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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 770-777
RAPID COMMUNICATION
Expression of Cyclin E and the Cyclin-Dependent Kinase Inhibitor
p27 in Malignant Lymphomas Prognostic Implications
By
Martin Erlanson,
Cajsa Portin,
Barbro Linderholm,
Jack Lindh,
Göran Roos, and
Göran Landberg
From the Departments of Oncology and Pathology, Umeå University,
Umeå, Sweden.
 |
ABSTRACT |
Cyclin E and the cyclin-dependent kinase inhibitor p27 are two
important regulators of the G1-S transition modulating the activity of
cyclin-dependent kinases. Aberrations in the cell cycle control are
often observed in tumors and might even be mandatory in tumor
development. To investigate the importance of cell-cycle defects in
malignant lymphomas we have characterized the expression of cyclin E
and p27 in 105 newly diagnosed lymphomas using immunohistochemistry. A
significant, inverse correlation between p27 and cyclin E expression was observed (rs =  .24, P = .02) and
both proteins correlated with the S-phase fraction
(rs = .35, P < .001 and
rs = .45, P < .001, respectively). The
inverse relationship between p27 expression and proliferation was
abrogated in some lymphomas, suggesting that p27 downregulation can
represent a genuine aberration. Survival analysis was performed in 105 patients with a median observation time of 86 months. Low p27 and high
cyclin E expression were significantly associated with a poor prognosis
(P = .0001 and .03, respectively). In a multivariate Cox
analysis, p27 expression, stage, serum lactate dehydrogenase level,
grade, and age were independent prognostic factors, in contrast to
S-phase fraction and cyclin E expression. This is the first report
showing that p27 expression in malignant lymphomas has independent
prognostic significance, which necessitates future studies regarding
its more precise biological role in lymphoid tumorogenesis.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
THE G1-S TRANSITION is controlled by
families of highly conserved proteins consisting of cyclin dependent
kinases (CDKs) and sets of activating and inhibitory
proteins.1,2 Cyclins D1 and E sequentially activate CDKs
triggering phosphorylation of key substrates such as the retinoblastoma
protein (pRB), thereby initiating DNA replication and passage through
the restriction point.3 There are two families of
CDK-inhibitors affecting the activity of the kinase complexes
contributing to proper control of the G1-S transition. The INK family
of proteins (p15, p16, p18, and p19) consists of specific
CDK-inhibitors mainly affecting the cyclin D-CDK4/CDK6
complexes.4 The other class of inhibitors, the CIP/KIP
family (including p21, p27, and p57), has a less selective inhibitory
effect on many CDK-complexes with a main activity during G1.5 p27 is affected by intrinsic and extrinsic factors,
such as transforming growth factor- (TGF-), cell-cell contact,
and elevated cyclic adenosine monophosphate (cAMP) levels
causing increased expression of the inhibitor with subsequent arrest in G1 or cell-cycle exit.6,7 p27 might also be involved in
terminal differentiation as observed for the promyelocytic cell line
HL-60.8 In lymphoid tissues p27 is expressed in
nonproliferating lymphocytes whereas activated lymphocytes, eg, in the
germinal centers, are negative, suggesting an inverse relation between
proliferation and p27 expression in normal lymphocytes.9
The cell cycle is often deregulated in tumors and several reports have
shown a high frequency of aberrant expression of cyclins, CDKs,
CDK-inhibitors, or suppressor proteins like p53 and
pRB.10,11 It has even been suggested that G1-S transition
defects are mandatory in tumor development.12 Genes coding
for the INK-family of CDK-inhibitors are often mutated in tumors in
contrast to the CIP/KIP-family where mutations are rare.13
Cyclin D1 is overexpressed in many tumors and can also transform cells
in collaboration with other oncogenes, proving that cyclin D1 is a
proto-oncogene.10,12 Despite the fact that cyclin E is
highly expressed in many tumors, it is not clear if cyclin E is a
proto-oncogene or not. Interestingly, high cyclin E expression in
breast cancer is associated with an increased risk of death in the
disease.14,15 Similar findings have been observed for low
p27 expression in several solid tumors and leukemia, suggesting that
specific cell-cycle defects are associated with aggressive tumor growth
and poor prognosis.15-20
In the present study we have characterized the expression of cyclin E
and p27 in malignant lymphomas and can establish a relationship between
these proteins and parameters such as tumor cell proliferation, tumor
grade, stage, and serum lactate dehydrogenase (LDH) level. Of special
interest is the finding that p27 expression was a significant, independent prognostic factor for malignant lymphomas.
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MATERIALS AND METHODS |
Patient material.
All newly diagnosed malignant lymphomas between 1987 and 1993 at Umeå
University hospital with available archive specimens and data regarding
immunophenotype, S-phase fractions, and serum LDH levels were included
in this study, giving a total of 105 patients. No patient
had received any treatment before the biopsy. Lymphomas were initially
classified according to the Kiel classification21 and
reclassified according to the Revised European-American Lymphoma classification (REAL)22 based on morphological examination
of imprints and paraffin sections and immunophenotyping with flow cytometry. Chronic lymphocytic leukemia (CLL, n = 19), follicular lymphoma (FL, n = 23), and other small cell lymphomas (n = 7) were
included in the indolent lymphoma group and diffuse large B-cell (n = 39), mantle cell (MCL, n = 11), and large T-cell lymphomas (n = 3) in
the aggressive group.23 Three cases of lymphoblastic lymphomas were included in the aggressive group. The treatments applied
were, with few exceptions, chlorambucil with or without steroids for
advanced indolent lymphomas and anthracyclin containing chemotherapy
combinations for aggressive lymphomas. Radiotherapy was given to stage
I patients and combined with three courses of chemotherapy for
aggressive cases before radiotherapy. Asymptomatic patients with
indolent lymphoma received deferred treatment. For control stainings
benign lymphoid tissues, mainly tonsils, were used.
Antibodies and immunohistochemistry.
Five-micrometer paraffin sections were dehydrated and
deparaffinized according to standard procedures. Optimal antigen
retrieval for the cyclin E and p27 proteins was achieved by microwave
treatment 3 × 5 minutes in citrate buffer, pH 8.0 for cyclin E
and pH 6.0 for p27. Staining was performed in an automatic
immunohistochemistry staining machine (Ventana 320-202; Ventana Inc,
Tucson, AZ) using anti-cyclin E (HE12, 1:500; Santa Cruz Biotechnology,
Inc, Santa Cruz, CA) and anti-p27 antibodies (K25020, 1:200;
Transduction Lab, Inc, Lexington, KY) according to the Ventana program.
The percentage of positively stained cells was evaluated using a 10 × 10 square grid fitted into the eyepiece of the microscope using an objective lens of × 40. At least 400 cells were counted from randomly chosen fields covering the specimen.
Cell kinetics and flow cytometry.
Cell suspensions were prepared by mechanical desintegration of freshly
obtained lymph node tissues, and DNA-staining was performed according
to Vindeløv et al.24 A FACScan flow cytometer was used
(Becton Dickinson Immunocytometry Systems, Inc, San Jose, CA) and
S-phase fractions were calculated by the Cellfit software using the
RFIT evaluation model (Becton Dickinson).
Clinical evaluation and statistical analysis.
Results from clinical investigations, staging and outcome were studied
retrospectively from the records. The Mann-Whitney rank sum test was
used for comparing two different groups, Kruskal-Wallis test for
variations between subgroups, and  2-test for comparing
proportions. Correlations between variables were tested according to
Spearman's test. Kaplan-Meier and Cox multiple regression analysis
were used for survival analysis. Statistical analysis was performed
using SPSS software (SPSS, Inc, Chicago, IL).
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RESULTS |
Cyclin E.
Immunohistochemical cyclin E expression could be evaluated in 98 of 105 cases, showing nuclear staining with various numbers of positive cells
often in combination with a quite distinct cytoplasmic staining
(Fig 1A). Only the nuclear staining was
evaluated because of earlier reports suggesting that the HE12 antibody
can react with unrelated cytoplasmic antigens22 and a
median fraction of 5.3% cyclin E positive cells was found. A
statistically significant correlation between the percentage of cyclin
E+ cells and S-phase fraction was observed
(rs = .45, P < .001) as shown in
Fig 2A. Regarding subgroups of malignant
lymphomas, low cyclin E positivity was observed in CLL and FL (median
labeling index = 2%), with higher values in MCL and, as expected, the
highest fraction of cyclin E+ positive cells in large cell
lymphomas (Fig 3). A significant difference
in cyclin E expression existed between the subgroups (P < .001) as well as between aggressive and indolent lymphomas (Table 1). Patient characteristics in
relation to cyclin E expression are presented in Tables 1 and
2.
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| Fig 1.
Immunostainings of cyclin E and p27 in normal lymphoid
tissues and malignant lymphomas. (A) Cyclin E staining in an indolent lymphoma showing both nuclear and cytoplasmic reactivity. (B) p27
staining of a reactive follicle in a tonsil. Notice the staining pattern in the dark and light zone. (C) p27 staining of a malignant follicular in an FL lymphoma. The staining pattern is representative for indolent lymphomas. (D) CLL with p27
pseudofollicles. (E) Large cell lymphoma with p27
blastic cells and occasional positive small lymphocytes (S-phase fraction = 11.5%). (F) Large cell lymphoma with p27+
(S-phase fraction = 3.4%).
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| Fig 2.
Scatter diagram showing the distribution of cyclin E,
p27, and S-phase fraction in lymphoma samples. (A)
rs = .45, P < .001, n = 98; (B)
rs = .24, P = .02, n = 93; (C)
rs = .35, P < .001, n = 100.
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| Fig 3.
Diagram showing cyclin E ( ), S-phase fraction
(), and p27 (· · ·) expression for
different lymphoma entities. Error bars represent mean values and 95%
confidence intervals. The histological subgroups are: CLL (n = 18),
FL (n = 18), MCL (n = 11), diffuse large cell lymphoma (LCL) (n = 34). Data concerning 12 cases with different other morphological types
are not shown in the figure.
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p27.
The expression of p27 was successfully analyzed in 100 of 105 cases. A
distinct nuclear staining was observed with very low background
staining making the p27 expression easy to evaluate, and a median value
of 30% positive cells was determined in the lymphomas. Small
lymphocytes were usually distinctly positive in contrast to larger
often negative cells. In benign germinal centers the centroblasts were
typically negative whereas centrocytes were weakly to moderately
positive corresponding to the dark and light areas of each follicle. In
the germinal center scattered cells were intensely p27+
(Fig 1B). In FL these follicular subcompartments had disappeared, giving a positive appearance in the neoplastic follicles (Fig 1C) with
a diffuse mixture of p27+ and p27 cells,
but also in the lymphomas the smaller cells were mostly negative. In
so-called pseudofollicles in CLL, containing proliferating cells, most
cells were p27 (Fig 1D). Large cell lymphomas were,
in general, p27 (Fig 1E) but cases were noted with
distinct staining of large, blastic cells (Fig 1F).
The expression of p27 was inversely correlated with both cyclin E
expression and S-phase fraction as illustrated in Fig 2B and C
(rs = .24, P = .02 and
rs = .35, P < .001, respectively). There was no significant difference regarding p27 expression in subgroups of lymphomas, but MCL cases showed the lowest p27 expression (Fig 3). The fraction of p27+ cells did not correlate to
the fraction of T cells in the B-cell lymphomas (data not shown). Low
p27 expression was associated with high serum LDH levels and age as
summarized in Tables 1 and 2, and for aggressive lymphomas also with
advanced stage (not shown). A weak significant positive correlation was
observed between p27 expression and leukocyte count and a negative
correlation to platelet count (not shown in figures). A strong
correlation was found between low p27 expression and higher age (Table
2).
Survival.
Survival analysis was performed in 105 malignant lymphoma
patients, with a median observation time of 86 months. As illustrated in Fig 4 there was a significant difference
in survival between cases with indolent/aggressive lymphomas (P = .007), elevated/normal serum LDH values (P < .001), and
high/low S-phase fractions (P < .001). When the patients were
subdivided according to cyclin E and p27 expression using median values
as cut off, no significant impact on survival was seen. Due to
uncertainty in the definition of the normal range of p27 and cyclin E
expression in lymphoid tissues, division into quartiles was performed
and for both p27 and cyclin E the lowest quartile versus the other
quartiles divided the patient material in statistically different
prognostic groups (Fig 5A and B). Patients
with low p27 expression ( 15% positive cells) had a significantly
reduced survival (P < .0001, Fig 5C) and a three times
increased risk of death in the disease compared with other patients
(data not shown). For cyclin E the results were more complex, with no
linear trend for the quartiles, but when using 2% as cut off (the
lowest quartile), patients with high cyclin E expression had a
significantly reduced survival (P = .03, Fig 5D).
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| Fig 4.
Crude overall survival for 105 lymphoma cases subdivided
in: (A) indolent (, n = 49) and aggressive
(· · ·, n = 56), P = .007; (B)
LDH 8 µkat/L (, n = 66) and LDH >8
µkat/L (· · ·, n = 39), P < .001; (C) S-phase
fraction 4% (, n = 53) and S-phase fraction
>4% (· · ·, n = 52), P < .001.
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| Fig 5.
Overall survival in relation to cyclin E and p27
expression. (A) Cyclin E expression divided in quartiles, first
(, n = 29), second (- - -, n = 20), third
(, n = 25), and fourth (· · ·, n
= 24), P = .03; (B) p27 expression divided in quartiles,
first (, n = 25), second (· · ·, n = 25), third (- - -, n = 25), and fourth quartile
(, n = 25), P < .001; (C) cyclin E
expression divided with a cut-off between the first and second
quartile, cyclin E 2% (, n = 29), and
cyclin E >2% (· · ·, n = 69), P = .03;
(D) p27 expression divided with a cut-off between the first and second
quartile, p27 15% (· · ·, n = 23) and p27
>15% (, n = 77), P < .001.
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Multiple regression was performed by Cox analysis in 93 lymphoma
patients including cyclin E, p27, LDH, age, stage, S-phase fraction,
and morphology. Cyclin E and p27 were dichotomized with cut off at 2%
and 15%, respectively, because no linear relation between predicted
survival and the variables was found (Fig 5). As presented in
Table 3, LDH, age, grade, stadium, and p27
expression were independent significant factors in contrast to S-phase
fraction and cyclin E expression. When the patients were subdivided
according to a combination of the independent parameters LDH and p27,
groups with highly different outcome were obtained
(Fig 6). Patients having lymphomas with a
p27 index >15% and an LDH value 8 microkatal (µkat)/L had a comparably good prognosis with 50%
survival rate after 8 years, in contrast to the poor outcome for the
group of patients with a p27 index 15% and LDH > 8 µkat/L (Fig
6).
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| Fig 6.
Overall survival for 100 lymphomas divided according to a
combination of p27 expression and serum LDH levels. LDH 8 µkat/L and p27 >15% (, n = 52); LDH >8 µkat/L and p27
>15% (- - -, n = 25); LDH 8 µkat/L and p27 15%
(, n = 11); LDH >8 µkat/L and p27
15% (· · ·, n = 12), P < .001.
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| |
DISCUSSION |
In the present study immunohistochemistry was used to characterize the
expression of cyclin E and p27 in malignant lymphomas, and to optimize
the staining conditions we used antigen retrieval methods and a
semiautomatic instrument giving reproducible staining patterns. The p27
reactivity was easily evaluated as reported earlier,9,15
and even if occasional cells showed cytoplasmic staining various
fractions of clearly p27+ nuclei were detected in the
lymphomas. Cyclin E antibodies produced a mixed staining pattern with
an often notable cytoplasmic staining, making the evaluation process
more laborious. A similar, presumably unspecific reactivity has been
reported using the same anti-cyclin E antibody25 and more
specific cyclin E antibodies applicable on formalin-fixed material are
needed for routine purposes. Concerning the choice of
immunohistochemistry as a method for analysis of p27 and cyclin E
protein expression, we have observed a good agreement between
immunohistochemical and immunoblotting analyses of cyclin E and cyclin
D1 (unpublished data). Immunohistochemical protein detection also gives the opportunity to characterize specific tissue
compartments, such as follicle centers, regarding protein expression.
The cyclin E expression was in the present lymphoma series linked with
proliferation, but this relationship seems ambiguous for other tumor
types. Some investigators claim that there is no relation between
cyclin E levels and proliferation in tumors overexpressing the protein
and that the cell-cycle phase-specific expression of cyclin E is
disturbed in these tumor cells.26,27 Other reports have
observed a connection between cyclin E expression and proliferation as
well as a cell-cycle phase-specific expression of the protein
determined with immunohistochemistry or flow cytometry.15 Our data showed a rather strong association between cyclin E expression and proliferation determined by the S-phase fraction and all lymphomas, except aggressive lymphomas, had in principle higher cyclin E index
than S-phase fractions. Despite no obvious cell-cycle independent overexpression of cyclin E in lymphomas, a potential deregulation of
the protein could not be excluded for some cases. Higher levels of
cyclin E have been reported in low-and intermediate-grade malignant lymphomas compared with chronic lymphocytic leukemia,28 and in lymphoblastic leukemias the cyclin E levels were higher in recurrent
cases, suggesting an association between cyclin E expression and
disease progress.29
MCL lymphomas have a characteristic translocation, t(11;14), leading to
an overexpression of cyclin D1, but additional aberrations in the
RB-pathway have also been reported.30 The MCL cases
included in the present study, with a presumable cyclin D1
overexpression, showed high cyclin E expression, which is in contrast
to the inverse relation between cyclin E and cyclin D1 expression
observed in breast cancer.31 Further studies are needed to
better define patterns of aberrations in the cyclin E-cyclin
D1-RB-pathway in MCL.
Small lymphocytes were in general p27+ whereas activated
cells, such as centroblasts and immunoblasts, displayed weak or no p27
staining, suggesting an inverse association between proliferation and
p27 expression. This association, verified statistically, was expected
from the theoretical function of p27 as a CDK-inhibitor and cell-cycle
blocker. Normal lymphocytes also display an inverse correlation between
p27 and proliferation,9 but studies on various tumors have
reported conflicting results.15,17 In our material the link
between p27 positivity and S-phase fraction was not observed in several
lymphoma cases, suggesting that p27 has biological functions aside from
cell-cycle regulation.
Expression of the p27 protein was associated with high lymphocyte and
low platelet counts and male gender, which could be explained by a
strong connection to CLL lymphomas. More difficult to explain is the
relationship between high age and low p27 expression. A feasible
hypothesis might be that downregulation of p27 protein expression is
age related, possibly indicating stepwise-occurring alterations where
p27 is affected in a late stage. Age has been reported as an important
prognostic32 factor for malignant lymphomas, and one reason
for this might be the p27 downregulation observed here.
Our patient series seemed to represent a nonbiased material of
lymphomas based on general patient characteristics and survival rates
when subdivided according to LDH-values, S-phase fraction, and
morphological grade.32-35 From a clinical point of view,
the impact of cell-cycle regulators in relation to outcome is
interesting. Regarding cyclin E, a weak but significant association
between high cyclin E expression and poor prognosis was observed, but the impact on prognosis was not significantly independent in the Cox
analysis. p27 expression alone or in combination with one or two other
factors was highly significant as a prognostic factor, but when
additional factors were introduced the prognostic impact decreased.
This implicates an association between p27 and other prognostic
factors, but importantly p27 seemed to have an independent impact on
prognosis in contrast to S-phase fraction or cyclin E expression. Low
p27 expression has been found to be associated with a poor prognosis in
tumors such as breast cancer, lung cancer, colorectal cancer, and
gastric cancer, suggesting that downregulation of p27 is a general
phenomenon in malignancies associated with aggressive tumor
growth.15-19,36
The adverse effect of low p27 values in malignancies like lymphomas is
not fully understood, but several contributing explanations are
possible. Most obvious is an abrogated cell-cycle block due to
downregulation of p27 leading to less strict G1/S checkpoint surveillance with facilitated transit into the S-phase. Furthermore, at
low p27 levels G0 cells are recruited into the cell cycle and aberrant
p27 expression might therefore stimulate the recruitment of tumor cells
into the cell cycle with effects on the tumor growth fraction.6,12 Expression of p27 is influenced by
cell-to-cell contact and downregulation of p27 can inhibit cell
adhesion.37 Tumors with low p27 expression may consequently
have an impaired cell adhesion, promoting tumor dissemination. A recent
report also defines a role for p27 in the regulation of apoptosis,
proposing that lymphomas with low p27 expression might have a growth
advantage due to few apoptotic events.38 Interestingly,
preliminary data indicate that in some large cell lymphomas, p27
expression seems to be present in cases with high apoptotic rate.
Our data suggest that p27 expression is an important parameter that
could be included in a future panel of diagnostic markers for lymphomas
and, when combined with serum LDH levels, distinct prognostic subgroups
of patients can be defined. The results clearly demonstrate the
importance of G1-S transition regulators in lymphomas illuminating an
important research area in hematologic neoplasias.
| |
FOOTNOTES |
Submitted February 19, 1998;
accepted May 15, 1998.
Supported by grants from the Swedish Cancer Society, The Medical
Faculty, Umeå University, and Lion's Cancer Research Foundation, Umeå University.
Address reprint requests to Göran Landberg, MD,
Department of Pathology, Umeå University, S-901 87 Umeå, Sweden;
e-mail: goran.landberg.us{at}vll.se.
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 |
The authors thank Britta Lindgren (Department of Pathology, Umeå
University) for technical assistance and Björn Tavelin
(Oncological Center, Umeå University Hospital) for statistical help.
| |
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Abstract
Introduction
Abstract