Inactivating I kappa B epsilon mutations in Hodgkin/Reed-Sternberg cells.
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.
Humboldt University of Berlin, Universitätsklinikum Charité, Robert-Rössle-Klinik, Lindenberger Weg 80, 13125 Berlin, Germany. emmerich@mdc-berlin.de
Florian
F
Emmerich
Sebastian
S
Theurich
Michael
M
Hummel
Antje
A
Haeffker
Magnus S
MS
Vry
Konstanze
K
Döhner
Kurt
K
Bommert
Harald
H
Stein
Bernd
B
Dörken
D015153:Blotting, Western / Q000379:methods; D002874:Chromosome Mapping / Q000379:methods; D003001:Cloning, Molecular / Q000379:methods; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000032:analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D012334:RNA, Neoplasm / Q000032:analysis; D016539:Reed-Sternberg Cells; D014407:Tumor Cells, Cultured
D020672:I-kappa B Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm