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

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Abstract
The pathogenesis of Hodgkin lymphoma (HL) is still unclear. Previous investigations have demonstrated constitutive nuclear activity of the transcription factor NF kappa B (NF‐κB) in Hodgkin/Reed–Sternberg (HRS) cells as an important prerequisite in protecting these cells from apoptosis. As a molecular mechanism leading to constitutive NF‐κB activity in HRS cells, mutations of the NF‐κB inhibitor I kappa B alpha (IκBα) have recently been identified in classical (c) HL‐derived cell lines in a patient with cHL. In the present study, the NF‐κB inhibitor I kappa B epsilon (IκBε) has been analysed for somatic mutations in the same group of six patients already studied for IκBα 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 IκBε gene was found. These results, in combination with recently described IκBα mutations, indicate that defective NF‐κB inhibitors appear more frequent than previously thought and might explain the constitutive nuclear activity of NF‐κB in a significant proportion of cHL cases. Copyright © 2003 John Wiley & Sons, Ltd.