hansmann
M L
ML
Rajewsky
K
K
Küppers
R
R
D000328:Adult; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006689:Hodgkin Disease / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha