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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3129-3134
Overexpression of I Kappa B Alpha Without Inhibition of NF- B
Activity and Mutations in the I Kappa B Alpha Gene in
Reed-Sternberg Cells
Florian Emmerich,
Martina Meiser,
Michael Hummel,
Gudrun Demel,
Hans-Dieter Foss,
Franziska Jundt,
Stephan Mathas,
Daniel Krappmann,
Claus Scheidereit,
Harald Stein, and
Bernd Dörken
From Humboldt University of Berlin, Universitätsklinikum
Charité, Robert-Rössle-Klinik, Berlin; the Max
Delbrück Center for Molecular Medicine, Berlin; and the Institut
for Pathology, Universitätsklinikum Benjamin Franklin, Free
University Berlin, Berlin, Germany.
The transcription factor NF kappa B (NF- B) mediates the
expression of numerous genes involved in diverse functions such as inflammation, immune response, apoptosis, and cell proliferation. We
recently identified constitutive activation of NF-B (p50/p65) as a
common feature of Hodgkin/Reed-Sternberg (HRS) cells preventing these
cells from undergoing apoptosis and triggering proliferation. To
examine possible alterations in the NF-B/IB system, which might
be responsible for constitutive NF-B activity, we have analyzed the
inhibitor I kappa B alpha (IB ) in primary and cultured HRS cells
on protein, mRNA, and genomic levels. In lymph node biopsy samples from
Hodgkin's disease patients, IB mRNA proved to be strongly
overexpressed in the HRS cells. In 2 cell lines (L428 and KM-H2), we
detected mutations in the IB gene, resulting in C-terminally
truncated proteins, which are presumably not able to inhibit
NF-B-DNA binding activity. Furthermore, an analysis of the IB
gene in single HRS cells micromanipulated from frozen tissue sections
showed a monoallelic mutation in 1 of 10 patients coding for a
comparable C-terminally truncated IB protein. We suggest that the
observed IB mutations contribute to constitutive NF-B activity
in cultured and primary HRS cells and are therefore involved in the
pathogenesis of these Hodgkin's disease (HD) patients. The
demonstrated constitutive overexpression of IB in HRS cells evidences a deregulation of the NF-B/IB system also in the
remaining cases, probably due to defects in other members of the IB family.
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