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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 2084-2092
NEOPLASIA
A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4
protein in a subset of germinal center B cells, plasma cells, and
activated T cells
Brunangelo Falini,
Marco Fizzotti,
Alessandra Pucciarini,
Barbara Bigerna,
Teresa Marafioti,
Marcello Gambacorta,
Roberta Pacini,
Cristina Alunni,
Laura Natali-Tanci,
Barbara Ugolini,
Carla Sebastiani,
Giorgio Cattoretti,
Stefano Pileri,
Riccardo Dalla-Favera, and
Harald Stein
From the Institutes of Hematology and Internal Medicine, University
of Perugia, Perugia; the Institute of Pathology, Niguarda Hospital,
Milan, Italy; the Institute of Pathology, University of Bologna,
Bologna, Italy; the Department of Pathology, College of Physicians and
Surgeons, Columbia University, New York, NY; and the Institute of
Pathology, Benjamin Franklin University, Berlin, Germany.
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Abstract |
A new monoclonal antibody (MUM1p) was used to study the cell/tissue
expression of human MUM1/IRF4 protein, the product of the homologous
gene involved in the myeloma-associated t(6;14) (p25;q32). MUM1 was
expressed in the nuclei and cytoplasm of plasma cells and a small
percentage of germinal center (GC) B cells mainly located in the
"light zone." Its morphologic spectrum ranged from that of
centrocyte to that of a plasmablast/plasma cell, and it displayed a
phenotype
(MUM1+/Bcl-6 /Ki67)
different from that of most GC B cells
(MUM1/Bcl-6+/Ki67+) and
mantle B cells
(MUM1/Bcl-6/Ki67).
Polymerase chain reaction (PCR) analysis of single MUM1+
cells isolated from GCs showed that they contained rearranged Ig
heavy chain genes with a varying number of VH
somatic mutations. These findings suggest that these cells may
represent surviving centrocytes and their progeny committed to exit GC
and to differentiate into plasma cells. MUM1 was strongly expressed in
lymphoplasmacytoid lymphoma, multiple myeloma, and approximately 75%
of diffuse large B-cell lymphomas (DLCL-B). Unlike normal GC B cells,
in which the expression of MUM1 and Bcl-6 were mutually exclusive,
tumor cells in approximately 50% of MUM1+ DLCL-B
coexpressed MUM1 and Bcl-6, suggesting that expression of these
proteins may be deregulated. In keeping with their proposed origin from
GC B cells, Hodgkin and Reed-Sternberg cells of Hodgkin's disease
consistently expressed MUM1. MUM1 was detected in normal and neoplastic
activated T cells, and its expression usually paralleled that of CD30.
These results suggest that MUM1 is involved in the late stages of
B-cell differentiation and in T-cell activation and is deregulated in
DLCL-B.
(Blood. 2000;95:2084-2092)
© 2000 by The American Society of Hematology.
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Introduction |
Chromosomal translocations (14q+) affecting band 14q32
and unidentified partner chromosomes are common in multiple myeloma, suggesting that they may cause the activation of novel
oncogenes.1,2 Recently, Iida et al1 reported
that the 14q+ translocation occurring in multiple myeloma is a cryptic
translocation (6;14) (p25;q32) that causes juxtaposition of the
immunoglobulin heavy-chain (IgH) locus to the multiple
myeloma oncogene 1 (MUM1)/IRF4 gene.3 It
has been suggested that as consequence of this translocation, the
MUM1/IRF4 gene is overexpressed, an event that may contribute to tumorigenesis because MUM1/IRF4 has oncogenic activity in
vitro.1
The product of the MUM1/IRF4 gene (also called PIP, LSIRF,
ICSAT)3-6 is a member of the interferon regulatory factor
(IRF) family of transcription factors, known to play an
important role in the regulation of gene expression in response to
signaling by interferons and by other cytokines.6 By
Northern blot analysis, strong expression of MUM1 mRNA has been
detected in mature B cell-derived lymphoma and myeloma cell
lines1 and in human T-cell leukemia virus type 1 (HTLV-1)-infected T cells.6 Moreover, IRF4-deficient mice
(IRF4/) were unable to form germinal centers
(GCs), lacked plasma cells in the spleen and lamina propria, and
exhibited a profound reduction of serumimmunoglobulin levels and an
inability to mount detectable antibody responses or to generate
T-lymphocyte cytotoxic or antitumor responses.7 These
findings provide evidence that the MUM1/IRF4 gene is essential
for the function of both mature B cells and cytotoxic T
lymphocytes.7 At molecular level, MUM1/IRF4 acts by forming
a cooperative ternary complex with the transcription factor PU.1 at
immunoglobulin enhancer elements, such as  B and  E3'
sites.8-11
In spite of its recognized importance in the development of the immune
system, the expression of MUM1/IRF4 protein in normal and neoplastic
lymphohematopoietic tissues is unknown. To gain further insights into
this issue, we produced a monoclonal antibody (MUM1p) specifically
directed against a fixative-resistant epitope of the human MUM1
protein. The antibody was used to detect by immunohistochemistry
expression of the MUM1 protein in human cell lines and in paraffin
sections from normal and neoplastic lymphohematopoietic tissues. The
results presented in this article indicate that the MUM1 protein is
more strongly expressed in late plasma cell-directed stages of B-cell
differentiation and in activated T cells and suggest that the MUM1p
monoclonal antibody may serve as a marker for lymphohematopoietic
neoplasms thought to be derived from these cells.
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Materials and methods |
Generation of the recombinant glutathione S-transferase-MUM1
protein
A cDNA fragment corresponding to amino acids 144 to 451 of the human
MUM1 protein was subcloned to BamHI and EcoRI cloning sites of pGEX 3X (Pharmacia Biotech, Piscataway, NJ) bacterial expression vector.1 The insert was cloned in frame to
glutathione S-transferase (GST) coding sequences and confirmed by
sequencing. N-terminal sequences encoding DNA-binding motifs were
eliminated because they have extremely high homology with other family
proteins. The GST-MUM1 fusion protein was then expressed in
BL21-competent bacteria and purified by affinity chromatography
following the manufacturer's instructions.
Production of a monoclonal antibody (MUM1p) against the
MUM1 protein
BALB/c mice were injected intraperitoneally (3 times at 10-day
intervals) with 150 µg GST-MUM1 fusion protein (amino acids 144 to
451) plus Freund's adjuvant. A 150-µg booster of the recombinant GST-MUM1 protein was injected intraperitoneally, and fusion was carried out 3 days later, as described previously.12
Hybridoma supernatants were screened by the immuno-alkaline phosphatase (APAAP) technique13 on cytocentrifuge preparations of the
IM9 human myeloma cell line and on paraffin sections of normal human tonsil. Two of 1000 hybridoma supernatants (MUM1p and MUM97) that reacted strongly with the IM9 myeloma cells and with normal plasma cells in tonsil paraffin sections were cloned by a limiting dilution technique, and 1 of them (MUM1p) was selected for further study.
Other antibodies
The reactivity pattern of the MUM1p monoclonal antibody was compared
with that of a goat polyclonal antibody directed against the carboxy
terminus of the murine IRF4/ICSAT molecule that is marketed by the manufacturer (Santa Cruz Biotechnology,
Heidelberg, Germany) as cross-reacting with its human homologue.
Double immuno-enzymatic stainings on frozen and paraffin tonsil
sections were performed using the MUM1p monoclonal antibody in
combination with antibodies directed against the following antigens:
and light chains, IgD, CD19, CD20, CD3, the follicular dendritic cell markers CD21 and CD23, and the intermediate cytokeratin filaments (antibody MNF116) (all purchased from DAKO A/S, Glostrup, Denmark); against the following plasma cell markers VS38 (DAKO A/S),
CD138/syndecan clone BB4 (Serotec, Oxford, UK), and CD38 (kindly
provided by Prof Fabio Malavasi, Turin, Italy); and against CD30 and
Ki67 (both generated in the laboratory of H.S.),
CD68/PG-M1,14 and Bcl-612 (both produced in the
laboratory of B.F.).
Transfected cells
A pHeBo-CMV-MUM1-HA and a pHeBo-CMV (as control) were used for the
transient transfection of HeLa cells by a calcium chloride HEPES-buffered-saline method. MUM1-transfected and control cells were
grown in Dulbecco modified essential medium containing 10% fetal calf
serum, penicillin (100 IU/mL), and streptomycin (100 µg/mL). Cells
were lysed and analyzed by Western blotting (see below). Cells were
also grown exponentially on slides, air dried overnight, fixed in
acetone for 10 minutes, and immunostained by the APAAP technique.
Cell lines
MUM1 expression was studied on the following human cell lines: IM9
(myeloma); Namalwa, Bjab, Ramos (B-lymphoid); MOLT-4, Jurkat (T-lymphoid); Karpas 299 (CD30+ anaplastic large-cell
lymphoma with 2;5 translocation); U937 and HL60 (myeloid); and HeLa
(epithelial). Cell lines were cultured in RPMI 1640 containing 10%
fetal calf serum (Life Technologies, Grand Island, NY). Cytospin was
prepared from exponentially growing cells, fixed in acetone for 10 minutes at room temperature, and then used for immunocytochemical studies.
Phytohemagglutinin stimulation
Ficoll-separated normal peripheral blood mononuclear cells were
cultured in RPMI 1640 medium supplemented with 10% fetal calf serum
and phytohemagglutinin (PHA) (2.5 µg/mL) at a concentration of
1 × 106/mL in a humidified incubator at 37°C
with 5% CO2 atmosphere. The proliferative response of the
cultured cells was assessed in cytospin with the monoclonal antibody
Ki67. Basal and stimulated cells were cyto-centrifuged and subjected to
immunostaining. An aliquot of cells was tested for MUM1 protein
expression by Western blotting.
Western blotting
Western blotting was performed on cell lysates from the
MUM1-transfected and control HeLa cells and from IM9, U937, and HeLa cell lines. Unfractionated tonsil cell suspensions and Ficoll-separated peripheral blood T cells (both in basal condition and after stimulation with PHA) were also studied. Cells were lysed with sodium dodecyl sulfate (SDS) loading buffer, and an aliquot of each lysate was loaded
onto an 8% SDS polyacrylamide gel and electrotransferred to
nitrocellulose sheets, as previously described.12
Immunoprecipitation and Western blotting
IM9 myeloma cells were lysed with a single detergent lysis buffer
(150 mmol/L NaCl, 50 mmol/L Tris HC1, pH 8, 1% NP40, 1 mmol/L EDTA)
containing a protease inhibitor cocktail (leupeptin, aprotinin, pepstatin A, and phenylmethylsulfonyl fluoride) and immunoprecipitated with the MUM1p monoclonal antibody (supernatant at 1:5 dilution). The
immunoprecipitates were Western blotted and then incubated overnight at
4°C with the goat anti-MUM1 polyclonal antibody (Santa Cruz
Biotechnology). Finally, the blots were incubated for 1 hour at room
temperature with a horseradish peroxidase-conjugated antigoat antibody
and stained by the ECL system (Amersham, Arlington Heights, IL).
Tissue specimens
Expression of the MUM1 protein was studied in normal
lymphohematopoietic tissues (tonsil, n = 10; spleen, n = 5; bone
marrow, n = 6) and lymphomas (n = 150) representative of most
categories of the Revised European American Lymphoma
Classification.15 Normal and neoplastic samples were fixed
either in 10% buffered formalin or in B5 (followed by 2 hours'
decalcification in EDTA for bone marrow biopsies) and routinely
processed for paraffin embedding. Immunohistologic analysis was also
performed on cryostat sections cut from tonsil specimens that had been
previously snap-frozen in liquid nitrogen.
Tissue processing for immunohistochemistry
Paraffin sections (5-µm thick) were attached on silane-coated
slides, rehydrated, and subjected to microwaving (750 W × 3 cycles at 5 minutes each) using 1-mmol/L EDTA buffer, pH 8, as the
antigen retrieval solution.12,16 Tonsil frozen sections (5-µm thick) were air dried overnight and fixed in acetone for 10 minutes before immunostaining.
Single immunoenzymatic labeling
Immunostaining was performed using the APAAP procedure, as
previously described.13 Endogenous alkaline phosphatase was
blocked with 1 mmol/L levamisole.17 Slides were
counterstained for 5 minutes in Gill hematoxylin and mounted in Kaiser
glycerol gelatin.
Double-staining procedures
Paraffin and tonsil frozen sections were double stained for MUM1/
and MUM1/ light chains, MUM1/IgD, MUM1/CD21, MUM1/CD23, MUM1/cytokeratin, MUM1/Bcl-6, MUM1/VS38, MUM1/CD138, MUM1/CD38, MUM1/CD3, MUM1/CD30, and MUM1/Ki67. The MUM1 protein was usually detected by a biotin-avidin peroxidase technique using
diaminobenzidine (Sigma-Aldrich, Milan, Italy)/hydrogen peroxide as
substrate.18 The second pair of antigens was revealed by
the APAAP procedure,13 using naphthol AS-MX plus Fast Red
TR (both purchased from Sigma-Aldrich) or naphthol AS-MX plus Fast Blue
BB salt (both purchased from Sigma-Aldrich) as substrate.18
Because the Bcl-6 and CD20 proteins and cytokeratin proved to be
partially or totally denatured or masked by the reaction product of
peroxidase substrate, a reverse procedure (immunoperoxidase detection
of Bcl-6, CD20, and cytokeratin followed by APAAP labeling of MUM1) was
used for double staining of MUM1/Bcl-6, MUM1/CD20, and
MUM1/cytokeratin. Slides were mounted in Kaiser gelatin after
counterstain for 30 seconds in Gill hematoxylin or without counterstain.
Double immunofluorescence labeling19 for MUM1/Bcl-6 was
also performed on tonsil frozen sections by 30-minute incubation with a
mixture of rabbit polyclonal anti-Bcl-6 (Santa Cruz Biotechnology) and
MUM1p monoclonal antibody. After extensive washing, the primary antibodies were detected with fluorescein-conjugated antirabbit and
rhodaminated antimouse secondary antibodies.
Polymerase chain reaction (PCR) analysis of single MUM1+
cells
Immunostaining and isolation of single cells.
Tonsil frozen sections immunostained for MUM1 were overlaid with
phosphate-buffered saline. Single MUM1+ cells, totaling 30 cells per section, were isolated from GCs using a hydraulic
micromanipulator as previously described20 and were
transferred to PCR tubes containing 10 µL proteinase K (1 mg/mL). In
each PCR tube, 5 single MUM1+ cells were pooled together.
From each section, aliquots of the overlaying buffer were aspirated and
used as negative controls. B cells isolated from the mantle zone served
as positive controls.
PCR and cloning.
After proteinase K digestion (1 hour at 55°C), fully nested PCR was
performed for the detection of the rearranged VH
gene using family-specific framework (FW)1 primers for the first
amplification, as previously described.20 In the second
round of amplification, we further amplified 2-µL aliquots from the
first round with family-specific FW2 primers. Both FW primer sets were
used in conjunction with 2 nested primers for the joining region
(JH). The PCR products were analyzed on an ethidium
bromide-stained polyacrylamide gel (6%). Visualized PCR products were
then gel-purified, cloned to plasmid, and sequenced on an automatic
fluorescence DNA sequencer (377A; Applied Biosystem, Weiterstadt,
Germany) by using the dye deoxy terminator method. At least 6 clones
derived from each amplified portion were analyzed by sequencing in each
direction using SP6 and T7 primers in 2 separate reactions.
Sequence analysis
Sequences were compared with the corresponding germ line VH
(VBASE databank)21 to determine the VH
family usage and to demonstrate the number of somatic mutations.
Furthermore, all sequences were compared with each other to detect
intraclonal diversities and with our own and published databank sequences.
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Results |
Western blotting
A single band of 52 kd corresponding to the molecular weight of the
MUM1-HA protein was observed on lysates from MUM1-transfected, but not
control HeLa, cells (Figure 1A, line 2). A
50-kd band corresponding to the expected molecular weight of the MUM1
protein was detected with the MUM1p antibody on Western blot lysates
from IM9 myeloma cells (Figure 1B, line 2) and on unfractionated
lysates from normal tonsil (Figure 1B, line 4). In the latter lysates, the 50-kd band was weaker probably because of the dilution of plasma
cells with other tonsil cell populations. No bands were detected by
MUM1p in lysates of the U937 and HeLa cell lines that served as
negative controls because they did not express MUM1 RNA (Figure 1B,
lines 1 and 3).
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| Fig 1.
Western blotting with the MUM1p monoclonal antibody.
(A) A band of 52-kd of the expected size of the MUM1-HA protein is seen
in line corresponding to pHeBo-CMV-MUM1-HA HeLa-transfected cells but
not in negative control HeLa cells. (B) A 50-kd band of the expected
molecular size of the MUM1 protein is seen in lanes 2 and 4, corresponding to the IM9 myeloma cell line and normal tonsil. No bands
are detected in lanes 1 and 3, corresponding to U937 and HeLa cell
lines. Identical results (not shown) were obtained with the monoclonal
(clone MUM97) and polyclonal anti-IRF4/ICSAT antibody. In both
experiments,  tubulin levels are shown below to control for the
integrity and amount of the loaded protein.
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Lysates of the MUM1p-immunoprecipitated IM9 myeloma cells revealed by
Western blotting with an anti-MUM1 polyclonal antibody gave the
expected 50-kd band of MUM1.
These results demonstrated that MUM1p reacted specifically with the
MUM1 protein and that this antibody was suitable for both Western
blotting and immunoprecipitation studies. Identical results (not shown)
were obtained with the monoclonal antibody MUM97 generated in the same fusion.
Expression of the MUM1 protein in human cell lines
The MUM1p antibody strongly reacted with the nuclei of
MUM1-transfected HeLa cells but not those of control cells (data not shown), and this further supported the specificity of the antibody (see above).
MUM1p reacted with the nucleus and with the cytoplasm of the IM9
myeloma cells; nuclear positivity was stronger than that observed in
the cytoplasm. Both nucleus and cytoplasm showed a microgranular
positivity (Figure 2A), but the nucleoli
were consistently MUM1 (Figure 2A). A similar
reactivity (not shown) was observed with the cell line Karpas 299, derived from a T-cell anaplastic large-cell lymphoma with t(2;5). Only
a small percentage of the Namalwa cells was labeled for MUM1. The
Burkitt cell line Daudi was MUM1 but strongly
expressed the Bcl-6 protein. In contrast, the Burkitt cell line Ramos
coexpressed strongly the MUM1 and the Bcl-6 proteins. In general,
nuclear reactivity of the MUM1-expressing cell lines was stronger with
the MUM1p monoclonal antibody than with the polyclonal anti-IRF4/ICSAT.
The myeloid-derived (U937 and HL60) and the epithelial-derived (HeLa)
cell lines were consistently MUM1.
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| Fig 2.
MUM1 expression in myeloma cell line and normal lymphoid
tissues.
(A) IM9 human myeloma cell line. Microgranular positivity for the MUM1
protein is observed in the nucleus (stronger) and in the cytoplasm
(weaker) of tumor cells. Arrowheads indicate negative nucleoli (APAAP;
× 1000). (B) MUM1 protein expression in the nucleus (stronger)
and in the cytoplasm (weaker) of plasma cells in a lymph node involved
by a plasmacellular variant of Castleman disease (paraffin section;
APAAP; × 800). (C) Paraffin section from normal tonsil double
stained for cytokeratins (tonsil epithelium labeled in brown) and MUM1
(plasma cells labeled in blue) (APAAP; × 250). (D) All plasma
cells in the tonsil epithelium double stain for intracytoplasmic light
chains (brown) and nuclear MUM1 (blue) (× 1000). (E) Isolated or
small clusters of MUM1+ cells (arrowheads) are present
within GC (APAAP; × 250). (F) At higher magnification,
some of the MUM1+ cells in the GC show a markedly irregular
(often multilobated) nucleus (arrows). Arrowhead points to a
MUM1 macrophage (APAAP; × 1000). (A-F)
Immunostaining with MUM1p monoclonal antibody; hematoxylin
counterstain.
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Expression of the MUM1 protein in normal and reactive lymphoid
tissues
In tissue paraffin sections and cytospins, the MUM1p monoclonal
antibody gave stronger positivity and lower background than the
polyclonal reagent. There was no difference in terms of MUM1p specificity in tissue samples processed as frozen or paraffin sections
(B5 or formalin fixed) and immunostained either with peroxidase
or APAAP procedures, by hand or by an automatic DAKO immunostainer
(Techmate 500). However, the intensity of MUM1 labeling was
usually stronger in paraffin sections than in frozen sections.
The immunostaining results on paraffin sections from normal
lymphohematopoietic tissues are summarized in Table
1. The most striking reactivity of MUM1p in
sections of normal tonsil and reactive lymph nodes was with plasma
cells (Figures 2B-2D) that showed strong MUM1 nuclear positivity in
addition to weaker labeling of cytoplasm (Figure 2B). Negativity of
nucleoli, clearly evident in the cytospin of unfractionated tonsil
cells (not shown), was not detectable in paraffin sections from tonsil
(or other tissues) in which the nucleus of MUM1+ cells
appeared to be homogeneously stained (Figures 2B-2D). Diffuse nuclear
positivity with the inability to recognize in paraffin sections the
reactivity pattern of specific nuclear structures (nucleoli, nuclear
bodies) was probably a fixation artifact because it is also observed
with monoclonal antibodies directed against other nuclear-located
antigens (PML, Bcl-6, NPM-ALK, NPM).22-24 In double-stained
sections, most plasma cells were usually found to coexpress MUM1 and
other plasma cell-associated markers (intracytoplasmic Ig light
chains, CD138/syndecan, VS38, CD38) (Figure 2D). However, occasional
MUM1+ plasma cells that failed to express 1 or more of the
plasma cell markers, and vice versa, were also present.
In the B-cell follicles, IgD+ mantle lymphocytes were
usually MUM1 but occasionally showed faint nuclear MUM1
positivity. Rare cells strongly expressing the MUM1 protein were
sometimes observed in the mantle zones, and they probably represented
MUM1+ cells exiting the GC and transiting through the
follicle mantle. This view is supported by the finding that PCR
analysis on such isolated cells revealed mutations in their rearranged
VH region genes (Table 2). Most
GC cells were MUM1, but a percentage of them
(ranging from 3% to 10%, depending on the GC) strongly expressed the
MUM1 protein (Figure 2E). These MUM1+ cells were
morphologically heterogeneous. Some had markedly irregular nuclei
(Figure 2F), whereas others had an immunoblast-like or a plasma
cell-like appearance and were predominantly located in the light zone
of the GCs (the centroblasts of the dark zone were usually
MUM1) (Figure 3A). This
topographic distribution was clearly evident in sections double stained
for MUM1/CD23 or MUM1/CD21 that showed the intimate contact of
MUM1+ elements with the meshwork of follicular dendritic
cells (Figures 3A and 3B). Double staining for MUM1/CD19 and MUM1/CD20
was difficult to interpret because the few MUM1+ cells
within the GCs were surrounded by
MUM1/CD19+/CD20+ GC B-cells,
and it was impossible to establish whether the membrane positivity for
CD19 and CD20 belonged to the MUM1+ elements or the
adjacent MUM1 B cells. Thirty percent to 50% of
MUM1+ cells in the GCs contained intracytoplasmic Ig light
chains (data not shown). Many MUM1+ cells in the GC were
negative for the plasma cell marker CD138/syndecan (not shown),
suggesting that MUM1 expression most likely precedes that of CD138.
Double staining for MUM1/VS38 and MUM1/CD38 was difficult to interpret.
These findings, together with the results of MUM1/CD3 double staining
and of single-cell PCR (see below), provide evidence that more then
95% of MUM1+ cells within the GC are B cells.
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| Fig 3.
Double-stained GC of normal tonsil (paraffin sections).
(A) Double staining for MUM1 (brown) and CD23 (red) shows that GC
MUM1+ cells (arrowhead) are located in the light zone in
close association with CD23+ follicular dendritic reticulum
cells (arrow). Asterisk indicates negative centroblasts in the dark
zone (× 250; hematoxylin counterstain). (B) The intimate contact
of brown MUM1+ cells (arrowhead) with red CD23+
follicular dendritic cells (arrow) is shown at higher magnification
(× 1000). Double arrowheads indicate a
MUM1/CD23 GC cell. (C) Expression
of MUM1 (red) and Bcl-6 (green) are mutually exclusive within the GC of
tonsil (double immunofluorescence; × 800). (D) Expression for
brown nuclear Bcl-6 (arrowhead) and blue nuclear MUM1 (arrow) in GC
B-cells appears to be mutually exclusive (× 1000; no
counterstain). (E) Expression for brown nuclear MUM1 protein
(arrowhead) and blue Ki67 proliferation antigen (arrow) appears to be
mutually exclusive, with the exception of rare cells (double
arrowheads) that double stain for the 2 antigens (× 1000; no
counterstain). (F) The MUM1 protein (brown) and the CD68 antigen (blue)
are clearly expressed in different cell types. The arrow points to a
CD68+ tingible body macrophage, whereas the arrowhead
indicates a MUM1+ GC cell (× 1000; no counterstain).
(A-F) Biotin-avidin peroxidase/APAAP.
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Notably, the totality of the MUM1+ GC cells failed to
express the Bcl-6 protein (Figures 3C, 3D) that was in turn detectable in most centroblasts and centrocytes. Expression of the Ki67
proliferation antigen and MUM1 within the GC was also mutually
exclusive (Figure 3E), and only scattered MUM1+ cells
appeared to express a positivity for Ki67 usually associated to
nucleoli (Figure 3E). Tingible body macrophages within the GC were
consistently CD68+/MUM1 (Figure
3F).
Most T cells in the interfollicular area of normal tonsil and reactive
lymph nodes were negative for MUM1, but some of them (1%-5%) strongly
expressed the protein (not shown). Similar findings (not shown) were
observed in the GCs, whereas the MUM1+/CD3+
elements represented only a minority (less than 5%) of all
MUM1+ cells in the light zone. Most large CD30+
cells in the tonsil coexpressed the MUM1 protein (Figures 4A and 4B).
As expected, the CD30+/MUM1+ cells were mostly
located in the area adjacent to the follicle mantle and appeared to be
proliferating (Ki67+) (Figure
4C). No MUM1 expression was detected in
peripheral blood T lymphocytes under basal conditions, but the molecule
was strongly induced after PHA stimulation, as demonstrated by Western
blotting (Figure 5) and immunocytochemistry
(not shown). Taken together, these findings strongly suggest that the
MUM1 protein is expressed in activated T cells.
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| Fig 4.
Double stainings in the interfollicular area of normal
tonsil.
(A,C) Paraffin sections. (B) Frozen section. (A) A large cell
coexpressing surface CD30 (blue) and nuclear MUM1 (brown) is indicated
by the arrow; a MUM1+/CD30 small cell is
also observed (arrowhead) (× 1000; no counterstain). (B) A large
cell coexpressing surface CD30 (red) and nuclear MUM1 (brown) is
indicated by the arrow (× 1000; hematoxylin counterstain). (C)
Many large cells in the area adjacent to the follicle mantle (most
likely CD30+ cells) coexpress the proliferation antigen
Ki67 (blue labeling of nucleoli) and the brown nuclear MUM1 protein
(double arrowheads). Arrowhead indicates a
Ki67+/MUM1 cell. Arrow indicates a
Ki67/MUM1+ cell (× 800 ; no
counterstain).
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| Fig 5.
MUM1 expression in normal activated T cells.
A 50-kd band of the expected molecular size of the MUM1 protein is seen
in lanes (+) corresponding to PHA-stimulated peripheral blood T cells
(at days 1, 3, 4), whereas no band is observed in lanes ( )
corresponding to T cells under basal conditions (Western blotting with
the MUM1p monoclonal antibody). Tubulin levels are shown below to
control for the amounts of the loaded protein.
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MUM1 expression appeared to be lymphoid-restricted because other cell
types, such as follicular dendritic cells, macrophages, interdigitating
reticulum cells, myeloid and erythroid precursors, megakaryocytes, and
endothelial and epithelial cells, were consistently negative for the protein.
Single-cell polymerase chain reaction studies
Frozen sections of nonneoplastic tonsil were immunostained for MUM1.
Single MUM1+ cells were isolated by micromanipulation from
different GCs, mantle zones, and cryptic epithelia and studied by PCR.
Results are summarized in Table 2 and show rearranged Ig genes in the MUM1+ cells of all regions, which confirms their B-cell
nature. Sequence analysis of the rearrangements revealed a functional
coding region and somatic mutations within the V segment. In terms of
number of somatic mutations, the MUM1+ cells can be
considered as GC or post-GC cells. This is also valid for the
MUM1+ cells picked from the mantle zone, thus supporting
the view that they did not represent mantle cells but GC-derived cells
migrating through the mantle zone. In contrast, the MUM1
cells isolated from the mantle zone were devoid of somatic
mutations and thus belonged to the unmutated mantle cell pool.
MUM1 expression in lymphohematopoietic neoplasms
The immunostaining results on paraffin sections from 150 cases of
human lymphoma are summarized in Table 3.
The MUM1 protein was usually absent in tumor cells of B-cell
lymphoblastic leukemia. Most mantle cell-derived lymphomas were
MUM1, but approximately 30% showed weak to moderate
nuclear positivity for the protein. Two of 3 nodal marginal zone
lymphomas contained 30% to 50% MUM1-positive cells (usually showing
plasmacytoid morphology). The tumor cells of follicular lymphomas
(grades 1 and 2) were usually MUM1, and only a small
percentage (less than 20%) of MUM1+ cells (possibly
representing normal residual GC cells) was observed within neoplastic
follicles. In B-cell chronic lymphocytic leukemia, small neoplastic
lymphocytes were usually MUM1 or showed only faint
MUM1 expression, whereas prolymphocytes and paraimmunoblasts in
pseudofollicles (proliferation centers) showed moderate MUM1
positivity.
Among B-cell lymphomas, the strongest expression of MUM1 was observed
in lymphoplasmacytoid lymphoma/immunocytoma and in multiple myeloma
(Figure 6C). The MUM1 protein was also
strongly expressed in approximately 75% of diffuse large B-cell
lymphomas (range of positive tumor cells, 30%-100%) (Figure 6A), but
it was absent in approximately 25% (Figure 6B). Double staining for
MUM1/Bcl-6 showed that about 50% of MUM1+ diffuse, large
B-cell lymphomas coexpressed the MUM1 and Bcl-6 proteins (data not
shown). Notably, tumor cells in all cases of Hodgkin's disease were
consistently and strongly MUM1+ (Figure 6D). In conclusion,
the MUM1 protein appeared to be predominantly and strongly expressed in
lymphoid neoplasms thought to be derived from late-stage B cells. In
contrast to normal B cells, in which Bcl-6 and MUM1 expression were
mutually exclusive, coexpression of the 2 proteins was commonly
detected in diffuse, large B-cell lymphomas.
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| Fig 6.
MUM1 expression in lymphomas and myeloma.
(A) Diffuse, large B-cell lymphoma showing nuclear and cytoplasmic
positivity for the MUM1 protein. Arrowheads point to large
MUM1+ tumor cells with prominent nucleoli (lymph node
paraffin section; × 800). (B) Diffuse, large B-cell lymphoma
showing no expression of the MUM1 protein. The arrow points to a normal
residual MUM1+ cell (lymph node paraffin section;
× 1000). (C) Multiple myeloma showing strong nuclear and
cytoplasmic positivity of tumor cells for the MUM1 protein (paraffin
section from bone marrow trephine biopsy; × 250). (D) Strong
nuclear and weak cytoplasmic expression of the MUM1 protein in a
Reed-Sternberg cell of Hodgkin's disease, nodular sclerosing type
(lymph node paraffin section; × 1000). (A-D) Immunostaining with
the MUM1p monoclonal antibody; APAAP procedure; hematoxylin
counterstain.
|
|
In keeping with the detection of MUM1 in normal activated T cells, we
also found strong expression of the protein in CD30+
anaplastic large-cell lymphomas, both ALK and
ALK+23 (not shown), that were thought to derive from
activated T cells. In other peripheral T-cell lymphomas (Table 3), MUM1
expression usually paralleled that of CD30.
| |
Discussion |
In this article, we describe the characteristics of a new murine
monoclonal antibody (MUM1p) specifically directed against the human
MUM1 protein. The epitope recognized by MUM1p is fixative resistant,
and the antibody is suitable for immunohistochemical detection of the
MUM1 protein on routinely fixed, paraffin-embedded samples and Western blotting.
In cultured cells and primary tissues, MUM1+ cells strongly
expressed the protein in the nucleus. This finding is expected because
MUM1 is a member of the IRF family that acts as a transcription factor.1,6 Nuclear positivity was diffuse and microgranular and did not associate with specific nuclear organelles, such as nuclear
bodies or nucleoli. In addition to the strong nuclear labeling,
weak-to-moderate positivity was also observed in the cytoplasm of
MUM1-expressing cells. It is unlikely that this was caused by a
fixation/embedding-related artifactual diffusion of the protein from
the nuclear to the cytoplasmic compartment because, in addition to
paraffin sections, it was also observed in cytospin preparations of the
IM9 myeloma cells and in tonsil frozen sections. Cross-reactivity of
the MUM1p antibody with a cytoplasmic protein other than MUM1 also
appears unlikely because it was observed with antibodies (monoclonal
and polyclonal) directed against different epitopes of the MUM1
protein; all indicated a diffuse/microgranular cytoplasmic pattern
similar to that observed in the nucleus. Moreover, cytoplasmic
expression of MUM1 was observed at variable degrees in various normal
and neoplastic cell types, including some GC B cells, plasma cells, and
activated T cells, tumor cells in multiple myeloma, diffuse large
B-cell lymphomas, T/null CD30+ anaplastic large-cell
lymphoma, and Hodgkin's disease. Finally, no additional bands other
than that typical (50 kd) of MUM1 were detected on Western blotting
from the lysates of different cell types. The finding of MUM1
expression in the cytoplasm was in contrast to previous
observations7 that nuclear, but not cytoplasmic, extracts
of mouse lymph node cells expressed by Western blotting the 50-kd band
typical of IRF4 (the murine homologue of MUM1). These conflicting
findings may result from 1 or more of the following: lower sensitivity
of Western blot analysis than that of APAAP immunocytochemistry for
detecting small amounts of the protein; higher affinity of the MUM1p
monoclonal antibody used in this study than that of the polyclonal
antimurine IRF4 used by other investigators7; and different
subcellular distribution of MUM1/IRF4 in humans and in mice.
Colocalization and immunoelectron microscope studies should provide
additional insights concerning the topographic distribution of the MUM1
protein in the nucleus and in the cytoplasm. In keeping with previous
data in knockout mice,7 immunohistologic studies of various
human tissues with MUM1p clearly proved that the expression of
MUM1/IRF4 is lymphoid-restricted. Recently, it has been reported that
IRF4 can be expressed in murine macrophages.25 Perhaps
these two studies have conflicting results because in mice the
MUM1/IRF4 protein has a different distribution than it has in humans or
because Marecki et al25 used a lower specificity polyclonal
anti-IRF4 antibody.
In normal lymphohematopoietic tissues, the MUM1 protein was mainly
expressed in B cells, but it was mapped to B-cell compartments different from those occupied by other transcription factors involved in B-cell development. For example, Bcl-6 is strongly expressed in GC B
cells (most centroblasts and centrocytes),12,26,27 and the
Pax-5 protein28 has been predominantly found in lymphocytes of the mantle zone.29 The most striking characteristic of
the MUM1p monoclonal antibody in tissue sections of lymphohematopoietic tissues was its strong reactivity with the nucleus and cytoplasm of
mature plasma cells, whereas other B-cell types eg, most GC B cells
and IgD+/IgM+ virgin B lymphocytes of the
follicle mantleusually failed to express the protein. This finding
strongly suggests that the MUM1 protein may play a key role in the
terminal phases of B-cell differentiation toward the plasma cell, and
it is in keeping with the finding that IRF4(/) mice show
an absence of plasma cells associated with a dramatic reduction in
serum immunoglobulins.7
In addition to plasma cells, a small percentage of GC B cells strongly
expressed MUM1. Interestingly, these MUM1+ cells were
mainly located in the light zone of the GC, but the highly
proliferating, follicle-colonizing B blasts (centroblasts) of the dark
zone failed to express the protein. Thus, it is unlikely that the MUM1
protein is involved in the process of clonal expansion and somatic
hypermutation of the IgV-region genes known to occur in the dark zone
of the GC,30,31 though such involvement is conceivable for
the Bcl-6 protein that is strongly expressed and is a target for
somatic hypermutation in the centroblasts.32-34 In the
normal GC, the dividing centroblasts of the dark zone give rise to
nondividing centrocytes that upregulate their immunoglobulin receptors
and migrate to the light zone, where they interact with an extensive
network of follicular dendritic cells (harboring the antigen on their
surfaces in the form of immunocomplexes) and with T
cells.30,31 The centrocytes that are not selected by
follicular dendritic cell-held antigens are believed to die through
apoptosis, whereas the centrocytes showing high affinity for the
antigen on follicular dendritic cells are presumed to be positively
selected and can follow 1 of 2 main pathways (memory B cell or
immunoblastic/plasma cell differentiation), depending on the
costimulatory signals they receive from the follicular dendritic cells
and T cells.30,31 Our immunohistologic studies clearly
identified a population of B cells in the light zone that was in
intimate contact with follicular dendritic cells and expressed strongly
the MUM1 protein. These MUM1+ cells often displayed
enlarged plasma cell-like cytoplasm but showed, in contrast to mature
plasma cells, markedly irregular nuclei (resembling those of
centrocyte-type GC cells). These findings suggest that the expression
of MUM1 protein was initiated within the light zone of the GC and that
these MUM1+ B cells may represent antigen-selected
surviving centrocytes and their progeny committed to differentiate
further into plasma cells. This explanation is consistent with the
observation that the MUM1+ GC B cells contain mutated Ig
gene rearrangements with functional coding sequences and do not express
Bcl-6, whose down-regulation has been associated with differentiation
toward plasma cells.27,35
Although predominantly associated with late-stage B-cell
differentiation, expression of the MUM1 protein did not appear to be
B-cell specific. This was supported by the findings that a small
percentage of T cells (1%-5%) in the GC and in the interfollicular areas of normal tonsil and reactive lymph nodes double stained for MUM1
and CD3, that most normal CD30+ cells in the
interfollicular area did express MUM1, and that the expression of the
MUM1 protein could be induced by the stimulation of peripheral blood T
cells with PHA. These immunohistologic findings clearly indicated that
MUM1 is expressed in activated T cells, and they are in keeping with
the experimental evidence that knockout mice for the IRF4 gene
(the murine homologue of MUM1) are unable to generate cytotoxic or
antitumor responses.7 Moreover, the MUM1 gene shows
complete homology to the ICSAT gene that was independently cloned from an HTLV1-positive adult T-cell leukemia cell
line.6 Although the function of the MUM1 protein in T cells
is unknown, it is of interest to note that other transcription factors
known to play a fundamental role in B-cell development (Bcl-6,
BOB1/OBF1, OCT2) have also been found in activated T
cells.27,36-39
Among B-cell lymphomas, the strongest and most consistent expression of
MUM1 was observed in lymphoplasmacytoid lymphoma/immunocytoma and
multiple myeloma, and this finding was in keeping with the strong
expression of the MUM1 protein detectable in normal and reactive plasma cells.
We also found that approximately 75% of diffuse large B-cell lymphomas
expressed strongly the MUM1 protein. Unlike observations in normal GC B
cells, in which Bcl-6 and MUM1 appear to be mutually exclusive, many
tumor cells in approximately 50% of MUM1+ diffuse large
B-cell lymphomas coexpressed the MUM1 and Bcl-6 proteins. These
findings suggested that at least a proportion of diffuse large B-cell
lymphomas may be derived from MUM1+ GC B cells with
deregulated Bcl-6. In contrast, MUM1 diffuse, large
B-cell lymphomas may be related to the GC B cells that do not express
the protein.
Notably, MUM1 was consistently and strongly expressed in Hodgkin and
Reed-Sternberg cells of classic Hodgkin's disease (nodular sclerosing
and mixed cellularity). This finding is in keeping with the current
concept that the tumor cells of classic Hodgkin's disease represent a
clonal expansion of neoplastic B cells, probably related to some
differentiation stage of GC B cells.40,41 Finally, we found
that the MUM1 protein was expressed in lymphomas thought to be derived
from activated T cells (eg, CD30+ anaplastic large-cell lymphomas).
In conclusion, this article describes a new monoclonal antibody, MUM1p,
suitable for detecting the MUM1 protein on routine bioptic samples and
Western blot analysis, and it provides novel data about MUM1 expression
in normal and neoplastic lymphohematopoietic tissues. Based on these
findings, it may be expected that the MUM1p monoclonal antibody will be
a valuable tool for research and possibly diagnosis.
| |
Acknowledgments |
We thank A. Foerster and D. Jahnke for their skillful technical
assistance in subcloning and sequencing of isolated MUM+
cells. We also thank Mrs Claudia Tibidò for her excellent
secretarial assistance.
| |
Footnotes |
Submitted June 28, 1999; accepted October 29, 1999.
Supported by the Associazione Italiana per la Ricerca sul
Cancro. A.P. and C.S. were supported by the Federazione Italiana per la
Ricerca sul Cancro.
Reprints: Brunangelo Falini, Istituto di Ematologia,
Policlinico, Monteluce, 06122 Perugia, Italy; e-mail:
faliniem{at}unipg.it
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