Research Article
Anaplastic, Plasmablastic, and Plasmacytic Plasmacytomas of Mice:
Relationships to Human Plasma Cell Neoplasms and Late-Stage
Differentiation of Normal B Cells
1
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Chen-Feng Qi, Jeff X. Zhou, Chang Hoon Lee, Zohreh Naghashfar, Shao Xiang,
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Alexander L. Kovalchuk, Torgny N. Fredrickson, Janet W. Hartley, Derry C. Roopenian,
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Wendy F. Davidson, Siegfried Janz, and Herbert C. Morse III
1
Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases and 2Laboratory of Genetics, National Cancer
Institute, NIH, Rockville, Maryland; 3Jackson Laboratory, Bar Harbor, Maine; and 4University of Maryland School of Medicine,
Department of Microbiology and Immunology, Baltimore, Maryland
Abstract
We have compared histologic features and gene expression
profiles of newly identified plasmacytomas from NFS.V+
congenic mice with plasmacytomas of IL6 transgenic, Fasl
mutant, and SJL-B2M/ mice. NFS.V+ tumors comprised an
overlapping morphologic spectrum of high-grade/anaplastic,
intermediate-grade/plasmablastic, and low-grade/plasmacytic cases with similarities to subsets of human multiple
myeloma and plasmacytoma. Microarray and immunohistochemical analyses of genes expressed by the most prevalent
tumors, plasmablastic plasmacytomas, showed them to be
most closely related to immunoblastic lymphomas, less so to
plasmacytomas of Fasl mutant and SJL mice, and least to
plasmacytic plasmacytomas of IL6 transgenic mice. Plasmablastic tumors seemed to develop in an inflammatory environment associated with gene signatures of T cells, natural
killer cells, and macrophages not seen with plasmacytic
plasmacytomas. Plasmablastic plasmacytomas from NFS.V+
and SJL-B2M/ mice did not have structural alterations in
Myc or T(12;15) translocations and did not express Myc at
high levels, regular features of transgenic and pristaneinduced plasmacytomas. These findings imply that, as for
human multiple myeloma, Myc-independent routes of transformation contribute to the pathogenesis of these tumors.
These findings suggest that plasma cell neoplasms of mice and
humans exhibit similar degrees of complexity. Mouse plasmacytomas, previously considered to be homogeneous, may thus
be as diverse as their human counterparts with respect to oncogenic mechanisms of plasma cell transformation. Selecting
specific types of mouse plasmacytomas that relate most
closely to subtypes of human multiple myeloma may provide
new opportunities for preclinical testing of drugs for treatment of the human disease. [Cancer Res 2007;67(6):2439–47]
Introduction
It is well established that different classes of mature B-cell
neoplasms of humans and mice exhibit features that mimic specific
stages of normal B-cell differentiation and that these similarities
Note: Supplementary data for this article are available at Cancer Research Online
(http://cancerres.aacrjournals.org/).
Requests for reprints: Herbert C. Morse III, Laboratory of Immunopathology,
National Institute of Allergy and Infectious Diseases, NIH, Twinbrook I, Room 1421,
Rockville, MD 20852. Phone: 301-496-6379; Fax: 301-402-0077; E-mail: [email protected].
I2007 American Association for Cancer Research.
doi:10.1158/0008-5472.CAN-06-1561
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provide a perspective important to their classification and
nomenclature (1, 2). Diagnoses in both species are made through
a synthesis of histologic, immunohistochemical, and molecular
data, with the added contribution of clinical findings to analyses of
human disorders. The histologic and molecular tools brought to
bear on classifications of human lymphomas are frequently
reevaluated and revised in efforts to provide more precise
diagnoses as guides in choosing among treatment options.
One of the greatest challenges in developing consensus
nomenclatures of lymphomas for use by the clinical and scientific
communities is disease heterogeneity, perhaps best exemplified by
diffuse large B-cell lymphoma. Hematopathologists have long
recognized the heterogeneity of this disease in humans, but efforts
to define subgroups as distinct entities based on morphologic
features have proven to be unsuccessful (3). The most common
genetic marker—deregulated expression of BCL6 due to chromosomal translocations or mutations of 5¶ regulatory sequences—can
be identified in only f50% of cases (reviewed in ref. 4). In addition,
gene expression profiling, despite tremendous promise, has failed
to establish a comprehensive consensus molecular approach to
subset identification or outcome prediction (5, 6).
Multiple myeloma is another B-cell lineage disease entity, one
that is diagnosed histologically with relative ease but that has
recently been found to be unexpectedly heterogeneous in terms of
numerical and structural cytogenetic abnormalities, and gene
expression profiles (reviewed in ref. 7). Recent studies suggest that
this heterogeneity can be distilled to define eight subtypes of the
disease (8), raising the possibility that these represent eight disease
entities, each with its own therapeutic targets. Of interest, earlier
histologic studies of large series of multiple myeloma cases also
identified as many as seven or eight histologic subtypes (9–11) with
prognostic implications. Notably, an overlapping spectrum of
histologic types has been described for patients with another
plasma cell disease, extraosseus plasmacytomas (12), although, to
our knowledge, no attempt was made to assess the prognostic
potential of these subtypes.
Although mice rarely develop bone marrow plasma cell tumors
with similarities to human multiple myeloma (13, 14), extraosseus
plasmacytomas develop spontaneously in some strains such as SJL/
J (15), are readily induced in others, including BALB/c (16) and NZB
(17), and occur at variably high frequencies in a number of model
systems. Published studies from our laboratories and others have
revealed that these plasmacytomas are heterogeneous and can be
divided into subtypes based on histologic features and gene
expression profiles, some with human counterparts (18–23). Here,
we describe a new set of mouse plasmacytomas that developed in
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NFS.V+ mice (24). Histologically, they comprise three subsets—low
grade/plasmacytic, intermediate grade/plasmablastic, and high
grade/anaplastic—that closely parallel the terminologies suggested
by Bartl et al. (9) for variants of human multiple myeloma. We also
show that, in contrast to plasmacytomas from pristane-treated (16)
or IL6 transgenic mice (20), NFS.V+ cases do not exhibit structural
alterations in Myc and do not express Myc at high levels, indicating
that other transforming pathways are in play. The possible
relations of this heterogeneity to defined, distinct pathways of
plasma cell differentiation, to subtypes of plasma cell neoplasms in
humans, and to tumor progression are discussed.
Materials and Methods
Mice, histology, and immunohistochemistry. The characteristics of
NFS.V+ congenic (24) BALB/c-IL6 transgenic (20), SJL-h2M knockout (21),
BALB/c-Fasl/Fasl mutant (18, 21), and n-MYC transgenic mice (25) were as
previously described. Mouse protocols were approved by the Animal Care
and Use Committees of National Institute of Allergy and Infectious Diseases
(NIAID), National Cancer Institute (NCI), and the University of Maryland. At
necropsy, selected tissues were fixed in formalin for histologic studies and
immunohistochemistry. Samples of spleen and/or lymph nodes were snap
frozen for later preparation of DNA and RNA. Histologic diagnoses were
made according to the Bethesda classification of mouse lymphoid
neoplasms (2). Features of diffuse large B-cell centroblastic and immunoblastic lymphomas have been described (2, 24). Immunohistochemical
studies were done using the panel of antibodies listed in Supplementary
Table S1 and procedures described previously (26).
DNA analyses. High-molecular-weight DNA was digested, separated
electrophoretically, and transferred using standard techniques (18, 20, 24).
The membranes hybridized with 32P-labeled probe J11 and a Myc exon 2
probe for studies of immunoglobulin heavy chain and Myc gene
organization, respectively.
Interphase dual-color fluorescence in situ hybridization. Fluorescence in situ hybridization (FISH) was done on formalin-fixed, paraffinembedded sections as described.5 Bacterial artificial chromosome mapping
to Myc located on chromosome 15D2-3 (D15Mit17) and to Ca constant
region of IgH on chromosome 12F (189A22) were labeled using digoxygeninand biotin-nick translation kits (Roche, Indianapolis, IN), respectively, and
visualized by avidin Alexafluor 568 (Molecular Probes, Invitrogen, Carlsbad,
CA) and sheep antidigoxigenin fluorescein Fab (Roche). Confocal Z-stack
images taken at 0.5-Am intervals were acquired on an IX81 fluorescent
microscope (Olympus Optical, Tokyo, Japan) with a 60 or 100 oil lens.
Merged pseudocolor maximum-projection images were generated using
Slidebook software (Intelligent Imaging Innovations, Santa Monica, CA).
Oligonucleotide microarrays and analysis. Microarray experiments
were done as described (21) using chips comprising f14,000 mouse gene
targets represented by 70mer oligonucleotides (Compugen, Jamesburg, NJ)
and printed by the NIAID Microarray Research Facility.6 Total RNA was
extracted from primary tissues. A reference sample was prepared by pooling
equal amounts of RNA from a panel of cell lines (21). cDNAs were labeled
with Cy3 and Cy5 dyes for primary tissue and reference samples,
respectively, and hybridized to the chips. Data from the scanned chips
were stored at the microarray database maintained by the Center for
Information Technology, NIH.
The microarray data set was organized and analyzed using SAS software
(SAS Institute, Cary, NC). To remove variation among the hybridizations, all
the hybridizations (chips) were scaled together using a linear procedure
based on a selected set of features by setting the summed abundance of the
selected features equal to a constant (linear scaling). An imputation method
was developed based on the partial least square algorithm using SAS
software. Briefly, a partial least square model was built using all the non–
5
6
missing value genes as predictors and a gene with a missing value as the
response variable. Genes with missing values were added to the model one
at a time. This generated a matrix containing 11,181 genes without any
missing values that was used for the final analyses. The raw intensity ratio
was transformed into a logarithmic value log2. Two-way hierarchical
clustering (Ward method) of genes against mouse lymphoma samples was
done using software developed at NIH.7
Results
Occurrence and histologic features of plasma cell neoplasms. Among f2,700 cases of hematopoietic tumors studied
at necropsy in our laboratory over the last 5 years, 48 (1.8%) were
diagnosed as plasma cell–derived neoplasms that histologically
seemed to be less mature than those of pristane-treated or
IL6 transgenic mice. All but three had splenic involvement, with
weights averaging f1.3 g (range 0.1–3.0 g); most had affected
lymph nodes; and many exhibited infiltrates of liver, lung, or
kidney. The average age at diagnosis was f450 days (range 116–
788 days), and the male to female ratio was f1:1. Thirty-eight
cases occurred in NFS.V+ mice that express ecotropic murine
leukemia virus at high levels (24), three in virus-negative NFS
congenics, three in mice with Myc knocked into the IgH locus
(strain iMycEA; ref. 22), three in B6 mice bearing a n-MYC transgene
(25), and one in a B6.me/+ mouse.
The neoplasms exhibited a broad morphologic gradation,
ranging from uniform populations of mature-looking cells, to
more immature forms, to anaplastic cells. The occurrence of these
cells in large nodules or sheets and the presence of binucleate cells
differentiated them as neoplasms from accumulations of normal,
reactive plasma cell. Similar morphologic variants of malignant
plasma cell have been described for human multiple myeloma and
plasmacytomas. In addition, an association between plasma cell
maturity and survival of patients with multiple myeloma has been
recognized for >50 years (27). Subtypes defined by cytologic
features have numbered between two and seven in various studies
(9–11, 27–31) but can be generalized to three: (a) low grade/well
differentiated/plasmacytic; (b) intermediate grade/plasmablastic;
and (c) high grade/pleiomorphic/anaplastic. We adopted the
plasmacytic, plasmablastic, anaplastic system to categorize mouse
plasmacytomas.
The first two types of plasmacytoma, plasmacytic and plasmablastic, are fairly well defined from a cytologic perspective. The
plasmacytic type (Fig. 1A) consists mainly of mature or fairly
mature plasma cells, usually arranged in solid sheets. The cells have
a low nuclear to cytoplasmic ratio, abundant basophilic cytoplasm,
often a large juxtanuclear hof (Golgi), and a clock face nucleus
with clumped chromatin. Cytoplasmic immunoglobulin can readily
be detected by PAS staining (sometimes revealing Mott cells or
Russell bodies; Supplementary Fig. S1A) or immunohistochemistry
(Supplementary Fig. S2). Binucleate cells and mitoses are
sometimes seen, but rarely. This cell type is typical of the
pristane-induced plasmacytomas of BALB/c mice (16) and many
plasmacytomas that develop in IL6 transgenic mice (20). In our
cases, the spleen and lymph nodes are usually affected, but
infiltration of the kidneys, liver, and lung may also occur. This type
must be differentiated from accumulations of plasma cell reflecting
the effects of chronic inflammation on draining lymph nodes or
of systemic inflammatory, infectious, or autoimmune disorders
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Anaplastic, Plasmablastic, and Plasmacytic Plasmacytoma
Figure 1. Histologic features of
immunoblastic lymphomas and
plasmacytoma. A, plasmacytic
plasmacytoma with almost all mature cells
with central nucleoli in clock-face nuclei,
basophilic cytoplasm, and discernible
Golgi. A binucleate cell is near the
center of the field, and somewhat less
mature plasmablasts are near the top.
B, plasmacytic plasmacytoma, more
pleiomorphic with a greater proportion of
plasmablasts than in (A ). Some apoptotic
bodies and a mitosis can be seen.
C, plasmablastic plasmacytoma with a
near-uniform population of plasmablasts
that vary significantly in size and have
unusually large, magenta nuclei. Several
mitoses are present along with active
apoptosis. Occasional mature cells are
seen, and one immunoblast at the top.
D, plasmablastic plasmacytoma with
great variation in cell size, apoptosis,
and mitosis. E, anaplastic plasmacytoma
with a mixture of immunoblasts and
anaplastic cells as well as some
plasmablasts. Note the absence of mature
cells. F, immunoblastic lymphoma with
large magenta nucleoli attached to the
nuclear membrane. Note the presence of
centroblasts with nuclei featuring vesicular
chromatin and two nucleoli sited on the
nuclear membrane and the absence of
plasmablasts.
on both spleen and lymph nodes. In reactive lymph nodes, the
medullary cords are filled with mature plasma cell, and the cortex
is usually enlarged containing numerous, active germinal center
(GC). In spleens of mice with inflammatory conditions, the white
pulp is expanded and displays multiple large GC. The red pulp
features increased myeloid activity and accumulations of plasma
cell, often adjacent to the bridging channels between follicles and
the red pulp. The end-stage differentiation of plasma cell in lymph
node medullae and the splenic red pulp is uniform, and mitoses are
absent. In mice with localized inflammation, lymph nodes other
than those draining the site are usually normal.
The plasmablastic type is distinguished by aggregates of
plasmacytoid cells in all distinguishable stages of plasma cell
differentiation, especially plasmablasts (Fig. 1B and C). This is
sometimes evident in single fields of spleen, lymph node, or liver
sections. Cytologic features of plasmablasts are quite distinctive,
featuring a thickened, sometimes irregular, nuclear membrane
surrounding a vesicular nucleus with a single large, central nucleolus and plentiful violaceous cytoplasm. Unlike the plasmacytic
type, mitoses and active apoptosis are frequently seen. Areas of
infiltration are irregular and may be widespread, differentiating
them from the more confined presentation of the plasmacytic type.
The presence of GC with a transition zone blending into cells with
an obvious plasmacytoid phenotype may be a prominent feature
of the plasmablastic class, particularly in SJL disease.
The anaplastic form of plasmacytoid neoplasms presents a
considerable diagnostic challenge. Morphologically indistinguishable large blast cells, often with folded nuclear membranes
and open vesicular nuclei, can be numerous (Fig. 1D and E;
Supplementary Fig. S1B). Recognizable plasma cell at any stage of
differentiation are rare. Consequently, reliance must be placed on
the identification of plasmablasts and transitional forms between
plasmablasts and immunoblasts. The presence of a heavily
basophilic cytoplasm is sometimes very informative, and immu-
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nohistochemical studies demonstrating low to intermediate levels
of cytoplasmic immunoglobulin provide important support
(Supplementary Fig. S2). Mitoses, tingible body macrophages, and
apoptotic bodies are constant features, as is diffuse infiltration of
spleen, lymph nodes, and other tissues. In about half the cases,
there may be areas resembling the plasmablastic type, but the
general aspect is one of a very undifferentiated population.
The anaplastic cases can be very difficult to distinguish
from immunoblastic lymphomas (Fig. 1F), as both contain blasts
with vesicular nuclei and prominent magenta nucleoli frequently
fixed to one side of the nuclear membrane (Fig. 1E and F;
Supplementary Fig. S1B). Immunoblastic lymphomas often stain
for cytoplasmic immunoglobulin (Supplementary Fig. S2), but fail
to exhibit most other signs of progression toward terminal
differentiation such as accumulations of plasmablasts or expression of surface CD138, cytoplasmic XBP1, or nuclear IRF4.
It is not uncommon to see morphologic differences among
tumor cells present in spleen versus lymph nodes or among
different affected nodes in a single animal. The spectrum in any
one case, however, is usually limited to overlaps of plasmablastic
with plasmacytic areas and anaplastic with plasmablastic areas. Of
interest, composite lymphomas were identified in the spleens of
four cases, each comprising splenic marginal zone lymphoma and a
coexisting plasmablastic or anaplastic plasmacytomas. In humans,
nodal MZL (NMZL) may sometimes exhibit prominent plasma cell
differentiation (32) and some nodal lymphomas originally diagnosed as plasmacytomas have been shown to have features of
NMZL (33).
It has also been suggested that some nodal plasmacytomas with
features of NMZL may arise from plasma cell variants of localized
Castleman’s disease, a nonneoplastic lymphoproliferative disorder
of humans (34). Recent studies showed that the plasma cell variant
of multicentric Castleman’s disease is very responsive to treatment
with monoclonal anti–interleukin-6 receptor monoclonal antibody
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Figure 2. Immunohistochemical analyses
of a plasmacytic plasmacytoma. Sections
of formalin-fixed, paraffin-embedded
tissue were stained with H&E (A ) or
reacted with antibodies to IRF4 (B),
CD138 (C), and XBP1 (D ), followed by
appropriate second antibodies labeled
with horseradish peroxidase. Original
magnifications, 40.
(35) demonstrating, in parallel with our IL6 transgenic mice, the
importance of this cytokine to premalignant expansion and
transformation of plasma cell. GC were shown to be the source
of IL6 in the human disorder.
Using the criteria described above to subset the 48 cases of
plasmacytomas originally identified, 33 were classified as plasmablastic, 10 as anaplastic, and 5 as plasmacytic. SJL cases exhibited
combined plasmacytic/plasmablastic features; the plasmacytomas
of gld mutant mice, previously designated plasmacytoid lymphomas, were plasmablastic, and the IL6 transgenic cases were
plasmacytic.
Immunohistochemical analyses of GC and post-GC Blineage neoplasms. Histologic observations suggested that many
of the nontransgenic plasmacytomas included in this study had
features suggestive of stages in normal plasma cell differentiation
intermediate between immunoblasts and terminally differentiated
cells. To test this idea more directly, we did immunohistochemical
analyses of a panel, including centroblastic diffuse large B-cell
lymphoma, immunoblastic lymphomas, plasmablastic plasmacytomas, and plasmacytic plasmacytomas for expression of genes that
are normally expressed at high levels in B cells but are downregulated in mature plasma cell (PAX5, BCL6, IRF8, and PU.1) and
others that are normally expressed at low levels in B cells but are
up-regulated in plasma cells (IRF4, CD138, p18, XBP1, BLIMP, and
immunoglobulin n light chain). Typical results obtained with a
plasmacytic case are shown in Fig. 2. The population of mature
plasma cell seen in a section stained with H&E (Fig. 2A) showed
intense nuclear staining for IRF4 (Fig. 2B), membrane reactivity for
CD138 (Fig. 2C), and cytoplasmic staining for XBP1 (Fig. 2D).
Cases tested for expression of each protein were graded as
negative or as positive using a three-point scale to describe both
Cancer Res 2007; 67: (6). March 15, 2007
the frequency of positive tumor cells and their staining intensity.
The results of these studies (Table 1) showed that for each B-cell
marker, the frequency of positive cases and the expression levels for
the positive cases decreased progressively with the transitions from
centroblastic to immunoblastic lymphoma to anaplastic/plasmablastic plasmacytomas to plasmacytic plasmacytomas. Conversely,
for each plasma cell marker, except for p18, the frequency of
positive cases and the expression levels for the positive cases
increased progressively during the course of the same transitions.
These results strengthened the suggestions from histologic studies
that plasmablastic and anaplastic plasmacytomas are reflective of
intermediate stages of normal plasma cell differentiation.
Gene expression profiles of plasma cell–related neoplasms.
In an earlier study, we used gene expression profiling to show
that plasmacytoid lymphoma could be placed at an early stage of
plasma cell differentiation and that they could readily be
distinguished from other mature B-cell lineage lymphomas (21).
To place the plasmacytomas described here in this evolving
developmental scheme, we used oligonucleotide arrays that
queried over 11,000 genes to characterize the expression patterns
of immunoblastic lymphomas and the all subsets of plasma cell–
related neoplasms (Fig. 3). The plasmacytomas of IL6 transgenic
mice were chosen as representative of plasmacytic cases, and those
labeled ‘‘APCT’’ comprised nine plasmablastic and one anaplastic
case.
A hierarchical clustering algorithm was used to group the tumor
samples, based on similarities in expression patterns of the genes,
and to group the genes, based on similarities in expression patterns
across all the tumor cases. The cases segregated into two distinct
groups: IL6 transgenic plasmacytic plasmacytomas in one group
and all other cases in the other. The nonplasmacytic cases
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Anaplastic, Plasmablastic, and Plasmacytic Plasmacytoma
Table 1. Immunohistochemical analyses of lymphomas and plasmacytomas for genes differentially expressed during the
normal maturation of B cells from centroblasts to plasma cells
Genes
PAX5
BCL-6
IRF8
PU.1
IRF4
CD138
P18
XBP1
BLIMP
KAPPA
Centroblastic
lymphoma (n = 10)
Immunoblastic
lymphoma (n = 10)
Anaplastic/plasmablastic
plasmacytoma (n = 30)
Plasmacytic
plasmacytoma (n = 10)
Expression level
Expression level
Expression level
Expression level
Positive
(%)
+++
++
+
Positive
(%)
+++
++
+
Positive
(%)
+++
++
+
Positive
(%)
+++
++
+
100
80
80
80
20
20
20
10
0
100
3
6
5
5
0
0
0
0
0
0
5
2
2
3
0
0
0
0
0
1
2
0
1
0
2
2
2
1
0
9
0
2
2
2
8
8
8
9
10
0
80
90
20
30
50
20
20
10
10
100
1
6
0
0
0
0
0
0
0
0
5
3
0
0
2
0
0
0
0
3
2
1
2
3
3
2
2
1
1
7
2
1
8
7
5
8
8
9
9
0
33
20
17
20
96
96
10
80
80
100
0
0
0
0
5
1
0
1
1
10
0
0
0
0
16
12
0
6
2
10
10
6
5
6
8
16
3
17
21
10
20
24
25
24
1
1
27
6
6
0
0
0
0
10
100
100
20
100
100
100
0
0
0
0
8
9
0
5
0
2
0
0
0
0
2
1
0
5
2
7
0
0
0
1
0
0
2
0
8
1
10
10
10
9
0
0
8
0
0
0
comprised two major subsets, one of which encompassed all SJL
and two plasmacytoid lymphoma cases. The second subset was
made up of all immunoblastic lymphomas, all the plasmablastic
cases, and four plasmacytoid lymphoma cases. These results
indicted that the plasmablastic cases were most closely aligned
with immunoblastic lymphomas and some plasmacytoid lymphoma cases, with the remaining plasmacytoid lymphoma and the SJL
cases being more related to the immunoblastic lymphomas and
NFS.V+ plasmablastic cases than to the plasmacytic plasmacytomas
of the IL6 trangenics.
Of interest, the immunoblastic lymphomas and new plasmablastic plasmacytomas segregated into two compartments of nearequal size. A review of the histologic features of all these cases
revealed no defining differences between the subsets, although the
Figure 3. Relations of immunoblastic
lymphomas and plasma cell–related
neoplasms as determined by gene
expression profiling, hierarchical clustering
of histologically defined cases, and gene
expression. Dendrogram at the top, the
samples studied and their relationships
based on similarities in gene expression.
Dendrogram at the right, the expression
patterns of genes across all samples
with intensities depicted according to
the color scale (bottom). The bars under
the heat map are color coded according
to the histologic classification of each
tumor sample. PCT, plasmacytic
plasmacytoma; PL, plasmacytoid
lymphoma; SJL, SJL lymphoma;
APCT, anaplastic and plasmablastic
PCT; IBL, immunoblastic lymphoma.
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anaplastic case fell with the immunoblastic lymphomas. In
addition, there were no histologic features that segregated with
the two subsets of immunoblastic lymphomas.
The array analyses showed that Myc transcripts were greatly
increased in the plasmacytic plasmacytomas of IL6 transgenic mice
but that levels expressed by the other plasma cell neoplasms did not
differ significantly from the levels in normal splenic B cells.
The features of Myc expression identified by the arrays were
confirmed by real-time quantitative reverse transcription-PCR
(Supplementary Fig. S3A). The Myc phenotype of the IL6 transgenic
plasmacytic plasmacytomas was consistent with the regular but not
universal occurrence of cis-activating T(12;15) translocations in the
B-cell neoplasms of these mice (20) and the activation of Myc in
trans in cases without translocations (36). Previous studies of
plasmacytoid lymphoma showed that they did not exhibit structural
alterations in the Myc locus detectable by Southern analyses and
did not express Myc transcripts at high levels (18). The data from
studies of Myc transcripts in immunoblastic lymphomas and SJL
lymphomas and our newly described cases could thus be
interpreted to suggest that Myc translocations were unlikely to be
involved in the pathogenesis of those tumors.
To test this prediction for the plasmablastic plasmacytomas,
DNA was tested by Southern blotting for structural alterations in
Myc. DNA from a plasmacytoma of a Myc knockin mouse (36) and
a plasmablastic plasmacytoma of a n-MYC transgenic mouse
served as positive controls (Fig. 4, bottom). The results showed that
none of 12 plasmablastic nontransgenic plasmacytomas had a
structural change in Myc (Fig. 4 and data not shown). The failure to
detect structural changes in Myc in our neoplasms could not be
ascribed to polyclonality, as each exhibited clonal rearrangements
of IgH loci (Fig. 4, top; and data not shown). Studies of sections
for T(12;15) by tissue FISH identified translocations in two IL6
transgenic plasmacytomas but not in any of five NFS.V+ or three
SJL cases (Supplementary Fig. S3B).
To gain a broader perspective on the differences that distinguish
plasmablastic from plasmacytic plasmacytomas, we identified a set
of genes that differ in expression by 4-fold between the two subsets.
The results of these analyses showed that the two groups of
plasmacytomas differed in the expression of cell surface markers
defining lineage, state of differentiation, and signaling pathways
(Table 2; data not shown). Among others, the plasmablastic cases
preferentially expressed a variety of mature B-cell genes (Cd19,
Mta3), cytokine receptors (Il5ra,), and genes involved in BCR
signaling (Cd79a, Blk), growth, survival, and differentiation
(Tnfsf13b, Il21r). The high level of mitotic activity that characterizes
plasmablastic plasmacytomas was reflected in the elevated expression of receptor and nonreceptor tyrosine kinases, the activity of G
protein and other signaling components, and the overrepresentation of transcription factors. In keeping with the high apoptotic
index of the plasmablastic cases, they expressed many more genes
involved in regulating apoptosis than did the plasmacytic cases. Of
interest, the plasmablastic cases expressed a series of genes
suggesting active involvement of T cells (Cd3d, Cd3e, Cd4), natural
killer cells (Klrd1), and macrophages as well as genes involved in
inflammatory responses not seen with the plasmacytic cases.
Among other elements involved in cell-matrix interactions, the
plasmablastic cases exhibited expression of a large number of integrins, whereas the plasmacytic cases featured a substantial number
of collagen genes. Finally, there were significantly more genes
encoding cytoskeletal proteins for plasmablastic than plasmacytic
plasmacytomas.
Cancer Res 2007; 67: (6). March 15, 2007
Figure 4. Organization of IgH and Myc loci by Southern blot analysis. DNA from
normal spleen (Normal ), a plasmacytic plasmacytoma (PCT ), and nine cases of
plasmablastic and anaplastic plasmacytomas (1–9 ) were digested with
appropriate enzymes and hybridized to an IgH JH probe (A) or a Myc exon 2
probe (B ).
Not surprisingly, the gene group that characterized the
plasmacytic cases included many governing protein metabolism
and stability as well as transcriptional activity. Xbp1, which
encodes a protein required for the unfolded protein response of
mature plasma cells, was prominent among the transcription
factors. It is noteworthy that a number of other genes commonly
associated with terminal B-cell differentiation-Prdm1 (BLIMP1),
Sdc1 (Syndecan), and Irf4-did not appear in the plasmacytic series,
indicating that they were expressed at relatively similar levels by
the two sets of plasmacytomas.
Discussion
It is well established that different classes of mature B-cell
neoplasms exhibit features that mimic specific stages of normal Bcell differentiation and that these similarities provide a perspective
important to their classification and nomenclature. The studies
presented here define an ordered spectrum of transformed cells
that mirror the stages by which normal immunoblasts gradually
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Anaplastic, Plasmablastic, and Plasmacytic Plasmacytoma
assume the mantle of mature plasma cells. We have classified
plasmacytomas of increasing maturity as anaplastic, plasmablastic,
and plasmacytic to provide a parallel with the classification
systems used for human plasmacytoma and multiple myeloma and
because of the ease with which the mouse variants could be
assigned to parallel subtypes.
The results from immunophenotypic studies clearly placed
plasmablastic plasmacytomas at a stage intermediate between
immunoblastic lymphomas and plasmacytic plasmacytomas of IL6
transgenic mice. Analyses of gene expression profiles of these and
other plasma cell–related malignancies, including plasmacytoid
lymphoma and SJL disease, refined this assignment by showing the
plasmablastic plasmacytomas to be more closely related to
immunoblastic lymphomas than the other types. In light of earlier
findings that SJL cases were more mature than plasmacytoid
lymphoma cases but less mature than the plasmacytoma cell lines
analyzed in one study (21), our data suggest that the fate of normal
cells committed to the plasma cell pathway is mirrored within the
neoplastic progression of immunoblastic lymphomas ! anaplastic
plasmacytomas ! plasmablastic plasmacytomas ! plasmacytoid
lymphoma ! SJL ! plasmacytic plasmacytomas.
This pathway will certainly deviate from that followed by normal
B cells, because certain features of the tumors will reflect
mechanisms involved in their transformation or interactions with
other cell types and noncellular stromal elements. This is best
exemplified by the high levels of Myc expressed by the mostly
plasmacytic pristane-induced plasmacytomas of BALB/c mice and
the plasmacytic plasmacytomas of IL6 transgenic mice studied
here compared with the negligible levels of Myc expressed by
normal plasma cell. In almost all cases of plasmacytomas induced
Table 2. Genes that best discriminate plasmablastic from plasmacytic plasmacytomas as determined by microarray analyses
Plasmablastic
B-cell signaling/immunoglobulin
Cytokines/growth factors
Chemokines
Receptor tyrosine kinase
Nonreceptor tyrosine kinase
G proteins
Signaling
Transcription factors/cofactors
Apoptosis
T cells
NK cells
Macrophages
Inflammation/IFNs
Extracellular matrix/adhesion
Cytoskeleton
Protein metabolism/
stability/HSP
Ubiquitin/proteases/
protease inhibitors
www.aacrjournals.org
Plasmacytic
Blk, Brdg1, Card11, Cd19, Cd22, Cd24, Cd40, Cd79a, Dapp1,
Dntt, Fcer2, Ly86, Mta3, Nfam1, Raftlin, Rag1, Rgs1, Vav1
Cish, Igf1, Il1r2, Il2rb, Il2rg, Il4r, Il5ra, Il12a, Il17rb, Il18, Il18bp,
Il18rap, Il20, Il21r, Il27ra, Pdgfb, Plac8, Socs1, Tgfb1, Tnf,
Tnfaip2, Tnfaip3, Tnfrsf14, Tnfsf11, Tnfsf13b
Ccl3, Ccl4, Ccl5, Ccl19, Ccr1, Ccr2, Ccr5, Cxcl4, Cxcl7, Xcl1
Axl, Epor, Flt3, Kit
Fgr, Hck, Limk1, Stk10, Stk39
Arf5, Arhgdib, Arrb1, Centd1, Centd2, Frmd4b, Gnb4, Gng11, Gpsm3,
Rabep2, Rac2, Rassf2, Rassf4, Rgl1, Rgs16, Rrad, Rras2, Sh3bp1
Adcy7, Btg1, Cnp, Dok1, Dusp2, Ehd1, Gna15, Grb2, Hcls1,
Mobk1b, Pak1ip1, Pdlim7, Plcl2, Plek, Plxnc1, Ppbp, Pstpip1,
Ptpn1, Ptpn6, Ptpn18, Rbp4, S100a13, Sh2d1a, Sh3bp2, Sla,
Slamf1, Sts-1, Tlr1, Tlr9, Traf1
Abi3, Ankrd1, Batf, Bhlhb2, C2ta, Dek, Gata1, Id2, Lrrfip1, Mtpn,
Myb, Mycn, Nfkbia, Nfkbie, Nr1h3, Nrob1, Rb1, Relb, Sox11,
Sp100, Spib, Srf, Tcfeb, Wtap, Znf318, Zfp36l1, Zfpm1, Znf238
Anxa11, Apaf1, Arl6ip, Arl6ip5, Bag2, Bcl2, Casp1, Casp3, Casp4,
Casp6, Casp7, Clu, Dnase1l2, Dnase1l3, Fas, Hrk, Phlda2, Plscr1,
Ptpn13, Rps6ka1, Stk17b, Tegt
Cd3d, Cd3e, Cd3g, Cd4, Cd7, Cd37, Cd53, Cd82, Cdc42se1,
Dpp4, Icoslg, Lag3, Lat, Lck, Trat1, Tgtp, Trim30, Zap70
Cd244, Klrd1
Cd5l, Cnr2, Csf1r, Marco, Myo10, Nramp2
Abp1, Alox5ap, Bdkrb2, Clec4e, Ddt, Gbp1, Gbp2, Irgm, Ifi35, Ifngr1,
Iigp1, Irf1, Irf2, Irf8, Ltb, Ptges, Ptgs1, Rnase1, Rsad2, Slc43a3
Cd47, Cib1, Fgl2, Itga6, Itgb1, Itgb2, Itgb3, Itgb7, Lgals9, Mfap1,
Mmp10, Ntn1, Sema4a, Tjp3
Actg2, Actr2, Arpc4, Avil, Cap1, Capg, Cdc42ep3, Cnn2, Fscn1,
Lasp1, Lcp1, Lsp1, Lst1, Marcks, Plekho1, Pdlim7, Pfn1, Plec1,
Rp2, Scin, Swap70, Tln1, Tmod3, Tmsb4x, Tmsb10, Tuba8,
Tubb3, Vasp, Wdr1, Zyx
Dnajb1, Gng10, Hps3, Pcsk1n, Pcsk6, Snx2, Snx10, Tgm2
Capn1, Cst7, Fbxw8, Mkrn1, Prtn3, Psmb8, Psmb9, Serpinb1,
Trim21, Ube2d1, Ube2d2
2445
Blnk
Bmp1, Igfbp3, Inhbb,
Jub, Pdgfra, Vegf
Ccl11
Csnk1e, Matk,
Arhgap8, Farp2, Maged1, Mageh1,
Nol8, Pscdbp, Rabggta, Rgsl1
Dusp22, Ick, Pik3gc, Ppp2r5a, Skil,
Snd1, Stat2, Tbrg4, Rob1, Trib1
Aebp1, Basp1, Etv4, Figla,
Gcn5l2, Ixl, Lztr1, Mybbp1a,
Myc, Rnf25, Usf1, Xbp1
Nol3, Park7
Ctsw, Klra17, Pvr
Lbp, Ptgis
Agr2, Alpl, C1qbp, Chst1, Col1a1,
Col4a2, Col5a2, Col6a2, Extl2,
Fstl1, Itgb5, Lamb1, Lamc2,
Lypd3, Mmp2, Krtha2, Loxl4,
Muxc1, Pvrl4, Sparcl1, Spon1,
St14, Tacstd1, Timp1, Xlkd1
Dnch2, Mfap2, Myh14, Rsn,
Svil, Trip6, Wasl
Calu, Ddost, Dnajb11, Eef1a2, Eif4a1,
Ganab, Gne, Ipo4, Itm1, P4ha2,
P4hb, Pigk, Prmt7, Sec61a1, Sec63,
Senp2, Srp9, Ssb1
Arfip2, Bsg, Enpep, Epas1, Klk2, Os-9,
Psmb3, Ube2t, Serpina3, Slpi, Uchl5
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Cancer Research
by pristane or occurring spontaneously in transgenic mice, elevated
expression of Myc is due to chromosomal translocations that
juxtapose the Myc locus to IgH, T(12;15), or, less commonly, one of
the IgL chain loci (16, 20). High-level expression of Myc in the
absence of translocations is uncommon (16, 36). In contrast,
structural alterations in Myc detectable by Southern analysis
were not detected in the anaplastic, plasmablastic, and SJL
plasmacytomas studied here and are not a feature of plasmacytoid
lymphoma (18). Furthermore, none of the plasmacytoid lymphoma,
SJL, and plasmablastic plasmacytoma cases studied here by
quantitative PCR exhibited elevated levels of Myc transcripts or
exhibited T(12;15) by tissue FISH, indicating that these tumors
did not have Myc-activating translocations involving the Pvt1
region (16) that would have escaped detection by our Southern
analyses.
The Myc-independent mechanisms involved in transformation of
the plasma cell–related cases described here and previously (36)
are not known but are of considerable interest. Given the different
routes that can give rise to normal plasma cell maturation of B1
cells, extrafollicular foci, and products of GC reactions, it may be
that Myc-dependent and Myc-independent plasmacytoma subsets
have different cellular origins. B1 cells might be the cell of origin of
pristane-induced plasmacytomas and those of iMycEA and IL6
transgenic mice. This notion stems from several facts. First, the
vast majority of pristane-induced cases express IgA (16, 37).
Second, the plasmacytomas of iMycEA and IL6 transgenic, which
are mostly IgG producing, develop preferentially in gut-associated
lymphoid tissues (20), whereas pristane-induced tumors arise from
peritoneal granulomas (16). Third, pristane-induced plasmacytomas are similar to B1 cells in expressing antibodies to a variety of
polysaccharide or other repeating antigens as well as autoreactive
polyspecific antibodies that are similar to ‘‘natural’’ antibodies of
the normal immune repertoire (38). Finally, BALB/c mice that carry
the xid mutation in Btk, and as a consequence are devoid of B1
cells, are strikingly resistant to pristane-induced plasmacytoma
induction (39).
Extrafollicular foci of plasma cell can develop from antigenstimulated follicular B cells (40) or marginal zone B cells (41). The
marginal zone B-cell subset has many features in common with B1
cells that include overlapping repertoires and favored isotypes,
similarly heightened sensitivity to proliferative stimuli, and
prominent contributions to T-independent responses (42). In
addition, the marginal zones of mice bearing the xid mutation
are scantly populated by B cells (43). The many parallels between
B1 and marginal zone B cells and their plasma cell progeny make it
difficult to favor plasma cell derived from one subset versus
the other as the normal forerunners of pristane-induced, IL6
transgenic, or iMycEA plasmacytomas. If this model is correct, it
remains to be determined why overexpression of Myc would result
in the seemingly selective transformation of these cells.
Of interest, previous studies of autoimmune NZB mice, the only
strain besides BALB/c to be highly susceptible to plasmacytoma
induction by pristane (17) and to exhibit much enlarged marginal
zones, suggested that the cell population susceptible to transformation by pristane was different from that in BALB/c. This view
was based on the finding that the frequency of IgG-producing
plasmacytomas was more than twice as high and that the
frequency of plasmacytomas producing IgA was less that half that
observed with BALB/c. In addition, few NZB plasmacytomas
secreted antibody specific for the antigens bound most frequently
by BALB/c plasmacytomas; however, NZB mice also have an
Cancer Res 2007; 67: (6). March 15, 2007
expanded population of peritoneal B1 cells that could be the target
for transformation rather than MZ B cells; NZB plasmacytomas
also have translocations involving the Myc locus.
Turning to cases of plasmacytomas without Myc translocations,
the plasmacytoid lymphoma of autoimmune BALB/c-Fasl/Fasl
mutant mice exhibited an even higher ratio of IgG-producing
tumors to IgA-producing tumors than pristane-induced plasmacytomas of NZB; however, the antigenic specificities were often
polyreactive, including anti-self (21). SJL mice are well known for
their sensitivity to experimentally induced autoimmune disorders
such as experimental autoimmune encephalomyelitis, potentially
tying them through autoimmunity to BALB/c Fasl mutant mice.
Perhaps more important, SJL mice exhibit increasing splenomegaly
and lymphadenopathy with age, due in large part to the expansion
of lymphoid follicles with large, active GC. This phenotype is also
true of NZB and Fasl/Fasl mutant mice. In SJL and NZB mice,
plasma cells can sometimes be seen to spill from the enlarged,
active GC and may be the precursors to plasmacytoma. If the ‘‘nonMyc phenotype’’ of the plasmacytoid lymphoma, SJL, and NFS.V+
plasmacytomas reflects a GC origin, the declension of Myc-driven
versus non–Myc-driven plasmacytoma may provide direction for
further experimental studies.
The range of cytologic variation for mouse plasmacytoma
described here was first recognized in a review of cases occurring
in EA-v-abl transgenic mice (19, 44) but has also been seen in
studies of a number of other strains of genetically engineered and
conventional inbred mice, including the published studies of IL6
transgenic (20) and iMycEA knockin mice (22, 23). This strongly
suggests that the conclusions we have drawn can be generalized to
other settings in mice and may be relevant for understanding
human plasma cell neoplasms.
It is important to note that our observations were made only at
necropsy. This leaves open the question of whether the plasmablastic and anaplastic plasmacytomas arose de novo or represent a
progression from a low-grade, more differentiated plasmacytic
malignancy. Studies of patients with multiple myeloma showed
that some progressed from a plasmacytic type to a clonally related,
more aggressive form characterized by the presence of proliferating
immunoblasts of varying sizes with amphophilic cytoplasm and
thickened nuclear membranes (45, 46), features seen with regularity
in our anaplastic and plasmablastic subsets of plasmacytoma.
Progression from a low-grade lymphoma to immunoblastic
lymphoma is also characteristic of the emergence of Richter’s
syndrome in patients with chronic lymphocytic leukemia (47),
which seems to be a malignancy of memory B cells. Although
these results could be interpreted as the manifestations of dedifferentiative processes, studies of cells from patients with
multiple myeloma have suggested otherwise. In particular, the
data of Matsui et al. (48) indicate that the cell type responsible for
the initiation and maintenance of multiple myeloma is a minor
population of proliferative post-GC CD19+CD20+sIg+CD138 B cells
with the capacity to differentiate into the mass of CD138+ plasma
cells that comprise the bulk of the disease. This phenotype is
similar to that of cells comprising anaplastic and plasmablastic
plasmacytomas, respectively.
Further analyses of mouse plasmacytomas of different origins
may enhance our understanding of the relations between mouse
and human plasma cell–related tumors, help define the transitions
involved in the later stages of normal B-cell differentiation, and
provide experimental models for understanding the nature of stem
cells that are postulated to drive these diseases.
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Anaplastic, Plasmablastic, and Plasmacytic Plasmacytoma
Acknowledgments
Received 5/2/2006; revised 8/22/2006; accepted 12/27/2006.
Grant support: Intramural Research Program of the NIH, NIAID, and NCI grants
DK56597 and CA34196 (D.C. Roopenian) and CA82872-02 (W.F. Davidson).
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
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Anaplastic, Plasmablastic, and Plasmacytic Plasmacytomas
of Mice: Relationships to Human Plasma Cell Neoplasms and
Late-Stage Differentiation of Normal B Cells
Chen-Feng Qi, Jeff X. Zhou, Chang Hoon Lee, et al.
Cancer Res 2007;67:2439-2447.
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