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Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2381-2386
Mutation Analysis of the Rearranged Immunoglobulin Heavy Chain
Genes of Marginal Zone Cell Lymphomas Indicates an Origin From
Different Marginal Zone B Lymphocyte Subsets
By
A. Tierens,
J. Delabie,
S. Pittaluga,
A. Driessen, and
C. DeWolf-Peeters
From the Laboratory of Hematology, University Hospitals of Leuven;
and the Department of Pathology II, University Hospitals of Leuven,
Leuven, Belgium.
 |
ABSTRACT |
Marginal zone cell lymphoma is a recently described entity among the
non-Hodgkin's lymphomas. It likely originates from the marginal zone B
cells in the spleen and equivalent cells in the lymph node and
extranodal tissues. Recent evidence indicates that marginal zone B
cells are functionally heterogeneous and may differ with respect to the
pattern of somatic hypermutation in their Ig variable genes. To test
whether marginal zone lymphomas may originate from different subsets of
marginal zone B cells, we performed a sequence and mutation analysis of
the rearranged Ig heavy chain (IgH) variable genes
(VH) of a series of 14 cases of
marginal zone lymphoma, occurring in the spleen (4), the lymph node
(4), the stomach (2), the orbit (2), the tongue (1), and the skin (1).
Our data show that marginal zone cell lymphomas preferentially
rearrange the VH4, VH3,
and VH1 family genes, without preference for
any particular VH gene. Somatic mutations are
present in 13 cases; one case of marginal zone cell lymphoma of the
skin showed a germline configuration of the rearranged
VH gene. Mutation analysis shows evidence of
antigen selection in three cases of marginal zone cell lymphoma, one of
the spleen, stomach, and orbit, respectively. No evidence of antigen
selection was present in the other cases. These data indicate that
marginal zone cell lymphomas may arise from different subsets of
marginal zone B cells. In addition, lymphomagenesis may not be
triggered by antigen in all cases of marginal zone cell lymphoma.
| |
INTRODUCTION |
MARGINAL ZONE cell lymphoma is a recently
recognized entity among the non-Hodgkin's lymphomas.1 It
typically occurs in the spleen.2,3 Although clinically
distinct, the monocytoid B-cell lymphomas of the lymph node and the
lymphomas of the extranodal sites, the so-called MALT lymphomas, have
also been argued to represent marginal zone cell lymphomas based on
similar morphological, immunophenotypic and cytogenetic
features.4-6 The lymphoma cells characteristically express
pan B-cell markers such as CD20 and CD22 but no CD5, CD10, or CD23.
IgM, or to a lesser extent IgA or IgG are expressed. IgD is variably
coexpressed.7-9 Trisomy 3 is the most frequently detected
cytogenetic abnormality in marginal zone cell
lymphomas.10,11 Because of the localization, morphology, and immunophenotypic characteristics, marginal zone cell lymphomas are
thought to derive from marginal zone cells of the spleen or equivalent
cells in the lymph nodes and extranodal tissues. Interestingly, normal
marginal zone B cells are most likely a functionally heterogeneous population of B cells.12 From studies in rodents, it is
clear that the marginal zone contains three distinct subsets of B
cells. Two subsets represent memory B cells generated by a
T-cell-dependent (TD) and T-cell-independent type 1 (TI-1) immune
reaction, respectively. The third population of marginal zone cells do
not represent memory cells and are involved in the T-cell-independent
primary immune reaction to type 2 antigens (TI-2).12
Mutation analysis of rearranged VH genes of
human microdissected marginal zone B cells provided evidence that human
marginal zone B cells may be functionally heterogeneous as
well.13,14 Only a subpopulation of the cells shows a
characteristic pattern of somatic mutations in the rearranged VH genes indicative of positive antigen
selection or affinity maturation and therefore likely participates in
the T-cell-dependent immune reaction. The rearranged
VH genes of the other marginal zone B-cell
subset show somatic mutations that do not exhibit the distribution
pattern characteristic of affinity maturation. It was postulated that
this subset of marginal B cells is an early memory B cell of the TD
immune reaction.13 The relative presence of these subsets
of B cells probably differs between the marginal zones in the spleen
and Peyer's patch,14 attributed to the differences in
antigen exposure in these organs.14 In addition,
circumstantial evidence shows that a subset of human splenic marginal
zone cells is involved in the TI immune response.15 The
presence of somatic mutations in these cells is not yet documented.
The presence of distinct B-cell subsets in the marginal zone led us to
postulate that the marginal zone cell lymphomas arise from different
subsets of marginal zone cells. To test this hypothesis, we performed a
VH gene mutation analysis of a series of
marginal zone cell lymphomas.
| |
MATERIALS AND METHODS |
Case selection.
We selected 14 cases of marginal zone cell lymphoma documented by
morphology and immunophenotypic analysis. Four patients presented with
primary lymphoma in the spleen, four in the lymph node, two in the gut,
two in the orbit, one in the skin, and one in the tongue. Most of the
patients were included in a previous study.11 The patient
and lymphoma characteristics are summarized in Table
1. In addition, cyclin D1 staining was
performed in case 13, to rule out the possibility of a diagnosis of
mantle cell lymphoma. Two monoclonal anti-cyclin D1 antibodies
(Novocastra, Newcastle upon Tyne, UK; Immuno-Biological Laboratories,
Gunma, Japan) were used, but no cyclin D1 was expressed by the lymphoma cells. The clinical history of a lymphoma that has been recurring at
the same site for 7 years without dissemination to other locations strongly argues against the diagnosis of mantle cell lymphoma as well.
cDNA synthesis.
RNA was extracted from 10 20-µm frozen tissue sections using TRIzol
reagent (Life Technologies, Gaithersburg, MD) following the
manufacturer's recommendations. In this study, 1 µg of total RNA was
used for reverse transcription (RT). RT was performed using Superscript
II Reverse Transcriptase (Life Technologies) according to the
manufacturer's instructions. Briefly, the RNA was added to 8 µL
DEPC-treated H2O containing 150-ng random primers (Life
Technologies). This mixture was heated to 70°C for 10 minutes and
quickly chilled on ice water. Subsequently, 12 µL of a reaction mixture containing 15 mmol/L KCl, 10 mmol/L Tris-HCl, pH 8.3, 0.75 mmol/L MgCl2, 0.1 mol/L DTT, 10 mmol/L dNTPs, 200 U Reverse Transcriptase and 2.5 U Ribonuclease Inhibitor (Life Technologies) was
added.
PCR amplification of the rearranged Ig heavy chain genes.
A total of 4 µL of a 1:100 dilution of the cDNA product was used for
the polymerase chain reaction (PCR). The rearranged Ig heavy chain
genes were amplified using a semi-nested PCR method as previously
described.16 In the first round of the PCR, a mixture of
six framework I (FR I) VH family-specific primers and three primers complementary to all
JH genes was used. The second round of the PCR
was performed in six separate reactions with one of the six
VH FR I primers and internal JH primers.
The DNA was added to the PCR buffer (50 mmol/L KCl, 10 mmol/L Tris-HCl
pH 8.4, 0.01% gelatin) containing 200 µmol/L dNTPs, 2.5 mmol/L
MgCl2, 100 nmol/L of each primer, and 1.5 U Taq polymerase, in a total volume of 50 µL. In the second round of amplification, the
same reagent concentrations were used, except for that of MgCl2, which was 1.5 mmol/L; 2 µL of the first-round PCR
product was added to the semi-nested reaction as the template. The PCR conditions of the first round consisted of one cycle at 95°C for 2 minutes, 59°C for 4 minutes, 72°C for 80 seconds followed by 34 cycles at 95°C for 90 seconds, 59°C for 30 seconds, 72°C for 80 seconds, and one final cycle of 72°C for 5 minutes. The second PCR
consisted of a total of 35 cycles, using annealing temperatures of
65°C and 61°C for the VH3,
VH4, and VH1, VH2, VH5,
VH6, primers, respectively. The denaturing and
extension temperatures as well as the cycle conditions were identical
to those of the first round of PCR. All PCR reactions were performed
using a hot-start procedure and appropriate positive and negative
controls. All samples were analyzed in duplicate. An aliquot of 10 µL
PCR product was size-fractionated through a 6% polyacrylamide gel
(PAGE) in 1× TBE buffer.
Sequencing of the PCR products.
The PCR products to be sequenced were gel-purified. Briefly, the gel
bands containing the monoclonal rearranged VH gene PCR products were
excised from the 6% PAGE and eluted in TE buffer (50 mmol/L Tris, 1 mmol/L EDTA; pH 7.4) at 55°C. Two microliters of this PCR product was
re-amplified in a 50-µL volume using the respective VH
family-specific primer and the internal JH primers as in the second PCR
amplification. Forty microliters of re-amplified PCR products were
subsequently analyzed on a 1.5% agarose gel. The appropriate bands
were excised and the PCR products were extracted from the gel with
Qiaquick spin columns (Qiagen GmbH, Hilden, Germany) following the
manufacturer's recommendations.
An aliquot of the isolated DNA was directly sequenced on both strands,
using Sanger's chain termination method and fluorescent dideoxynucleotide chain terminators.17 Sequencing primers
were identical to the primers used for the second round of the
semi-nested PCR of the rearranged VH genes. The
JH primer used for the reverse sequencing
reaction was determined based on the sequence obtained in the forward
sequencing reaction. The products of the sequencing reaction were
analyzed using the Applied Biosystems 373A sequenator (Applied
Biosystems, Foster City, CA).
Sequence analysis.
The identification of the VH, Ig heavy chain
diversity genes (DH) and
JH germline sequences was performed by sequence
comparison to the March 1997 update of V Base, a comprehensive database
of human Ig germline gene sequences compiled from published sequences
(V BASE sequence directory, I.M. Tomlinson, MRC Centre for
Protein Engineering, Cambridge, UK). Mac Vector 5.0 sequence analysis
software (Oxford Molecular Group, Campbell, CA) was used for this
sequence analysis. For the germline DH gene attribution,
the longest stretches with the highest homology were retained with a
minimum of six successive matches or seven successive matches,
interrupted by one mismatch.
Somatic mutation analysis.
The probability that somatic mutations in the rearranged
VH genes resulted from antigen selection was
analyzed according to Chang and Casali.18 The probability
that an excess of replacement (R) mutations in
VH complementarity determining regions (CDRs)
or FRs occurred on the basis of chance alone was calculated using the
binomial distribution model
where
n is the total number of observed mutations, k is the
number of observed R mutations in the CDRs or the FRs, and q is
the probability that an R mutation will localize to CDRs or FRs:
The
inherent susceptibility of R mutations of the CDRs and FRs (CDR
Rf and FR Rf, respectively) has been calculated for each of
the identified germline genes and is based on the chances of the
occurrence in each codon of an amino acid replacement, given any single
nucleotide change that does not result in a termination codon.
| |
RESULTS |
Sequence analysis.
The distribution of the VH gene families used
by the marginal zone cell lymphoma cases studied is summarized in Table 2. The marginal zone cell lymphoma cases
preferentially rearranged gene members of the
VH4 family and, to a lesser extent, of the
VH3 and VH1 families.
The nucleic acid sequences are available from Genbank. The deduced
amino acid sequences are given in Fig 1. No
preferential rearrangement involving any particular
VH gene was seen. A slight overrepresentation of the DH gene family Dxp was observed in the
lymph node- and spleen-based marginal zone cell lymphomas. In four of
six cases of MALT lymphomas no definitive assignment of the
DH gene could be made. In case 14, a
DH gene was absent. A predominance of
JH4 and JH6 gene rearrangements was observed.
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| Fig 1.
Deduced protein sequences of the rearranged
VH genes of the cases of marginal zone
lymphomas. Lowercase, replacement mutations with regard to the germline
sequences. FR, framework; CDR, complementarity determining region. CDR
regions are underlined.
|
|
Mutation analysis.
The mutation analysis data are summarized in Table 2. In all but one
case, the sequences of the rearranged IgH genes contained point
mutations with respect to the closest germline sequences. These
mutations are most likely due to somatic mutations and are not
introduced by the Taq polymerase, as direct sequencing of the PCR
products was performed. As such, any Taq polymerase-introduced errors
are masked. It cannot be excluded that some of the so-called mutations
may actually represent germline polymorphisms. However, these are
likely few because most of the human VH
germline genes have been identified.19
Thirteen cases of marginal zone lymphoma showed point mutations in
their rearranged IgH genes. Analysis demonstrated statistically significant evidence for positive antigen selection in case 11 only,
originating in the orbit. In that case, more replacement mutations than
expected were observed in the CDR regions, as compared with the FR
regions. Statistically significant evidence for negative antigen
selective pressure was seen in two cases, cases 2 and 9, a marginal
zone lymphoma of the spleen and stomach, respectively. In these cases,
fewer replacement mutations than expected were observed in the FR
regions, indicating antigen selective pressure to maintain the germline
configuration. In the other 10 cases with somatic mutations, no
statistically significant evidence for antigen selection was observed.
The VH gene of case 13, localized in the skin,
was in germline configuration.
| |
DISCUSSION |
Our study shows that marginal zone cell lymphomas predominantly
rearrange the VH4 gene family and, to a lesser
extent, the VH3 and VH1
gene families, in contrast to peripheral blood B cells. A biased
VH gene family usage with respect to the
peripheral blood cell repertoire has previously been observed in
defined non-Hodgkin's lymphoma subtypes.20-24 In some
studies, including some on the MALT lymphomas of the gut and salivary
gland, an overrepresentation of only a few of the VH genes within these families accounts for
this bias. These overrepresented VH genes
frequently seem to be involved in auto-antibody production (eg,
agglutinins, rheumatoid factors, and anti-DNA
antibodies).20,22,23,25 This finding suggests that these
B-cell non-Hodgkin's lymphomas may arise from autoreactive B cells.
This hypothesis cannot be tested by the analysis of our cases of MALT
lymphoma because the number of cases localized to specific sites is too
small. However, the hypothesis does not seem valid, at least for the
marginal zone cell lymphomas of the spleen and lymph node in our study,
because no restricted use of any particular VH
gene was noted. Alternatively, the bias with respect to the usage of
VH genes belonging to certain
VH gene families in marginal zone lymphoma may
be explained by the preferential use of certain
VH families by subsets of B cells out of which
the lymphoma arises. Indeed, certain compartments of rodent B cells
show a bias of the VH gene family usage,
irrespective of selection by antigen.26 Further analysis of
VH gene usage in normal marginal zone B-cell
subsets is needed to test this hypothesis.
All cases of splenic marginal zone lymphoma in our study showed somatic
mutations in their rearranged VH genes. One of
the cases showed statistically significant evidence of antigen selective pressure against replacement mutations in the rearranged VH gene to maintain the germline configuration.
The presence of somatic mutations in the rearranged
VH genes with evidence of antigen selection has
also been reported in splenic lymphoma with villous lymphocytes
(SLVL).27 However, the rearranged VH genes of the cases of SLVL reported showed
evidence of positive antigen selection and were present in most cases, in contrast with the findings in our cases of splenic marginal zone
lymphoma. SLVL is a B-cell lymphoma that usually presents with
splenomegaly.28 The morphology of the leukemic cells, the immunophenotype, and cytogenetics are well characterized, but the
relationship of SLVL to the marginal zone cell lymphomas of the spleen
is still debated.3,8,27-30 SLVL has been argued to
represent the leukemic counterpart of marginal zone cell
lymphoma.29,30 Although the number of cases studied is
small, the data with respect to the pattern of somatic mutations in the
rearranged VH genes indicate that marginal zone
cell lymphoma and SLVL might arise from different subsets of B cells
within the spleen, that is, predominantly early and late memory cells,
respectively.
Recently, a VH gene mutation analysis of 5 cases of marginal zone cell lymphomas of the monocytoid B-cell type was performed by Küppers et al.31 Four of their cases
showed somatic mutations in the VH genes with
characteristics of positive antigen selection. These findings contrast
with the absence of evidence for antigen selection in our cases of
monocytoid B-cell lymphoma or marginal zone lymphoma of the lymph node.
It is difficult to compare their findings with ours, however, because
the primary localization of their lymphoma cases was not reported. At
least one of their cases of monocytoid B-cell lymphoma did apparently not localize to the lymph node, but to the stomach.
In our series, two MALT lymphomas that localized to the stomach and to
the orbit showed evidence of negative or positive antigen-driven selection, respectively, whereas three MALT lymphoma cases showed somatic mutations in the VH genes but no
evidence of antigen selection. The rearranged
VH gene of the sixth MALT lymphoma case,
presenting in the skin, did not contain any somatic mutation. Our
findings are similar to the heterogeneous data previously reported for
the MALT lymphomas.22-25 The four cases of low-grade MALT
lymphomas studied by Qin et al22 and two of a total of six
MALT lymphomas reported in two studies conducted by Du et
al23,24 showed a VH gene mutation pattern
indicative of positive antigen selection. In a recent analysis of five
MALT lymphoma cases of the salivary gland, Bahler et al25
found somatic mutations in the rearranged VH
genes, but no statistically significant evidence of antigen selection
could be documented.
The occurrence of somatic mutations, in the absence of apparent antigen
selection, as observed in most of the marginal zone lymphomas studied
in this report, might indicate that an early memory cell of the TD
immune reaction (ie, a cell that has not undergone multiple rounds of
antigen selection in the germinal center) is the cell of origin of
these lymphomas.32 Interestingly, it was recently shown
that the normal human marginal zone harbors such cells with a low level
of somatic mutations, which are presumed to be early memory B
cells.13 It has been postulated that these memory cells are
similar to a recently identified peripheral blood IgM-expressing B-cell
population that displays a similar pattern of somatic mutations in its
rearranged VH genes.33 Alternatively, these
cells, with a low level of somatic mutations, might be memory cells
involved in the TI immune reaction. However, there is no compelling
evidence that the hypermutation mechanism in humans is activated in TI
immune reactions, which do not involve the germinal
center.34,35 This is in contrast with the findings in
Xenopus and sheep, where somatic mutations may occur outside the germinal center. In these species, these somatic mutations contribute to the diversification of the antibody
repertoire.36,37
At least a subset of the marginal zone lymphomas likely arises from
late memory cells showing affinity maturation. Such cells are indeed
present in the marginal zone of the spleen and Peyer's patch.13,14 Whether such cells are also present in the
marginal zones of the acquired mucosal lymphoid tissues in other organs has not been studied.
One patient with a MALT lymphoma that had originated in the skin showed
no mutations in the rearranged VH gene. These data are similar to those obtained in mantle cell lymphoma and chronic
lymphocytic leukemia and suggest that the cell of origin of this case of MALT lymphoma is a naive pregerminal center B cell.38,39 Interestingly, the lymphoma cells of this MALT
lymphoma case expressed IgM and strongly IgD, in keeping with such a
hypothesis. Naive pregerminal center B cells are predominantly present
in the splenic marginal zone of young persons.40 Their
presence in the adult marginal zone or in tissues other than the spleen has not been documented.
Whether antigenic stimulation plays a role in the lymphomagenesis and
cell growth of marginal zone cell lymphomas is unclear. There is good
evidence that this is the case for at least a subset of the MALT
lymphomas of the gut, where chronic Helicobacter pylori infection may be involved.41,42 However, the absence of
statistically significant evidence of positive or negative antigen
selection in many of our cases might indicate that antigen does not
play a major role in lymphomagenesis and tumor growth in those cases. The use of different VH genes, such as seen
within our series of lymph node-based or spleen-based marginal zone
cell lymphomas, at least indicates that no common antigen appears to be
involved.
In conclusion, the rearranged VH genes of the
marginal zone cell lymphomas belong primarily to the
VH4, VH3, and
VH1 families. Somatic mutations occurred in the
VH genes of 13 cases, whereas these were absent in one case. Evidence for antigen-driven selection was observed in only
three cases. These data indicate that marginal zone cell lymphomas may
originate from distinct subsets of marginal zone B cells, that is,
virgin B cells and early as well as late memory B cells.
| |
FOOTNOTES |
Submitted July 9, 1997;
accepted November 17, 1997.
Supported by Nationaal Fonds voor Wetenschappelijk Onderzoek
(NFWO) Grant No. G-0311-97.
Address reprint requests to J. Delabie, MD, Department of Pathology II,
University Hospitals of Leuven, Minderbroedersstraat 12, B-3000 Leuven,
Belgium.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We thank S. Taelemans for excellent technical assistance.
| |
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Abstract
Introduction
Abstract
