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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3964-3972
Somatic Mutations Within the Untranslated Regions of Rearranged Ig
Genes in a Case of Classical Hodgkin's Disease as a Potential
Cause for the Absence of Ig in the Lymphoma Cells
Andrea Jox,
Thomas Zander,
Ralf Küppers,
Johannes Irsch,
Holger Kanzler,
Martin Kornacker,
Heribert Bohlen,
Volker Diehl, and
Jürgen Wolf
From the Department of Internal Medicine I and the Institute for
Genetics, University of Cologne, Cologne, Germany.
Hodgkin-Reed-Sternberg (H-RS) cells are clonal B cells carrying Ig
gene rearrangements. However, in situ hybridization methods failed to
demonstrate Ig gene expression in H-RS cells of classical Hodgkin's
disease (HD). Because somatic mutations rendering potentially functional Ig gene rearrangements nonfunctional were detected in some
cases of the disease, it was speculated that H-RS cells in classical HD
may have lost the ability to express antigen receptor as a rule.
Recently, we established a novel cell line (L1236) from H-RS cells of a
patient with mixed cellularity subtype of HD. L1236 cells harbor a
potentially functional VH1 and a potentially functional
V 3 gene rearrangement. However, no antibody expression was detected. To show potential reasons for this lack of Ig expression, we analyzed the genomic organization of the Ig genes and their transcription in the primary and cultivated H-RS cells of this patient.
The H-RS cells were found to have switched their isotype to IgG4,
confirming their mature B-cell nature. By amplifying cDNA from L1236
cells as well as from frozen biopsy material transcripts of the
V3 and the VH1 gene rearrangement were
detected for both sources of cDNA. However, Northern blot
hybridization of L1236 RNA failed to demonstrate VH1 and
V3 transcripts, indicating only a low level of
transcription. Sequence analysis of the promoter and leader regions of
the VH1 gene rearrangement from L1236 cells as well as from
lymphoma-affected tissue showed a somatic mutation in the conserved
octamer motif of the promoter region. Somatic mutations were also
detected within the 3' splice site of the leader intron and
adjacent nucleotides in the rearranged V light chain
gene, leading to aberrant splicing. These mutations might prevent the
generation of adequate amounts of functional Ig gene transcripts as
template for translation into protein. Thus, mutations in H-RS cells
that prevent Ig gene expression might also be located outside the
coding region of the Ig genes.
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