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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 635-639
NEOPLASIA
Higher-grade transformation of follicle center lymphoma is
associated with somatic mutation of the 5' noncoding regulatory
region of the BCL-6 gene
Izidore S. Lossos and
Ronald Levy
From the Division of Oncology, Department of Medicine, Stanford
University Medical Center, Stanford, CA.
 |
Abstract |
Follicle center lymphoma (FCL) is an indolent low-grade B-cell
non-Hodgkin's lymphoma (NHL) that frequently transforms to aggressive
diffuse large B-cell lymphoma (DLBCL). Histologic transformation of FCL
is commonly associated with accumulation of secondary genetic alterations. The BCL-6 gene is altered by
chromosomal rearrangements and mutations clustering in its 5'
noncoding regulatory region in up to 70% of primary DLBCL, but in a
significantly smaller subset of FCL. Previous studies have shown that
both chromosomal rearrangements and mutations could deregulate
BCL-6 expression. To evaluate the association between
progressive accumulation of BCL-6 regulatory region mutations
and the histologic transformation of FCL, we analyzed by extensive
cloning and sequencing paired biopsy specimens obtained at the time of
FCL diagnosis and transformation (6 patients) or FCL relapse (3 patients). In an additional patient, biopsy specimens obtained at the
time of diagnosis, FCL relapse, and subsequent transformation to DLBCL
were evaluated. The presence of identical mutations in the paired
diagnosis and posttransformation DLBCL specimens confirmed the common
clonal origin of both the pretransformation and the posttransformation
lymphomas. No new mutations in the 5' noncoding regulatory region
of the BCL-6 gene were detected in any of the specimens
evaluated at the time of FCL relapse. In contrast, 5 of the 7 transformed specimens contained new mutations not found in the paired
original biopsy specimens obtained at the time of FCL diagnosis or
relapse. The number of these new mutations ranged from 1 to 6 per
specimen. Some of the new mutations tended to cluster in certain areas
of the 5' noncoding regulatory region of the BCL-6 gene.
Our results show that transformation of FCL to DLBCL is associated with
accumulation of new mutations in the 5' noncoding regulatory
region of the BCL-6 gene, that by deregulation of the
BCL-6 gene expression may play a role in lymphoma transformation.
(Blood. 2000;96:635-639)
© 2000 by The American Society of Hematology.
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Introduction |
Follicle center lymphoma (FCL) accounts for
approximately 40% of all non-Hodgkin's lymphomas (NHLs) occurring in
adults.1 It is generally characterized by a relatively
indolent clinical course and long survival. Nonetheless, it is well
recognized that FCL may transform to a more aggressive lymphoma in 25%
to 60% of patients.2,3 This transformation is associated
with an increasing proportion of large cells, rapidly progressive
clinical course, and short survival. Identification of the molecular
mechanisms associated with morphologic transformation and clinical
progression of FCL are critical issues in understanding the
pathogenesis of these lymphomas. Several secondary genetic
abnormalities, including nonrandom chromosomal changes,4-6
c-myc gene rearrangement,7,8 p53 tumor suppressor
gene mutations,9,10 somatic mutations of the translocated
BCL-2 gene,11 and p16 and p15 inactivation by
deletions, mutations, and hypermethylation12,13 were
associated with histologic transformation of FCL. However, the marked
heterogeneity of these secondary aberrations that are only observed in
a subset of transformed lymphomas suggests that other molecular
mechanisms must be implicated in FCL transformation.
The gene most commonly implicated in the pathogenesis of diffuse large
B-cell lymphomas (DLBCL) is the BCL-6 proto-oncogene, located
at chromosome 3q27 that encodes a POZ/Zinc finger sequence-specific transcription repressor.14-18 Clonal BCL-6 gene
rearrangements are observed in 30% to 40% of DLBCLs but in only 6%
to 10% of FCLs.16,18,19 These rearrangements cluster
within a highly conserved 4.0-kilobase (kb) regulatory region spanning
the promoter, the first noncoding exon and the 5' region of the
first intron the major breakpoint region (MBR) and result in
BCL-6 expression driven by a heterologous promoter from the
partner chromosomes.20 In addition, small deletions and
somatic point mutations occurring in the BCL-6 regulatory
region that overlap with the subdomain of MBR are reported in 70% of
DLBCLs but in only 45% of FCLs.21-23 The occurrence of
mutations is independent of translocation-generated rearrangements and
it was demonstrated that some mutations can significantly deregulate
BCL-6 expression.22,24
To gain further insight into the secondary molecular alterations
associated with transformation to higher-grade NHLs, we have analyzed
the nucleotide sequence of the 5' regulatory region of the
BCL-6 gene in sequential biopsy specimens from patients with FCL who underwent morphologic transformation to DLBCL.
| |
Materials and methods |
Tumor specimens
Sequential biopsy specimens from 10 patients with FCL were selected
for this study, based on availability of frozen viable single cell
suspensions for molecular analyses. Overall, 11 biopsy specimens
obtained at the time of FCL diagnosis (2 biopsy specimens from case
IL111), 4 biopsy specimens obtained at the time of FCL relapse, and 7 biopsy specimens obtained at the time of morphologic transformation to
DLBCL were evaluated (Table 1). All
lymphoma specimens were classified according to the Revised
European-American Lymphoma Classification1 and were
routinely immunophenotyped by flow cytometry for expression of Ig heavy
and light chains and B- and T-cell markers. The histology of the first
lymph node (9 patients) and spleen (2 patients) at the time of
diagnosis was FCL, provisional cytologic grade I (10 specimens), and
diffuse predominantly small cell (DPSC) lymphoma (1 specimen). The
lymph node histology at the time of NHL relapse was
classified as FCL, provisional cytologic grade I in 3 specimens and
provisional cytologic grade 2 in 1 specimen. Lymph node histology at
the time of transformation was classified as DLBCL in all 7 evaluated
specimens. Specimen IL105A was evaluated and reported in our
previous study.25
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Table 1.
Summary of BCL-6 5' regulatory region mutations
in 10 cases of paired FCL and subsequent FCL or DLBCL specimens
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DNA synthesis and polymerase chain reaction
High-molecular-weight DNA was extracted from
5.0 × 106 cells using a commercially available kit
as described by the manufacturer (QIAamp Tissue Kit; Qiagen, Valencia,
CA). The first intron region of the BCL-6 gene that has
previously been shown to undergo extensive mutation in B cells was
amplified by polymerase chain reaction (PCR) using
5'-CCGCTGCTCATGATCATTATTT and 5'-TAGACACGATACTTCATCTCAT primers, as was previously reported.25
For each PCR, a control with no added template was used to check for
contamination. PCR products were analyzed by 2% agarose gel
electrophoresis and staining with ethidium bromide. Bands of
appropriate size were excised from the gels and purified by adsorption
to a silica matrix (QIAquick columns, Qiagen).
Cloning and sequencing of polymerase chain reaction products
The purified PCR amplicons were ligated into a TA-PCR cloning vector
(Invitrogen, Carlsbad, CA) and were used for transformation of
competent Escherichia coli (1 Shot INV  F'; Invitrogen)
according to the manufacturer instructions. Twelve to 24 white colonies were picked per sample and used in a second round of PCR. All the PCR
amplicons (range: 8-21) were sequenced on a 373 automatic DNA sequencer
(Applied Biosystems, Foster City, CA) using the ABI Prism Big Dye
Terminator Kit (Perkin Elmer, Foster City, CA) as recommended by the
manufacturer. The same primers used for the PCR were used for forward
and backward sequencing. The Taq DNA polymerase error frequency
in our laboratory is 0.09%, which amounts to 0.71 mutations per
BCL-6 clone.
Sequence analysis was performed using the MacVector program (Oxford
Molecular Group, Campbell, CA). Sequences were aligned with the
BCL-6 hypermutation region germ line sequence previously established in our laboratory (GenBank accession number AF
191831).25 The first nucleotide of the amplified
BCL-6 gene region, corresponding to the first nucleotide of the
sense primer, was arbitrarily defined as position +1. Tumor mutation
status was determined after excluding previously established
polymorphisms.21,25 Only mutations defined as confirmed
mutations, observed more than once in the BCL-6 gene clones
from biopsy specimens from the same patient, were included in the
analysis. Unconfirmed mutations, defined as mutation observed in only 1 of the BCL-6 gene clones from biopsy specimens from the same
patient, were disregarded in our determination of the tumor mutation
status, because their rate was similar to the Taq DNA
polymerase error frequency in our laboratory, thus suggesting that at
least some of them could be Taq DNA polymerase errors and
not real mutations.
The BCL-6 alleles were easily identified by different mutation
clustering on the alleles and by the presence of polymorphisms.
| |
Results |
BCL-6 gene cloning and sequencing were performed in
sequential biopsy specimens from the time of FCL diagnosis and relapse in 4 patients and from the time of FCL diagnosis and transformation to
DLBCL in 7 patients (1 of these patients had 3 biopsy specimens obtained at the time of FCL diagnosis, relapse, and transformation).
BCL-6 gene mutations in the paired diagnosis-relapse
biopsies
Biopsy specimens from 4 patients with FCL were evaluated at the time
of diagnosis (5 specimens) and at the time of FCL relapse (4 specimens)
without evidence of morphologic transformation to a higher-grade NHL
(Table 1). At the time of diagnosis, only 1 of the patients had
confirmed mutation in the 5' regulatory region of the
BCL-6 gene, whereas in the remaining 3 patients, the
BCL-6 gene was unmutated. No new mutations were observed in any
of the specimens tested at the time of FCL relapse.
BCL-6 mutations in the paired diagnosis-transformation
biopsies
Biopsy specimens from 7 patients with FCL were evaluated at the time
of FCL diagnosis and at the time of transformation to DLBCL. Evaluation
of immunoglobulin gene in sequential pretransformation and
posttransformation biopsy specimens showed clonal relation between the
tumors in all the cases, except case IL119, in which it was not
performed (data not shown). At the time of diagnosis, confirmed
mutations in the 5' regulatory region of the BCL-6 gene were found in biopsy specimens from 5 of the 7 evaluated patients. Their number ranged from 1 to 3 per specimen, with an incidence ranging
from 1.3 × 10 3 to
3.8 × 103 per base pair (bp). Some of the
mutations were observed in all the molecular clones of the same allele,
whereas others were present in some but not all clones of the same
allele (Table 1 and Figure 1), confirming
the presence of ongoing mutation in the BCL-6 gene of FCL that
we have previously reported.25
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| Fig 1.
BCL-6 mutations in FCL transformation.
Schematic representation of the BCL-6 5'
noncoding region mutations in molecular clones derived from FCL
diagnosis biopsy specimen (A) and transformation to DLBCL biopsy
specimen (B) from representative IL116 case, demonstrating intraclonal
diversification at diagnosis and acquisition of new mutations in DLBCL
biopsy specimens. Each sequence is represented as a horizontal line.
The first nucleotide of the amplified BCL-6 gene region,
corresponding to the first nucleotide of the sense primer, is
arbitrarily defined as position +1. In each sequence, mutations are
indicated as circles. The nature of each mutation is specified in Table
1.
|
|
At the time of transformation to DLBCL, confirmed mutations in the
5' regulatory region of the BCL-6 gene were found in the biopsy specimens from 5 patients. In 1 of these patients (IL114, Table
1 and Figure 2), 2 previous biopsy
specimens, obtained at the time of FCL diagnosis and relapse, were
unmutated, whereas the biopsy specimen obtained at the time of
transformation to DLBCL contained a BCL-6 gene with 6 confirmed
mutations. In the additional 4 patients, the specimens obtained at the
time of transformation contained BCL-6 gene mutations, most of
which were identical to mutations observed in the paired FCL specimens,
confirming their common clonal origin. In addition, new mutations not
observed in the FCL diagnosis specimens were found (Figure 1). The
number of these new mutations ranged from 1 to 4 per specimen (Table 1). Most of the new mutations were present in all the tested molecular
clones, whereas some were ongoing. Most probably, only the mutations
observed in all or the majority (because of admixture of remaining
follicular cells) of the molecular clones may play a role in lymphoma
transformation. In the patients IL105, IL119, and IL120, some of the
ongoing mutations, observed in the minority of the molecular clones
evaluated at the time of FCL diagnosis, were not found in any of
molecular clones evaluated at the time of transformation. Finally, in
the case IL117, the paired diagnosis-transformation specimens were both
unmutated.
View larger version (20K):
[in this window]
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| Fig 2.
Mutation events of BCL-6 in FCL transformation.
Mutation events in the 5' noncoding regulatory
region of the BCL-6 gene derived from biopsy specimens at the
time of FCL diagnosis (IL114A), FCL relapse (IL114B), and
transformation to DLBCL (IL114C) in NHL patient IL116. Clonal
relationship of the molecular clone sequences (ovals) is shown. Number
of mutations is indicated along the lines in bold. The mutations are
listed by location as is specified in the "Materials and
methods."
|
|
To evaluate the potential significance of these new confirmed mutations
observed in the transformed but not in the FCL diagnosis specimens, we
examined the distribution of these mutations. These new mutations
appeared to cluster in certain areas of the 5' regulatory region
of the BCL-6 gene: identical mutation 507 (C  T) in 2 patients and mutations at positions 180, 182, and 188. We searched for
mutations at these positions in the previously described compilation of
all the published BCL-6 mutations in NHL and Hodgkin's
lymphoma for which nucleotide change and exact mutation positions have been reported.25 Mutations at positions 507, 180, 182, and
188 have not been previously reported. However, mutations located in
proximity to these positions (especially positions 186 and 190) have
been reported repeatedly. To evaluate the potential influence of these
mutations on BCL-6 regulation, we searched for possible
transcription factor-binding sites in and around these mutation
positions (TFSEARCH on the Internet). Mutations 180 (T A)
and 182 (T G) occurred in the potential binding site of
the GATA 2 transcription factor. It is possible that additional potential binding sites of presently unknown transcription factors may be affected by some of these mutations.
| |
Discussion |
Following recent reports that showed BCL-6 gene alterations
in NHL, and especially in DLBCL, by either chromosomal
rearrangements16,18 or somatic mutations in its 5'
noncoding regulatory region21,22,25 and previous
demonstration that some of these mutations may deregulate BCL-6
gene expression,24 we examined the possible role of
BCL-6 gene mutations in the process of FCL transformation to
DLBCL. Our findings demonstrate that histologic transformation of FCL may be associated with the accumulation of new mutations in the 5' noncoding regulatory region of BCL-6 oncogene.
Clustering of the new acquired mutations in specific parts of the
BCL-6 5' noncoding regulatory region suggests the
presence of currently unknown regulatory factors, which may effect
BCL-6 gene expression. While our work was under review, Capello
et al26 reported on accumulation of new BCL-6 gene
mutations in 2 of 5 transformed cases, similar to our data.
Several previous studies have found evidence that heterogeneous
secondary genetic changes may be associated with histologic transformation of FCL; nonetheless, none of them was a predominant genetic lesion responsible for the transformation.4-13 The
most common secondary cytogenetic findings seen in transformed FCL comprised of del(6q) and acquisition of additional copy of chromosome 7.4-6 New chromosomal translocations involving chromosome
3q27, on which BCL-6 gene is located, were not among the
commonly reported secondary changes observed during or after FCL
transformation. Therefore, if the BCL-6 oncogene has a role in
FCL transformation, it should be deregulated by a mechanism different
from gross chromosomal aberration.
BCL-6 gene may be altered by somatic mutations of the 5'
noncoding regulatory region. These mutations are regarded as a marker of B-cell transit through the germinal center, because they are absent
in pregerminal center naïve lymphocytes or B-cell malignancies originating from pregerminal center B cells.22,26 Previous studies showed that some of the mutations in the BCL-6 5'
regulatory region could deregulate its expression. Pasqualucci et
al24 evaluated the effect of regulatory region mutations on
BCL-6 expression in 11 lymphoma cases (6 DLBCLs and 5 Burkitt
lymphomas [BL], corresponding to 20 mutated alleles) and normal
germinal center (GC) cells (20 mutated alleles). Significant
overexpression of the reporter gene was observed in 33% of DLBCL
mutant alleles derived from 3 of 6 DLBCL cases. Conversely, none of the
alleles derived from the BL cases or normal GC cells displayed an
altered transcriptional activity.
In this study, we demonstrate association between FCL transformation
and accumulation of new mutations in the 5' noncoding regulatory
region of the BCL-6 oncogene. New mutations were observed in
transformed cases but not in cases relapsing without transformation. The time intervals between the diagnosis and the subsequent relapse or
transformation were overlapping, thus excluding the possibility that
accumulation of new mutations was predominantly time dependent. The
relatively small number of relapsed cases evaluated in this study
precludes the general conclusion of the lack of association between FCL
relapse and accumulation of new BCL-6 gene mutations. However,
our finding in the same patient of new mutations only in the biopsy
obtained at the time of transformation but not at the time of FCL
relapse (Figure 2) suggests their potential role in transformation. In
addition, our finding of identical mutations in transformed DLBCL
specimens from 2 different patients and clustering of the mutations in
a specific part of 5' regulatory region of BCL-6 gene may
suggest functional significance of these mutations and the presence of
BCL-6 regulatory factors that may bind to these regions.
Significant progress has been made in elucidation of BCL-6
function and its interaction with other cellular
factors,15,27-31 but almost no data exist on the potential
transcription factors involved in the regulation of BCL-6
expression. Clustering of the new confirmed mutations in the region of
GATA 2 binding site suggests a potential role for this transcription
factor in BCL-6 regulation. It is likely that additional,
presently unknown transcription factors may be involved in the
regulation of BCL-6 expression. Further studies mapping
functionally significant mutations will help to clarify the mechanisms
of BCL-6 regulation.
In our previous work25 and in the current study, we
demonstrated that mutations in the 5'regulatory region of the
BCL-6 gene are ongoing. It is possible that as a result of
ongoing BCL-6 gene somatic mutations, the lymphoma cell
population becomes heterogeneous, and a mutational variant having a
selective growth advantage because of BCL-6 overexpression
compared with parental clones gives rise to the higher-grade NHL
lymphoma cell population. Indeed, the finding of some of the mutations
in FCL subclones at the time of diagnosis but not at the time of
transformation to DLBCL (Table 1) and appearance of new mutations not
observed at the time of diagnosis confirm the concept of clonal
selection during transformation.
In conclusion, this study shows an association between somatic
mutations in the 5' regulatory region of BCL-6 gene and
FCL transformation. Furthermore, our data suggest the presence of particular subregions in the 5' noncoding regulatory region of the BCL-6 gene that may have a specific role in its regulation. Further studies are needed to determine the functional significance of
these new accumulated mutations and identification of transcription factors involved in BCL-6 gene transcription regulation.
| |
Footnotes |
Submitted December 14, 1999; accepted February 28, 2000.
Supported by grants CA33399 and CA34233 from the USPHS-NIH.
Reprints: Ronald Levy, Stanford University School of Medicine,
Division of Oncology M207, Stanford, CA 94305-5306.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Top
Abstract
Introduction