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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3865-3878
Deregulated PAX-5 Transcription From a Translocated
IgH Promoter in Marginal Zone Lymphoma
Aline M. Morrison,
Ulrich Jäger,
Andreas Chott,
Michael Schebesta,
Oskar A. Haas, and
Meinrad Busslinger
From the Research Institute of Molecular Pathology, Vienna, Austria;
the University of Vienna Medical School, Vienna, Austria; and St. Anna
Children's Hospital, Vienna, Austria.
The PAX-5 gene codes for the transcription factor BSAP,
which is expressed throughout B-cell development. Although
loss-of-function mutation in the mouse showed an essential role for
Pax-5 in early B lymphopoiesis, gain-of-function mutations have
implicated the human PAX-5 gene in the control of late B-cell
differentiation. PAX-5 (on 9p13) has been involved together
with the immunoglobulin heavy-chain (IgH) gene (on 14q32) in
the recurring t(9;14)(p13;q32) translocation that is characteristic of
small lymphocytic lymphoma with plasmacytoid differentiation. Here we
have characterized a complex t(2;9;14)(p12;p13;q32) translocation
present in a closely related non-Hodgkin's lymphoma referred to as
splenic marginal zone lymphoma (MZL). In this MZL-1 translocation, the
two promoters of PAX-5 were replaced on the derivative
chromosome 14 by an immunoglobulin switch Sµ promoter that was linked
to the structural PAX-5 gene upstream of its translation
initiation codon in exon 1B. Expression analyses confirmed that
PAX-5 transcription was upregulated due to efficient initiation
at the Sµ promoter in the malignant B lymphocytes of patient MZL-1.
For comparison we have analyzed PAX-5 expression in another
B-cell lymphoma, KIS-1, indicating that transcription from the distal
PAX-5 promoter was increased in this tumor in agreement with
the previously characterized translocation of the immunoglobulin Eµ
enhancer adjacent to PAX-5 exon 1A. In both lymphomas, the
J-chain gene, which is thought to be under negative control by BSAP,
was not expressed, whereas transcription of the putative target gene
p53 was unaffected by PAX-5 overexpression. Together
these data indicate that the t(9;14)(p13;q32) translocation contributes
to lymphoma formation as a regulatory mutation that leads to increased
PAX-5 expression in late B-cell differentiation due to promoter
replacement or enhancer insertion.
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