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J Pathol. 2003 Nov;201(3):413-20.

Inactivating I kappa B epsilon mutations in Hodgkin/Reed-Sternberg cells.

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Humboldt University of Berlin, Universitätsklinikum Charité, Robert-Rössle-Klinik, Lindenberger Weg 80, 13125 Berlin, Germany.


The pathogenesis of Hodgkin lymphoma (HL) is still unclear. Previous investigations have demonstrated constitutive nuclear activity of the transcription factor NF kappa B (NF-kappaB) in Hodgkin/Reed-Sternberg (HRS) cells as an important prerequisite in protecting these cells from apoptosis. As a molecular mechanism leading to constitutive NF-kappaB activity in HRS cells, mutations of the NF-kappaB inhibitor I kappa B alpha (IkappaBalpha) have recently been identified in classical (c) HL-derived cell lines in a patient with cHL. In the present study, the NF-kappaB inhibitor I kappa B epsilon (IkappaBepsilon) has been analysed for somatic mutations in the same group of six patients already studied for IkappaBalpha mutations, as well as in cHL-derived cell lines. In one cHL-derived cell line (L428), a hemizygous frame-shift mutation generating a pre-terminal stop codon resulting in a severely truncated protein was found. Moreover, in the HRS cells of one patient, a hemizygous mutation affecting the 5'-splicing site of intron 1 of the IkappaBepsilon gene was found. These results, in combination with recently described IkappaBalpha mutations, indicate that defective NF-kappaB inhibitors appear more frequent than previously thought and might explain the constitutive nuclear activity of NF-kappaB in a significant proportion of cHL cases.

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