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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 603-607
Heterologous Promoters Fused to BCL6 by Chromosomal
Translocations Affecting Band 3q27 Cause Its Deregulated Expression
During B-Cell Differentiation
By
Weiyi Chen,
Shinsuke Iida,
Diane C. Louie,
Riccardo Dalla-Favera, and
R.S.K. Chaganti
From the Cell Biology Program and The Departments of Human Genetics
and Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY;
and the Division of Oncology, Department of Pathology, College of
Physicians and Surgeons, Columbia University, New York, NY.
 |
ABSTRACT |
The BCL6 gene encodes a POZ/Zinc-finger protein, which acts
as a sequence-specific transcriptional repressor. It is expressed in B
cells within the germinal centers (GC) and is required for GC
formation. In  40% of diffuse large cell lymphomas (DLCL) and 14% of follicular lymphomas (FL), the BCL6 gene is
rearranged by chromosomal translocations, which juxtapose heterologous
promoters and 5 untranslated sequences derived from other
chromosomes to the BCL6 coding domain or by mutations in the
5 regulatory region. To understand the functional consequence of
the chromosomal translocations, we have studied the patterns of
expression of the promoters found juxtaposed to BCL6 in DLCL
and FL during B-lineage differentiation. Distinct heterologous 5
untranslated regions (IGH, IGL, TTF) were
identified fused to the BCL6 coding domain by analysis of BCL6 cDNAs in two DLCL cases and one mixed follicular lymphoma (MxFL). These three sequences, as well as three other previously identified BCL6 fusion partners (IGHG3, BOB1,
H4), were studied for their pattern of expression during
B-lineage differentiation by Northern blot analysis of B-cell lines
representative of the pre-B, B, immunoblast, and plasma cell stages. In
contrast to BCL6, whose transcription is activated only in B
cells within the GC, all of the other sequences displayed a broader
pattern of expression ranging from constitutive expression throughout B-cell differentiation to persistent expression in immunoblasts and
plasma cells. These results indicate that the expression of BCL6 is deregulated as a consequence of fusion to heterologous promoter regions. The persistent expression of activated BCL6 may contribute to lymphomagenesis by blocking B-cell differentiation within the GC.
| |
INTRODUCTION |
TRANSLOCATIONS INVOLVING the chromosome
band 3q27 are detected in 15% of B-cell lymphomas, especially
diffuse large cell lymphomas (DLCL).1,2 A gene rearranged
at this site, BCL6, has been isolated from 3q27 adjacent to the
chromosomal breakpoint.3-9 The BCL6 gene encodes a
95 kD nuclear phosphoprotein with six C-terminal
zinc-finger motifs and an N-terminal POZ/ZIN domain homologous to a
family of zinc-finger proteins.10,11 In the B-cell
differentiation pathway, BCL6 is expressed in mature B cells
within germinal centers (GC), but not in immature B-cell precursors or
differentiated plasma cells.12,13 The BCL6 protein functions as a DNA-binding transcription repressor involved in the
control of germinal center formation and T-cell-dependent antigen
response.14,15
Several studies have shown that BCL6 is rearranged in 30% to
40% of DLCL and 6% to 14% of follicular lymphomas (FL).9
The translocation breakpoints lie within the 5 flanking region
spanning the promoter and the first noncoding exon or within the first intron. As a result, the 5 regulatory region containing the
BCL6 promoter sequence is either removed or truncated and
causes the juxtaposition of BCL6 coding exons (2-10) downstream
to the promoter derived from the reciprocal chromosomal
partner.9
We and others have shown that translocations involving the chromosomal
band 3q27 affect not only the IG gene loci, but also a variety
of other loci, such as 1q21, 2q21, 4p11, 5p13, 9p13, 11q23, 12p11,
12q13, and 15q21, a phenomenon termed promiscuous translocation.16 The genes TTF,17
BOB1,18 and H419 have recently
been isolated and characterized from cases of non-Hodgkin's lymphoma
(NHL) carrying t(3;4)(q27;p11), t(3;11)(q27;q23), and t(3;6)(q27;p21)
translocations, respectively. Each of the translocations formed a
fusion transcript with BCL6 by removing the BCL6 first exon. We have recently shown that in the DLCL cell line, Ly8, the
IGHG3-BCL6 chimeric transcript was initiated from the
IGHG3 germline transcript promoter (I 3), suggesting
that the translocation alters BCL6 expression by promoter
substitution.20
The analysis of regulation of expression of the promoters of the
heterologous genes, which fuse to BCL6 during B-cell
differentiation, can provide insights into the functional consequence
of translocation. To investigate this, we studied the pattern of
expression of a number of BCL6 fusion partner genes by Northern
blot hybridization in a panel of cell lines representing various stages
of B-lineage differentiation. This analysis showed that, in contrast to
BCL6 whose expression is restricted to mature B cells
displaying a GC phenotype, all of the fusion partners studied
(IGH, IGL, IGHG3, TTF, BOB1,
and H4) displayed a different pattern of regulation including a
persistence of expression to the plasmacytoid stage. This finding
suggests that, driven by the heterologous promoter, BCL6
expression is inappropriately continued and may block B-cell differentiation.
| |
MATERIALS AND METHODS |
Tumor samples and cell lines.
Lymph node biopsies were obtained from patients undergoing diagnostic
evaluation for B-cell lymphoma at the Memorial Sloan-Kettering Cancer
Center (MSKCC). Biopsy samples were subjected to histologic, immunophenotypic, cytogenetic, and DNA rearrangement studies as described.21 Three tumors with 3q27 rearrangements were
used in this study. Tumor 352 was a DLCL with a t(3;22)(q27;q11), tumor 1020 was a DLCL with a t(3;8;14)(q27;q24;q32) translocation, and tumor
1547 was a MxFL with a t(3;4)(q27;p11) translocation. All three tumors
showed BCL6 rearrangements by Southern blot analysis. In
addition, the following B-lineage cell lines, which correspond to
different stages of B-cell development were also used in this study:
697 (pre-B cell), Ramos, Bjab, (mature B cell) CB33, RD (immunoblast),
and U266, Skmm1, JJN3, XG-4, XG-7 and XG-10 (plasma cell).
5 rapid amplification of cDNA ends (RACE) assay
and sequencing analysis.
Total RNA was extracted from biopsy samples using RNAgents
kit (Promega, Madison, WI). RACE analysis of the 5
end of BCL6 transcript was performed following the
manufacturer's recommendations (GIBCO/BRL, Gaithersburg,
MD). Briefly, first strand cDNA was synthesized by reverse
transcription using the primer 760 from exon 5:
(5-GTTGAGGAACTCTTCAC-3), followed by the addition of anchor primer to the 3 end of the cDNA and polymerase chain
reaction (PCR) using the anchor primer and the nest 1 primer 690 from
the 3 end of exon 4: (5-CAAGTGTCCACAACATGC-3)
(Fig 1). For uracil DNA glycosylase (UDG)
cloning, the PCR product was further amplified with the anchor primer
and nest 2 primer 567 from the 5 end of exon 4:
(5-CAUCAUCAUCAUAGGGTTGATCTCAGGATC-3). The final PCR product was fractionated by agarose gel electrophoresis and the altered
transcript was cut out from low-melting gel and purified using the Gene
Clean Kit (Bio 101) followed by cloning into vector pAMP1 (GIBCO/BRL).
DNA sequencing was performed by the dideoxy chain termination method
using the Sequenase sequencing kit (USB, Cleveland, OH) or
on the ABI373A DNA sequencer (Perkin Elmer, Applied Biosystem Division,
Norwalk, CT).
Northern blot analysis.
A total of 10 µg of total cellular RNA extracted from each cell line
was size fractionated on a 1% agarose/formaldehyde gel and transferred
to a nylon membrane (Oncor, Gaithersburg, MD). Hybridization was performed in 50% formamide, 3X standard saline citrate (SSC), 10% dextran sulfate, 5X Denhardt's solution, and 0.5%
sodium dodecyl sulfate (SDS) at 42°C for 17 hours. The filters were
washed in 0.2X SSC, and 0.1% SDS at room temperature for 15 minutes
and then at 55°C for another 20 minutes. Probes used in the
Northern blot hybridization comprised a 2.3-kb EcoRI cDNA fragment covering exons 3 to 7 of BCL6, a 5.5-kb
BamHI/HindIII fragment containing the J region
of IGH (provided by J.V. Ravetch, Rockefeller
University, New York, NY), an 8-kb BamHI fragment of the
IGHG3, which is in the same transcript unit with
the I region of IGHG3 and a probe, pc , covering
the constant region of the IGL (provided by I.R. Kirsch,
National Cancer Institute, Bethesda, MD), a 1.1-kb PCR
fragment flanking the first exon and the coding region of TTF
(Emb Z35225), a 1.2-kb PCR fragment covering the exons 1 to 5 of
BOB1 (Emb Z49194) and a 1.1-kb PCR fragment flanking the
leading sequence and the coding region of H4.
| |
RESULTS |
Identification of genes fused to BCL6.
RNAs from three NHL biopsies (352, 1020, and 1547), which carried
chromosomal translocations involving 3q27 and which showed BCL6
rearrangements by Southern blot analysis, were used in this study.
5 RACE and electrophoresis analysis showed an 400 bp PCR
fragment in all cases, which corresponded to the germ line BCL6
transcript (Fig 2). Extra PCR bands ranging
in size from 500 to 700 kb, possibly representing chimeric or
alternatively spliced transcripts were also noted in all three cases
(Fig 2). The altered PCR fragments were eluted from the gel, subcloned, and sequenced. Homology search showed that the sequences fused to the
5 end of BCL6 were identical to the IGH (1020),
IGL (352), and TTF (1547) genes, respectively.
As shown in Fig 3, 100 bp of sequence
derived from the D1 and J6 regions of the IGH
gene, 200 bp of the V pseudo region of IGL, and 240 bp
of exon 1 of TTF gene were all spliced to the acceptor splice
sites of exon 2 of BCL6, leading to complete removal of exon 1 of BCL6, where its promoter is located. The fusion transcripts
were in the same transcriptional orientation, except IGL, where
the IGLV pseudo region-BCL6 chimeric transcript was in
a head-to-head orientation.
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| Fig 2.
Detection of BCL6 fusion transcripts by 5
RACE analysis. RNA derived from tumors 1020, 352, and 1547 were
subjected to reverse transcriptase (RT)-PCR amplification as described
in the text. Arrows point to bands representing BCL6 chimeric
transcripts. RNA from tumor 1562 (C), which showed no BCL6
rearrangement by Southern blot analysis, was used as the negative
control. The fragment size of the marker  X174 RF DNA/HaeIII
is indicated.
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| Fig 3.
Schematic representation of BCL6 fusion
transcripts obtained by 5 RACE analysis on cases 1020, 352, and
1547. The BCL6 transcript is shown in the open box, and the
transcript fused to the BCL6 is shown in the closed box.
Sequence at the junction of each fusion transcript and its orientation
are also shown.
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|
Expression of BCL6 and its fusion partner genes during the B-cell
differentiation.
To compare the pattern of expression of BCL6 and its fusion
partners during B-cell differentiation, RNAs from a panel of B-cell lines at different stages of differentiation were subjected to sequential Northern blot hybridization with probes derived from the
BCL6 fusion partner sequences (IGH, IGL, and
TTF) identified in this study. In addition, the expression of
BOB1 and H4 genes and the IGHG3 seqeunce, which
have been previously identified to be fused to BCL6 in
t(3;11)(q27;q23) and t(3;6) (q27;p21) and t(3;14)(q27;q32)
translocations,18-20 also were studied. As shown in
Fig 4 and Table
1, BCL6 was expressed in cell lines, which corresponded to GC
cells (Ramos, Bjab), but not in pre-B cells (697), immunoblasts (CD33,
RD), or plasma cells (U266, Skmm1, JJN3, XG-4, XG-7, XG-10). In
contrast, all of the BCL6 fusion sequences and genes studied
displayed a different pattern of expression. BOB1 and
H4 were expressed throughout B-cell differentiation. TTF was
also expressed in all stages of B-cell differentiation, except in pre-B
cells. IGH and IGL were expressed in pre-B and mature B
cells; in addition, they showed persistent expression in both the
immunoblatic cell lines. IGHG3 also was expressed in
immunoblastic cells, although it was not expressed in pre-B cells and
GC B cells. The expression of the IG gene promoters was
variable in the plasmacytic cell lines; IGH was expressed in
Skmm1, XG-4, and XG-10; IGHG3 was expressed in Skmm1, JJN3, XG-4, and XG-10; while IGL was expressed in U266 and XG-4.
These results demonstrate that BCL6 and its fusion partner
sequences and genes are regulated differently during B-cell
differentiation.
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| Fig 4.
RNA expression of BCL6 and its fusion partner
genes in a series of B-cell lines at different stages of
differentiation (top panel). Cell lines described in Table
1. A mouse glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) probe was used to estimate the amount of blotted RNA. The genes
that fused to BCL6 are labeled on the right. The different
sizes of IGH, IGHG3, and IGL transcripts
represent the products of physiological rearrangements of these
genes.
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| |
DISCUSSION |
Previous studies of BCL6 expression by immunohistochemical
analysis showed it to be highly regulated during B-cell
differentiation, being restricted to B cells in the GC, but not in
pre-B or mature progenitor cells, including immunoblasts and plasma
cells.12 As shown previously and now in this study,
chromosomal translocations juxtapose heterologous promoters to the
BCL6 coding domain, leading to its deregulated expression,
probably shutting off its downregulation during B-cell differentiation.
We have identified three heterologous sequences (IGH,
IGL, and TTF) fused to BCL6 by translocation. These, as
well as three previously identified BCL6 fusion partners (IGHG3, BOB1, and H4), were studied for their
patterns of expression during B-cell differentiation by Northern blot
analysis. As expected, BCL6 expression was restricted to
GC-type B cells. In contrast, all of the BCL6 fusion partner
genes displayed a different pattern of expression, including their
persistent expression in immunoblasts and some, but not all, plasma
cells. The absence of expression of IG genes in some of the
plasma cells may be related to their state of differentiation. Although
the pattern of expression of BCL6 fusion partners detected here
in malignant cell lines may not reflect their physiologic pattern in
normal cells, our results clearly show that the heterologous promoters
display a regulatory pattern distinct from that of BCL6 in most
B cells analyzed.
The results presented here indicate that promoter substitution by
chromosome rearrangement leads to constitutive expression of
BCL6, dictated by the expression pattern of the new promoter. Consistent with these findings, recent immunohistochemical analysis of
DLCL, Burkitt's lymphoma (BL), and FL biopsy samples also showed high
levels of BCL6 protein,12,13 suggesting that its
expression is constantly upregulated during B-cell lymphomagenesis. The
pattern of expression of most of the promoters juxtaposed to BCL6
studied here, specifically the lack of expression of TTF and
IGHG3 in the pre-B-cell line, suggest that expression during
late stages of development may be critical for BCL6
deregulation. However, additional studies of cells representative of
the pre-B-cell stage are necessary to confirm this hypothesis.
A similar change in the pattern of expression during B-cell
differentiation following chromosomal translocation was previously reported in the case of the BCL2 gene. This gene is normally
expressed during pre-B-cell development, but is downregulated in
association with B-cell maturation or to facilitate apoptosis. However,
mature B-cell lymphomas with a t(14;18)(q32;q21) translocation express higher levels of BCL2 mRNA than normal mature B cells,
indicating that fusion of the BCL2 gene with the IG
gene leads to an inappropriately high level of BCL2-IG fusion
transcript at the mature B-cell stage leading to abrogation of
apoptosis signals and ultimately to lymphomagenesis.22,23
Recent analysis of BCL6 -/- mice showed that BCL6 is
required for GC formation and a normal T-cell-dependent antigen
response.15 B cells undergo a complex processing within the
GC, which includes proliferation, hypermutation of the V region
of IGH, and immunoglobulin isotype-switching.24
During this process, B cells either differentiate to memory cells or
plasma cells, or undergo apoptosis. Normal BCL6 downregulation
in the late stage of B-cell differentiation is therefore important for
terminal differentiation of B cells. As pointed out above, BCL6
is specifically expressed in GC B cells and its expression is required
for GC formation.12,15 Such constitutive expression by the
activated BCL6 allele may enforce on the cell a GC phenotype,
including constitutive proliferation, block of differentiation, or
inhibition of apoptosis. The resulting block of normal downregulation
of BCL6 may also expose the cells to genetic instability
typical of GC leading to lymphoma development.
| |
FOOTNOTES |
Submitted July 25, 1997;
accepted September 8, 1997.
Supported by Grants No. CA-66999 (to R.S.K.C.) and CA-44029 (to R.D-F.)
from the National Institutes of Health/National Cancer Institute,
Bethesda, MD.
Address reprint requests to R.S.K. Chaganti, PhD, Memorial
Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
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T. Akasaka, I. S. Lossos, and R. Levy
BCL6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma
Blood,
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L. Pasqualucci, A. Migliazza, K. Basso, J. Houldsworth, R. S. K. Chaganti, and R. Dalla-Favera
Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma
Blood,
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[Abstract]
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M. S. Gordon, C. M. Kanegai, J. R. Doerr, and R. Wall
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PNAS,
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I. Wlodarska, P. Nooyen, B. Maes, J. I. Martin-Subero, R. Siebert, P. Pauwels, C. De Wolf-Peeters, and A. Hagemeijer
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Blood,
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X. Wang, Z. Li, A. Naganuma, and B. H. Ye
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PNAS,
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H. Zan, Z. Li, K. Yamaji, P. Dramitinos, A. Cerutti, and P. Casali
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K. D. Huynh, W. Fischle, E. Verdin, and V. J. Bardwell
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Genes & Dev.,
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I. S. Lossos and R. Levy
Higher-grade transformation of follicle center lymphoma is associated with somatic mutation of the 5' noncoding regulatory region of the BCL-6 gene
Blood,
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H. Akasaka, T. Akasaka, M. Kurata, C. Ueda, A. Shimizu, T. Uchiyama, and H. Ohno
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I. S. Lossos and R. Levy
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A. Greiner, K. B. Muller, J. Hess, K. Pfeffer, H. K. Muller-Hermelink, and T. Wirth
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Abstract
Introduction
Abstract
