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in Non-Hodgkin's Lymphomas
From the Department of Pathology,*
University of
Massachusetts Medical School, Worcester, and Department of Health
Sciences and Technology,
Harvard
University-Massachusetts Institute of Technology,
Cambridge, Massachusetts
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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.
The expression and activity of both factors are increased transiently
when normal resting cells are stimulated to proliferate. They are
constitutively elevated in oncogene transformed cultured cells,
and overexpression of either initiation factor in rodent cells makes
them tumorigenic. In this study we investigate an association between
the expression of translation initiation factors and lymphomagenesis.
We have analyzed the expression of the protein synthesis initiation
factors 4E and 2 by immunohistochemistry in reactive lymph nodes and
several types of non-Hodgkin's lymphoma representing a wide range of
clinical behaviors based on the Revised European-American Lymphoma
behavioral classification. The study included 7 benign lymph nodes with
follicular hyperplasia, 26 indolent lymphomas (6 marginal zone
lymphomas, 7 small lymphocytic lymphomas, and 13
follicular lymphomas, grades 1 and 2), 16 moderately
aggressive lymphomas (8 mantle cell lymphomas and 8 follicular
lymphomas, grade 3), 24 aggressive lymphomas (14
large-B-cell lymphomas and 10 anaplastic large-cell lymphomas),
and 15 highly aggressive lymphomas (7 lymphoblastic lymphomas and 8
Burkitt's lymphomas). Strong expression of initiation factors 4E and
2 was demonstrated in the germinal centers of reactive follicles.
Minimal or no expression was seen in the mantle zones and surrounding
paracortices, indicating that high expression of initiation
factors 4E and 2 is associated with the active proliferation of
lymphocytes. Most cases of aggressive and highly aggressive lymphomas
showed strong expression of initiation factors 4E and 2, in
contrast to the cases of indolent and moderately aggressive
lymphoma, in which their expression was intermediate between
the germinal centers and the mantles of reactive follicles. A positive
correlation was found between the expression of both initiation factors
4E and 2 and the Revised European-American Lymphoma behavior
classification (P < 0.05). Thus,
constitutively increased expression of initiation factors 4E and 2
may play an important role in the development of lymphomas and is
correlated with their biological aggressiveness.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(eIF-4E and eIF-2)
increases after resting lymphocytes or fibroblasts are treated with
mitogens or growth factors, respectively.6-10
The least
abundant component of the eIF-4F complex is eIF-4E, which is
responsible for binding the 5' cap structure present on virtually all
eukaryotic mRNAs and transferring mRNAs to the ribosomes. The two other
subunits of the eIF-4F complex are eIF-4A, a helicase that is
responsible for unwinding mRNA secondary structures, and eIF-4G, which
holds the complex together and is responsible for ribosome
binding.4
The eIF-2 initiation factor complex, which
transfers initiator methionine tRNA to the 40 S ribosomal subunit, is
composed of eIF-2 and two other proteins, eIF-2ß and eIF-2
. The
eIF-2 subunit is the rate-limiting component of the protein
synthesis initiation factor 2 (eIF-2), and the phosphorylation of
eIF-2 by the interferon-inducible kinase (PKR) inactivates the whole
eIF-2 complex.11
The expression of both eIF-4E and
eIF-2 is transiently increased in normal cells when they leave the
resting G0 period and proliferate in response to
extracellular growth stimuli. The expression of these factors is
constitutively high in oncogene-transformed and tumor
cells.12-14
Importantly, overexpression of either eIF-4E
or eIF-2 is sufficient to transform cells to a malignant
phenotype.4,14-17
Non-Hodgkin's lymphomas (NHLs) are common neoplasms of the
lymphoreticular system, accounting for 60% to 70% of all
lymphomas.18
Previous findings demonstrate that increased
transcription of both eIF-4E and eIF-2 is induced by
c-myc8,19
and suggests that they may be
important in the genesis of Burkitt's lymphoma and other lymphoid
tumors with increased c-myc expression. The expression of
these initiation factors in lymphomas, however, has not been previously
investigated. NHLs may be categorized as indolent, moderately
aggressive, aggressive, or highly aggressive lymphomas based on the
Revised European-American Lymphoma (REAL)
classification.20
We hypothesized that the increased
expression of eIF-4E and eIF-2 might correlate with the biological
activity of NHLs. In this study, we evaluated eIF-4E and eIF-2 in
reactive lymph nodes and several types of lymphoma to determine their
level of expression and correlation with tumor grade.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We studied 7 cases of follicular hyperplasia; 26 cases of indolent lymphomas, including 6 marginal zone lymphomas, 7 small lymphocytic lymphomas, and 13 follicular lymphomas (grade 1 and 2); 16 cases of moderately aggressive lymphomas, including 8 mantle cell lymphomas and 8 follicular lymphomas (grade 3); 24 cases of aggressive lymphomas, including 14 large-B-cell lymphomas and 10 anaplastic large-cell lymphomas; and 15 cases of highly aggressive lymphomas, including 7 lymphoblastic lymphomas and 8 Burkitt's lymphomas accessioned between 1990 and 1997 at the University of Massachusetts Medical Center. All cases were reviewed by at least two pathologists (S. Wang and G.A. Pihan or S. Wang and B.A. Woda) to confirm the diagnoses. The lymphomas were grouped into indolent, moderately aggressive, aggressive, and highly aggressive lymphomas based on the REAL behavioral classification.20
Western Blot Protein Analysis
Western blot analysis was performed as described
previously,9,10,21
except that protein lysates were
obtained from lymph nodes that had been stored at -70°C. Protein
lysates were obtained by pulverizing portions of lymph node cooled in
liquid nitrogen. The frozen tissue powder was extracted with lysis
buffer (0.5% Nonidet P-40, 420 mmol/L NaCl, 20 mmol/L Tris, pH 7.5, 2
mmol/L phenylmethylsulfonyl fluoride, and 0.02 mmol/L leupeptin). The
suspension was forcefully passed 10 times through an 18-gauge needle to
disrupt cellular material, after which the lysates were kept on ice for
15 minutes, aliquoted, and frozen at -20°C. Before gel
electrophoresis, each lysate was centrifuged at 10 x
103
rpm at 4°C for 15 minutes. Supernatants were
collected, and the protein content was analyzed by the Bradford assay
(BioRad, Hercules, CA). Forty micrograms of total protein from each
lysate was run on 8% SDS-polyacrylamide gel and blotted for 18 hours
at 20 V at 40°C onto Immobilon polyvinylidene difluoride (PVDF)
membrane (Amersham, Arlington Heights, IL) using a liquid transfer
solution containing 25 mmol/L Tris, pH 7.5, 192 mmol/L glycine, 10%
methanol, and 0.01% SDS. The monoclonal mouse anti-eIF-4E antibody
(1:1000 dilution; Transduction Laboratories, Lexington KY), monoclonal
mouse anti-eIF-2 antibody (from E. Henshaw, Rochester University;
1:4000 dilution)22
and monoclonal mouse anti-actin
antibody (Amersham, N-350; 1:5000 dilution) were used sequentially,
followed by horseradish-peroxidase-conjugated anti-mouse IgG (1:3000
dilution; Promega, Madison, WI) to detect the corresponding proteins
using the ECL developing system (Amersham).
Immunohistochemistry
All biopsies in this study were fixed in 10% buffered formalin
and paraffin embedded by routinely processing with a VIP Tissue Tek
processor (Miles Scientific, Naperville, IL). Sections were cut at a
thickness of 4 µm, heated at 60°C for 30 minutes, and then
deparaffinized and hydrated through a series of xylene and alcohol
baths before staining. The slides were microwaved in a proprietary
citrate-buffered antigen retrieval solution (BioTek Solutions, Santa
Barbara, CA) for 5 minutes in an 800-W microwave oven. After
replenishment of this solution, the slides were microwaved again for an
additional 5 minutes and then allowed to cool for 20 minutes.
Immunohistochemical staining was performed with a monoclonal mouse
antibody to eIF-4E (1:100 dilution; Transduction Laboratories) and a
monoclonal mouse antibody to eIF-2 (1:2000; obtained from E.
Henshaw, University of Rochester), using a standard avidin/biotin
complex (ABC) method as implemented on a Techmate 1000 (BioTek)
automated immunostainer. Antibody diluent buffer was used as a negative
control. The staining procedure consisted of a 30-minute incubation in
the primary antibody followed by brief buffer washes and then
incubation in a cocktail of biotinylated anti-mouse IgG/IgM (BioTek)
for 30 minutes. The slides were then washed, incubated in avidin/biotin
complex (BioTek) for 30 minutes, rewashed, and then reacted with
diaminobenzidine and hydrogen peroxide to visualize the end product.
The sections were counterstained with hematoxylin.
Evaluation of Immunostaining
The immunostained sections were examined on an Olympus microscope
(Tokyo, Japan) at x400. The mantle zone and scattered small
lymphocytes, both representing the population of resting cells,
displayed barely detectable staining or no staining at all with
antibodies to either eIF-4E or eIF-2. Thus, these cells were used as
an internal negative control. The cytoplasmic staining was assessed as
follows: 0, no or barely detectable staining in the mantle zone
lymphocytes or in scattered small lymphocytes in the paracortex; 1+,
cells stained more intensely than small lymphocytes in the mantle areas
but weaker than in germinal centers of reactive follicles; 2+, cells
stained as strong or stronger than centroblasts in the germinal
centers. The blood vessels, which are strongly positive for eIF-2,
served as internal positive control for eIF-2. Scattered plasma
cells, demonstrating strong staining for eIF-4E, served as internal
positive control for eIF-4E.
Data Analysis
The nonparametric Wilcoxon-Mann-Whitney rank sum test was used to
assess the correspondences between eIF-2 expression and biological
behavior (indolent < moderately aggressive <
aggressive < highly aggressive) based on the REAL classification.
The Spearman Rank order correlation test was used to assess the
relationship between eIF-4E expression and biological
behavior.23
Statistical significance was set at the level
of P < 0.05 (two sided).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Expression in Normal Lymph
Nodes and Lymphoma-Affected Nodes by Western Blotting
We obtained frozen tissue from one nonreactive lymph node, two
lymph nodes with follicular hyperplasia, two cases of follicular
lymphoma, one small lymphocytic lymphoma, one Burkitt's lymphoma, and
one large-B-cell lymphoma. Equal amounts of total protein were
separated by gel electrophoresis, transferred onto PVDF membrane, and
analyzed with anti-eIF-4E and anti-eIF-2 antibody. The anti-actin
antibody was used to confirm even loading of total protein extracted
from lymph nodes.
As is illustrated in Figure 1
, the
antibodies that we used are specific for their protein targets. The
eIF-4E antibody recognizes a 25-kd protein,15
and the
eIF-2 antibody recognizes a 36-kd protein.22
It is of
note that the levels of both eIF-4E and eIF-2 is increased in
reactive lymph nodes and in the lymph nodes affected by lymphomas.
These data are consistent with previous data illustrating the specific
recognition of eIF-2 in cultured lymphocytes6,7
and
colonic tissue21
as assessed by Western blotting using
these antibodies.
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in Reactive Lymph Nodes and NHLs
We studied seven lymph nodes exhibiting follicular hyperplasia;
each strongly expressed eIF-4E and eIF-2 within the germinal centers
(Figure 2, A and B)
. Scattered activated
lymphocytes in the paracortical zones expressed high levels of eIF-4E
and eIF-2 as well.
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showed
weaker eIF-4E expression (2+) than the follicles of a reactive lymph
node. High level (2+) eIF-2 expression was seen in three of six and
two of seven cases (Figure 2D)
, respectively, with intermediate (1+)
expression in the remainder of cases.
Marginal zone lymphomas (MZL) showed weak (1+) expression of eIF-4E in
five of six cases and of eIF-2 in four of six cases. The remaining
cases of MZL showed strong (2+) expression of eIF-4E or eIF-2. We
noted that the tumor cells with plasmacytoid differentiation
demonstrated stronger expression of both eIF-4E and eIF-2 than the
monocytoid tumor cells (data not shown).
Small lymphocytic lymphomas (SLLs) demonstrated 2+ eIF-4E staining in a
geographical pattern in three of seven cases. The scattered
immunoblasts and paraimmunoblasts and the pseudofollicular
proliferation centers of SLLs demonstrated stronger expression of
eIF-4E than the small lymphocytic component (Figure 2E)
. Three of seven
cases of SLL were diffusely but strongly (2+) eIF-2 positive (Figure 2F)
, and the remainder were diffusely and weakly (1+) positive.
In mantle cell lymphomas, most of the cases displayed 1+ positivity for
both eIF-4E and eIF-2. The tumor cells express less eIF-4E (Figure 2G)
and eIF-2 (Figure 2H)
than the residual germinal centers in most
of these cases. However, they usually showed stronger staining than
normal mantle zone lymphocytes of non-neoplastic lymph nodes (Figure 2A
for eIF-4E and 2B for eIF-2; Table 1
).
Similarly, in the moderately aggressive follicular lymphomas (grade 3,
large-cell type), one of eight cases expressed both eIF-4E and eIF-2
strongly (2+), two cases expressed either eIF-4E or eIF-2 strongly
(2+) with intermediate (1+) expression of the other, and the remaining
five cases displayed intermediate expression of both.
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in several classes of aggressive
lymphomas was studied. eIF-2 was highly expressed (2+) in all cases
of large-B-cell lymphoma, whereas eIF-4E was strongly expressed in 10
of 14 cases (Figure 3, A and B)
. In our
10 cases of anaplastic large-cell lymphomas, 6 were strongly eIF-4E and
8 were strongly eIF-2 positive (Figure 3, C and D)
. The majority of
lymphoblastic lymphomas strongly expressed eIF-4E (six of seven) and
eIF-2 (five of seven) (Figure 3, E and F)
. All of the cases of
Burkitt's lymphomas were strongly positive for both
eIF-4E and eIF-2 (Figure 3, G and H)
. The residual non-neoplastic
lymphocytes in all lymphoma cases studied demonstrated very weak or
nondetectable expression of both eIF-4E and eIF-2, however, the
plasma cells were strongly positive for eIF-4E, and blood vessels were
strongly positive for eIF-2. Statistical analysis demonstrated a
strong correlation between the expression of both eIF-4E
(P < 0.05) and eIF-2
(P < 0.05) and the REAL behavior
classification, with weak expression of eIF-4E and eIF-2
corresponding with less aggressive lymphomas and strong
expression corresponding with more aggressive lymphomas. The
correspondence between eIF-4E and eIF-2 expression was strong
(P < 0.05), which neither indicates nor
precludes independence of expression (Table 1)
.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in reactive lymph nodes and a spectrum of
NHLs. In all cases, the expression of either eIF-4E or eIF-2 is
higher in lymphomas than in the mantle zones of reactive follicle
centers, which are composed of small virgin B cells (Table 1)
. Our data
demonstrate a strong correlation between the expression of both eIF-4E
(P < 0.05) and eIF-2
(P < 0.05) and the REAL behavior
classification, with increased expression of these factors as lymphomas
progress from indolent to aggressive clinical behavior.
Some lymphomas histologically and phenotypically resemble components of
the normal lymph node. The marginal zone lymphomas are indolent but
express higher levels of eIF-4E and eIF-2 than their quiescent,
non-neoplastic counterparts. Follicular lymphomas of all grades
frequently express eIF-4E and eIF-2 at a level intermediate to the
germinal centers and the mantle zones of reactive lymph nodes. The
constitutive expression of eIF-4E and eIF-2 at a moderately
increased level, as compared with resting lymphocytes in the mantles,
may reflect the slow, but continuous proliferation of the indolent and
moderately aggressive lymphomas.
A well known feature of small lymphocytic lymphoma (SLL) is that it can
convert from its indolent state into an aggressive diffuse large-B-cell
lymphoma (Richter's syndrome).25
In this study, more
cases of SLL demonstrated strong (2+) eIF-4E and eIF-2 expression
than other indolent lymphomas. Furthermore, some cases of SLL showed
strong eIF-4E staining in a geographical pattern with a stronger
expression in the pseudofollicle proliferation centers than in the
small lymphocytic component. As we have only limited clinical follow-up
on these patients, we have not determined whether the expression of
these initiation factors is associated with the aggressive
transformation of SLL.
Mantle cell lymphoma is a moderately aggressive
lymphoma.20
Our study demonstrates that the expression of
eIF-4E and eIF-2 in mantle cell lymphoma is similar to other
indolent lymphomas (Figure 2
and Table 1
), suggesting that additional
mechanisms (eg, transcriptional activation of cyclin D1 gene resulting
from t(11;14) chromosomal translocation)26
contribute to
the more aggressive course of mantle cell lymphomas as compared with
indolent lymphomas.
The aggressive and highly aggressive lymphomas, characterized by high
proliferation rates, including large-B-cell (Figure 3, A and B)
,
anaplastic large-cell (Figure 3, C and D)
, lymphoblastic (Figure 3, E and F)
, and Burkitt's (Figure 3, G and H)
lymphomas strongly express
eIF-4E and eIF-2. The expression of eIF-4E and eIF-2 in these
lymphomas is comparable or stronger than that expressed by reactive
follicle center lymphocytes (Figure 3, A–H
, and Figure 2, A and B
).
Our data show that strong expression of eIF-4E and eIF-2 correlates
with higher tumor grades. These results indicate that constitutively
increased expression of eIF-4E and eIF-2 and consequentially
increased protein synthesis, in part, account for high growth and
division rates and aggressive biological behavior. The data also
suggest that there might be cooperativity between eIF-4E and eIF-2
in the process of neoplastic transformation; however, this mechanism as
of yet has not been formally proven.
We have previously demonstrated that c-myc transcriptionally
activates expression of eIF-4E and eIF-2 in cultured
fibroblasts.8
Although c-myc rearrangement is
always present in Burkitt's lymphomas, it is found only in a subset of
other lymphomas, including diffuse large-cell and anaplastic large-cell
lymphomas arising in AIDS patients,27
and gastric
large-cell lymphomas28
as well as in post-transplant
lymphoproliferative disorders,29
and it may accompany
histological transformation of SLL to a clinically more aggressive
large-cell lymphoma.30
Our study shows that eIF-4E and
eIF-2 are almost always elevated in the non-Hodgkin's lymphomas.
Consequently, c-myc overexpression in Burkitt's lymphomas
and in some cases of other lymphomas may explain high levels of eIF-4E
and eIF-2, although in other types of lymphomas lacking
overexpression of c-myc, an alternate mechanism for
up-regulation of eIF-4E and eIF-2 should exist.
The role of eIF-4E and eIF-2 in lymphomagenesis warrants further
investigation. It has been demonstrated in cell culture models that
eIF-4E preferentially increases synthesis of specific growth-promoting
proteins, including cyclin D1, myc, ornithine decarboxylase,
and fibroblast growth factor (FGF) as well as proteins responsible for
tumor angiogenesis (vascular permeability factor and FGF) and
metastasis (V6 splice variant of CD44 surface glycoprotein and
collagenase type IV).9,10,31-35
It remains to be
established whether eIF-4E and eIF-2, in addition to their general
role in mRNA translation, may preferentially increase synthesis of
growth- and metastasis-facilitating proteins in lymphomas. It should be
emphasized that the general increase in protein synthesis due to
constitutively elevated activity of eIF-4E and eIF-2, by itself,
would facilitate accumulation of cellular proteins, providing for
accelerated growth and division rates. Noteworthy, it has been shown
that eIF-4E prevents apoptosis in response to both growth factor
withdrawal and c-myc activation in cultured
fibroblasts.36
It remains to be determined whether the
initiation factors eIF-4E and eIF-2 act to prevent apoptosis in
lymphomas, thus contributing to tumor growth.
The role of other proteins involved in the regulation of protein
synthesis and their association with hematopoietic malignancies are
being elucidated. An inactivator of eIF-2, eIF-2 kinase acts by
phosphorylation of eIF-2 in growth-factor-deprived cells and has
been mapped to the 2p21–22 locus, which is nonrandomly involved in
chromosome rearrangements in myeloproliferative
disorders.37
Furthermore, the gene encoding
interferon-regulatory factor-1 (IRF-1), known to induce expression of
eIF-2 kinase in response to interferon, has been mapped to the
5q31.1 region, which is deleted in 5q- associated
leukemias.38
Two genes encoding RNA helicases, which, like
eIF-4A, unwind mRNA secondary structures, potentially facilitating
translation initiation, are involved in chromosomal translocations,
inv(11)(p15q22) and 11q23, associated with lymphoid and myeloid
malignancies.39-41
It has been suggested that increased expression and function of
initiation factors and, consequently, a constitutive increase in
protein synthesis is a key tumorigenic event.14
Analysis
of these factors in human neoplasms is still limited; however, it has
been found that eIF-4E is elevated in breast and head and neck
carcinomas,42,43
and both eIF-4E and eIF-2 are
increased in colonic neoplasms.21
Our present findings
establish NHLs as one of the neoplasms associated with elevated
expression of eIF-4E and eIF-2. It remains to be established whether
these translation initiation factors could serve as markers for
lymphoma grading and progression or as targets for therapy.
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Acknowledgements |
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Footnotes |
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Accepted for publication March 18, 1999.
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References |
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in response to growth induction by c-myc. Proc Natl Acad Sci USA 1993, 90:6175-6178 in transformed cells. Cancer Lett 1996, 102:113-123[Medline]
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