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Blood, 15 May 2001, Vol. 97, No. 10, pp. 3191-3196
NEOPLASIA
Defective octamer-dependent transcription is responsible for
silenced immunoglobulin transcription in Reed-Sternberg cells
Jan Theil,
Helmut Laumen,
Theresa Marafioti,
Michael Hummel,
Georg Lenz,
Thomas Wirth, and
Harald Stein
From the Institute of Pathology, Consultation and
Reference Centre for Lymph Node Pathology and Haematopathology,
University Hospital Benjamin Franklin, Free University, Berlin,
Germany, and the Department of Physiological Chemistry,
Universität Ulm, Ulm, Germany.
The absence of immunoglobulin (Ig) expression in B-cell-derived
Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin disease
(cHD) was initially suggested to be caused by crippling mutations in
the Ig promoter or coding region. More recent investigations have,
however, challenged this concept. This study addressed the role of
mutations in the Ig promoter region in HRS cells. Nine cases of cHD and
3 B-cell-derived HD lines were analyzed for mutations in the TATA box
and octamer motif of the Ig promoter. Mutations in the octamer motif
were found in only 1 of the 9 cases and in 1 of the 3 HD cell lines
(L1236). Furthermore, in all cases either a complete lack or strong
reduction in the expression of the Oct2 transcription factor and the
BOB.1/OBF.1 coactivator were found. The relevance of the rare promoter
mutations was investigated by assaying the activity of Ig promoter
reporter constructs transfected into the HD cell line L1236, which
harbors a mutated octamer motif. These Ig reporter constructs were
completely inactive in L1236 cells; however, their activity could be
reconstituted by the cotransfection of a BOB.1/OBF.1 expression vector.
The additional transfection with an Oct2 expression vector did not
further enhance the Ig promoter activity. The conclusions drawn from
these results are that crippling mutations in the Ig promoter and
coding region are not the sole cause for the lack of Ig expression in
HRS cells and that defects in the transcription machinery such as
absence of BOB.1/OBF.1 are more important for this phenomenon.
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