|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 747-755
Differential Expression of BCL-6, CD138/Syndecan-1, and Epstein-Barr
Virus-Encoded Latent Membrane Protein-1 Identifies Distinct
Histogenetic Subsets of Acquired Immunodeficiency Syndrome-Related
Non-Hodgkin's Lymphomas
By
Antonino Carbone,
Gianluca Gaidano,
Annunziata Gloghini,
Luigi M. Larocca,
Daniela Capello,
Vincenzo Canzonieri,
Andrea Antinori,
Umberto Tirelli,
Brunangelo Falini, and
Riccardo Dalla-Favera
From the Divisions of Pathology and Medical Oncology and AIDS
Program, Centro di Riferimento Oncologico, Istituto Nazionale di
Ricovero e Cura a Carattere Scientifico, Aviano, Italy; the Division of
Internal Medicine, the Department of Medical Sciences, University of
Torino at Novara, Novara, Italy; the Institutes of Pathology and of
Infectious Diseases, Università Cattolica del Sacro Cuore, Roma,
Italy; the Institute of Hematology, University of Perugia, Perugia,
Italy; and the Division of Oncology, the Department of Pathology,
College of Physicians and Surgeons, Columbia University, New York, NY.
 |
ABSTRACT |
This study was aimed at defining the histogenesis of the pathologic
spectrum of acquired immunodeficiency syndrome-related non-Hodgkin's
lymphomas (AIDS-NHL), including AIDS-related small noncleaved cell
lymphoma (AIDS-SNCCL), AIDS-related large noncleaved cell lymphoma
(AIDS-LNCCL), AIDS-related large cell immunoblastic lymphoma
plasmacytoid (AIDS-IBLP), and AIDS-related primary effusion lymphoma
(AIDS-PEL). Forty-six cases of AIDS-NHL were investigated for the
expression pattern of BCL-6, a protein specifically expressed by
germinal center (GC) B-cells, and CD138/syndecan-1 (syn-1), a marker of
post-GC B-cell differentiation. Expression of BCL-6 and syn-1
segregated two major phenotypic patterns among AIDS-NHL: (1) the
BCL-6+/syn-1 pattern associated with
AIDS-SNCCL and AIDS-LNCCL; (2) the BCL-6/syn-1
+ pattern associated with AIDS-IBLP and AIDS-PEL. Among
systemic AIDS-NHL infected by Epstein-Barr virus (EBV), expression of
the EBV-encoded latent membrane protein-1 (LMP-1) preferentially
associated with the BCL-6/syn-1 + profile.
Analysis of nonneoplastic lymph nodes showed that the two phenotypic
patterns detected in AIDS-NHL correspond to physiologic stages of
B-cell development, ie, GC B-cells
(BCL-6+/syn-1) and preterminally
differentiated post-GC B-cells
(BCL-6/syn-1+). Thus,
BCL-6+/syn-1 AIDS-NHL reflects a GC stage
of differentiation, whereas AIDS-NHL which are
BCL-6/syn-1+, and LMP-1+
when infected by EBV, derive from B cells that have entered post-GC plasmacell differentiation. These findings are relevant for the pathogenesis and differential diagnosis of AIDS-NHL.
| |
INTRODUCTION |
ACQUIRED IMMUNODEFICIENCY
syndrome-related non-Hodgkin's lymphomas (AIDS-NHL) represent a
markedly heterogeneous group of lymphomas derived from mature B
cells.1-3 The pathologic spectrum of AIDS-NHL includes
systemic NHL, primary central nervous system lymphomas (PCNSL), and
primary effusion lymphoma (PEL). Systemic AIDS-NHL are histologically
classified into AIDS-related small noncleaved cell lymphoma
(AIDS-SNCCL) and AIDS-related diffuse large cell lymphoma
(AIDS-DLCL).2 Depending on the presence of immunoblastic
features, AIDS-DLCL may be further distinguished into large noncleaved
cell lymphoma (LNCCL) and large cell immunoblastic lymphoma
plasmacytoid (IBLP).1,2,4 AIDS-related PCNSL (AIDS-PCNSL) are represented in all cases by IBLP or LNCCL,5 whereas
AIDS-related PEL (AIDS-PEL) morphologically bridges immunoblastic and
anaplastic features.6-8
The pathologic heterogeneity of AIDS-NHL correlates with the
heterogeneity of the molecular lesions associated with these lymphomas.2,3,9-11 AIDS-SNCCL selectively associates with activation of c-MYC, whereas rearrangements of BCL-6
are restricted to a fraction of AIDS-DLCL. Infection by Kaposi's
sarcoma-associated herpesvirus (KSHV) clusters selectively with
AIDS-PEL,6-8 whereas infection by Epstein-Barr virus (EBV)
occurs at different rates in different AIDS-NHL types.12-15
The histogenetic derivation of the various types of AIDS-NHL has not
been elucidated, although it has been suggested that a fraction of
AIDS-NHL may be related to germinal center (GC) B cells.16
More recently, the study of the histogenesis of mature B-cell neoplasms
has been facilitated by the availability of biologic markers of
distinct subsets of mature B cells. Two such markers are represented by
BCL-6 and CD138/syndecan-1 (syn-1). BCL-6 is a proto-oncogene product
coding for a zinc finger transcriptional repressor which, in the B-cell
lineage, is expressed selectively in GC B-cells.17-21
Notably, animal models have shown that expression of BCL-6 is an
absolute requirement for GC formation and function.22,23 Syn-1 is a proteoglycan belonging to the syndecan
family.24,25 Within the mature B-cell compartment, syn-1 is
not expressed in GC B cells whereas it is expressed in specific subsets
of post-GC B cells, including immunoblasts and plasma
cells.26-28
In an attempt to elucidate the histogenesis of AIDS-NHL, we have
investigated the expression pattern of BCL-6 and syn-1 throughout the
pathologic spectrum of these lymphomas as well as in nonneoplastic lymphoid tissues. The results indicate that AIDS-NHL may be subdivided into two main phenotypic categories corresponding to the GC
(BCL-6+/syn-1) and the post-GC
(BCL-6/syn-1+) stage of physiologic B-cell
differentiation. In systemic AIDS-NHL carrying EBV infection,
expression of LMP-1 clusters with the BCL-6/syn-1+ phenotype. Overall, these
results have implications for the histogenesis and diagnosis of
AIDS-NHL.
| |
MATERIALS AND METHODS |
Neoplastic samples.
This study included AIDS-NHL samples from 40 patients (27 systemic
AIDS-NHL, 8 AIDS-PCNSL, and 5 AIDS-PEL). Pathological specimens were
classified according to the Working Formulation for NHL and the revised
European-American classification of lymphoid neoplasms (REAL).4 AIDS-PEL were classified on the basis of their
clinico-pathological and virological (eg, KSHV positivity)
characteristics.6,7 Tissues from systemic AIDS-NHL and
AIDS-PCNSL were fixed in Bouin solution or neutral buffered formalin.
In most cases, a portion of unfixed tissue was snap frozen in liquid
nitrogen and stored at  80°C. Samples of AIDS-PEL were collected
under sterile conditions during standard diagnostic procedures and
treated according to a standard regimen used at the Division of
Pathology of the Centro di Riferimento Oncologico.7,29 All
tissue-based AIDS-NHL and AIDS-PEL were B-cell monoclonal
proliferations according to their immunophenotypic and immunogenotypic
characteristics.
Cell lines.
In vitro established AIDS-NHL cell lines were also studied. The
detailed characterization of these cell lines has been reported previously. The cell lines HBL-6, BC-1 (purchased from American Type
Culture Collection [ATCC], Rockville, MD), BC-2 (purchased from
ATCC), BC-3, BCBL-1, and CROAP-2 were derived from
AIDS-PEL.29-33 Four AIDS-PEL cell lines (HBL-6, BC-1, BC-2,
and CROAP-2) carry EBV infection, whereas two AIDS-PEL cell lines (BC-3
and BCBL-1) are EBV.
Nonneoplastic samples.
Nonneoplastic lymph node samples from seven human immunodeficiency
virus (HIV)-seropositive patients with persistent generalized lymphadenopathy (PGL) were also included in the study. All PGL samples
carried EBV DNA sequences without evidence of monoclonal EBV episomes,
as assessed by Southern blot analysis. The histopathologic pattern of
PGL samples was predominantly represented by hyperplastic changes of
the lymphoid follicles.
Immunohistochemical studies and analysis of BCL-6 and syn-1
expression.
Deparaffinized and cryostat sections were used for immunophenotyping
and lineage assignment of AIDS-NHL and PGL samples. Sources and
specificities of the antibodies used in this study have been reported
in detail previously.29 Immunohistochemistry was performed by the avidin-biotin-peroxidase complex (ABC-px) or alkaline
phosphatase anti alkaline phosphatase (APAAP) methods as previously
described.34,35
The BCL-6 protein was detected by using the PG-B6 monoclonal antibody
(MoAb) that has been recently generated in the laboratory of one of the
investigators (B.F.) by immunizing BALB/c mice with a glutathione
S-transferase-BCL-6 fusion protein.36 The antibody is
directed against the aminoterminal portion of the human BCL-6 gene
product. Immunostaining for BCL-6 was performed on frozen or
formalin-fixed, paraffin-embedded sections and cytospin preparations by
the APAAP method.35,37
Anti-B-B4 MoAb (Serotec, Oxford, UK), which specifically recognizes
the syn-1 antigen,28 was applied to paraffin-embedded tissues from all 35 tissue-based AIDS-NHL and all 7 PGL samples included in this study. The MoAb was also applied to frozen tissues from a representative subset of AIDS-NHL cases for control purposes. The MoAb was applied to cytospin preparations from all AIDS-PEL cases
as well as from the AIDS-PEL cell lines. Air-dried frozen sections were
kept under vacuum for 3 hours and then fixed in a 1:1 solution of
acetone and chloroform for 10 minutes; sections were hydrated with
phosphate-buffered saline (PBS), pre-incubated with normal rabbit serum
(1:50 for 20 minutes at room temperature) and subsequently
incubated with anti-B-B4 MoAb for 1 hour at room temperature.
Paraffin-embedded tissue sections were pretreated in a microwave oven
(Jet 900 W; Philips, Eindhoven, The Netherlands) twice for
5 minutes at 650 W in citrate buffer (pH 6); immunostaining was
performed by incubating anti-B-B4 MoAb, with the addition of 3%
normal human serum, for 1 hour at room temperature. Cytospin preparations of AIDS-PEL and of AIDS-PEL-derived cell lines were fixed
in acetone-chloroform at room temperature for 10 minutes and
immunostained with anti-B-B4 MoAb by the APAAP (alkaline
phosphatase anti-alkaline phosphatase) method.35
The percentage of BCL-6+ or syn-1+ neoplastic
cells was assigned to one of the following categories: 0, less than
10%, 10% to 25%, 25% to 50%, 50% to 75%, and greater than 75%.
Two-color staining.
Multiple immunohistochemical staining was performed to detect BCL-6
plus syn-1 in selected PGL samples. Formalin fixed paraffin-embedded tissue sections were first treated twice for 5 minutes in 1 mmol/L EDTA
buffer pH 8.0 and immunostained with anti-BCL-6 MoAb by the APAAP method35,37 using naphthol AS-MX phosphate along with Fast Blue BB salt (Sigma Chemical Co, St Louis, MO) for
the development of alkaline phosphatase; subsequently, sections were
treated twice for 5 minutes in citrate buffer (pH 6) in a microwave
oven to denature bound antibody molecules and to inactivate alkaline
phosphatase present in the APAAP complex. Finally, sections were
incubated overnight at 4°C with anti-syn-1 MoAb and immunostained by
the APAAP method using naphthol AS-MX phosphate along with Fast Red TR salt (Sigma) for the development of alkaline
phosphatase.
Analysis of viral infection.
All samples of AIDS-NHL and PGL included in this study were subjected
to determination of tumor infection by EBV and KSHV, according to
previously reported strategies.7,29 EBER in situ hybridization (ISH) studies were performed on AIDS-NHL and PGL samples
to identify the nature and distribution of EBV-infected cells. ISH
studies were performed on Bouin or formalin fixed paraffin-embedded tissues or cell block sections, as previously described.16
In the case of EBER+ samples, immunostaining for LMP-1 was
performed with an LMP-1 specific antibody (Dakopatts A/S, Glostrup, Denmark) on Bouin or formalin-fixed paraffin-embedded tissue sections and cytospin preparations, as described above. The percentage of
LMP-1+ neoplastic cells was assigned to one of the
following categories: 0, less than 10%, 10% to 25%, 25% to 50%,
50% to 75%, and greater than 75%.
Analysis of c-MYC genetic lesions.
Genomic DNA of selected AIDS-NHL cases and of AIDS-PEL cell lines was
extracted by the "salting out" technique.38 Analysis of c-MYC genetic lesions was performed by a combination of
molecular approaches, including both Southern blot studies and
mutational analysis, as previously reported.9
Genetic studies of BCL-6.
The configuration of the BCL-6 locus was investigated by
Southern blot analysis using previously reported assays.10
The presence of mutations of BCL-6 5 noncoding regions was
tested in a 740-bp fragment within BCL-6 intron 1 and in
BCL-6 exon 1 (fragments E1.10, E1.11, E1.12 according to
Migliazza et al39), which contains  95% of mutations
detected in B-cell NHL of the immunocompetent host and
AIDS-NHL.11,39
| |
RESULTS |
Expression of BCL-6, syn-1, and LMP-1 among systemic AIDS-NHL.
The panel of 27 systemic AIDS-NHL biopsies included 11 cases of
AIDS-SNCCL and 16 cases of AIDS-DLCL (Table
1). Within the AIDS-DLCL group, 7 cases
were classified as AIDS-LNCCL and 9 cases were classified as AIDS-IBLP.
Immunologic/genotypic analyses showed a B-cell origin in all cases
(data not shown). Consistent with previous reports,9-16
infection of the tumor clone by EBV was detected in 6 of 11 AIDS-SNCCL,
2 of 7 AIDS-LNCCL, and 6 of 9 AIDS-IBLP cases (Table 1). As previously
observed,6,9-11 all samples were devoid of KSHV infection,
whereas structural alterations of c-MYC were detected in 100%
(8 of 8) of AIDS-SNCCL and in a minority (2 of 8) of AIDS-DLCL cases
(Table 1).
The immunoreactivity of anti-BCL-6, anti-syn-1, and anti-LMP-1 MoAbs
was scored using the criteria described in Materials and Methods. The
data are summarized in Tables 1 and 2 and
representative results are shown in Fig
1.
View this table:
[in this window]
[in a new window]
|
Table 2.
Expression of BCL-6 Protein and CD138/syndecan-1 (syn-1)
Throughout the Pathologic Spectrum of AIDS-Related NHLs
|
|
View larger version (140K):
[in this window]
[in a new window]
| Fig 1.
AIDS-related systemic NHLs. (A through C) AIDS-LNCCL
displaying the BCL-6+ (A), CD138/syndecan-1
(syn-1) (B), LMP-1 (C) phenotype. (A)
Large tumor cells show a nuclear staining pattern with
anti-BCL-6 MoAb. (B) A residual plasma cell shows cytoplasmic
staining for anti-syn-1 MoAb. (C) No LMP-1 expression is detectable.
(D through F) AIDS-IBLP displaying the BCL-6 (D),
syn-1+ (E), LMP-1+ (F) phenotype. (D) No
BCL-6 expression is detectable. (E) Most immunoblastic-plasmacytoid
tumor cells show strong cytoplasmic immunoreactivity with the
anti-syn-1 MoAb. (E inset) A higher-power photograph showing the
cytoplasmic staining pattern on large immunoblasts-plasmacytoid. (F)
LMP-1 positivity is manifested as cytoplasmic or membrane staining on
several large tumor cells displaying immunoblastic-plasmacytoid morphology. (G through I) AIDS-SNCCL displaying the
BCL-6+ (G), syn-1 (H),
LMP-1 (I) phenotype. (G) Most neoplastic cells show
strong nuclear immunoreactivity with the anti-BCL-6 MoAb. (H) A
residual plasma cell shows cytoplasmic staining for anti-syn-1 MoAb.
(I) No LMP-1 expression is detectable. APAAP immunostaining; (A), (D),
(G) frozen section; (B), (C), (E), (E inset), (F), (H), (I)
paraffin-embedded tissue section, hematoxylin counterstain. Original
magnification ×250 (A through I).
|
|
Overall, a positive BCL-6 staining was detected in 20 of 27 (74%)
systemic AIDS-NHL (Table 1). Expression of BCL-6 clustered with
AIDS-SNCCL (11 of 11, 100%) and AIDS-LNCCL (7 of 7, 100%), whereas it
was restricted to 2 of 9 (22.2%) AIDS-IBLP cases (Table 1). As
previously observed,16 expression of BCL-6 protein among systemic AIDS-NHL patients occurred both in the presence and in the
absence of structural alterations of the BCL-6 gene (Table 1).
Expression of syn-1 was detected in 6 of 27 (22%) cases of systemic
AIDS-NHL (Table 1). The syn-1+ phenotype preferentially
associated with cases displaying the AIDS-IBLP morphology (6 of 9, 66%), whereas it was not detected in any case of AIDS-SNCCL or
AIDS-LNCCL (Table 1). All systemic AIDS-NHL cases which scored positive
for syn-1 were found to be negative for BCL-6 expression (Tables 1 and
2).
Among systemic AIDS-NHL carrying EBV infection (n = 14), expression
of the EBV encoded LMP-1 antigen was detected in 5 cases (Table 1). All
cases of LMP-1+ systemic AIDS-NHL were morphologically
classified as AIDS-IBLP, expressed syn-1, and stained negative for
BCL-6 (Table 1). Conversely, expression of LMP-1 was consistently
negative in all cases of EBV+ systemic AIDS-NHL expressing
BCL-6 (Table 1).
Expression of BCL-6, syn-1, and LMP-1 among AIDS-PCNSL.
The panel of AIDS-PCNSL biopsies (n = 8) displayed in all cases a
morphology consistent with AIDS-DLCL (Table 3). Four cases were
classified as AIDS-LNCCL and four cases were classified as AIDS-IBLP.
All AIDS-PCNSL were EBV+ and KSHV (Table
3). Immunologic/genotypic analyses showed a
B-cell origin in all cases (not shown).
Results of immunoreactivity of anti-BCL-6, anti-syn-1, and
anti-LMP-1 MoAbs in AIDS-PCNSL are summarized in Tables 2 and 3.
Representative results are shown in Fig 2.
View larger version (84K):
[in this window]
[in a new window]
| Fig 2.
AIDS-PCNSL. (A) BCL-6 protein expression in a case of
AIDS-PCNSL (diffuse large cell lymphoma). The microphotograph shows that the tumor is relatively monomorphous and consists of large tumor
cells displaying a large noncleaved cell morphology. In this field,
nuclear positivity for BCL-6 is present on several tumor cells.
Paraffin-embedded tissue section, APAAP immunostaining, hematoxylin
counterstain. (B) LMP-1 expression in a case of AIDS-PCNSL (diffuse
large cell lymphoma). The microphotograph shows that the tumor is
polymorphous and consists of large tumor cells displaying an
immunoblastic-plasmacytoid morphology. LMP-1 positivity is manifested
as cytoplasmic or membrane staining on some large tumor cells.
Paraffin-embedded tissue section, APAAP immunostaining, hematoxylin
counterstain. Original magnification ×400 (A) and (B).
|
|
Overall, expression of BCL-6 was detected in 4 of 8 (50%) cases of
AIDS-PCNSL (Table 3). All BCL-6+ AIDS-PCNSL displayed a
morphology consistent with AIDS-LNCCL. Conversely, expression of BCL-6
was scored negative in all AIDS-PCNSL classified as AIDS-IBLP (Table
3). Expression of BCL-6 protein among AIDS-PCNSL occurred both in the
presence and in the absence of structural alterations of the
BCL-6 gene (Table 3).
Expression of the syn-1 antigen was detected in 2 of 8 (25%)
AIDS-PCNSL cases (Table 3). The two syn-1+ AIDS-PCNSL cases
displayed a morphology consistent with AIDS-IBLP and failed to express
BCL-6 (Tables 2 and 3).
Expression of LMP-1 was detected in 1 of the 2 BCL-6,
syn-1+ AIDS-PCNSL cases (Table 3). Conversely, LMP-1
stained consistently negative in all BCL-6+,
syn-1 AIDS-PCNSL cases (n = 4).
Expression of BCL-6, syn-1, and LMP-1 in AIDS-PEL.
The panel of AIDS-PEL, all positive for KSHV, included 5 primary cases
and 6 AIDS-PEL-derived cell lines (Table 3). Three primary AIDS-PEL
and 4 AIDS-PEL cell lines carried the EBV genome (Table 3).
Immunologic/genotypic analyses showed a B-cell origin in all primary
samples and cell lines (not shown). Structural alterations of
c-MYC were absent in all cases (Table 3).
Results of immunoreactivity of anti-BCL-6, anti-syn-1, and
anti-LMP-1 MoAbs in AIDS-PEL are summarized in Tables 2 and 3. Representative data are shown in Fig 3.
View larger version (152K):
[in this window]
[in a new window]
| Fig 3.
AIDS-related primary effusion lymphoma. The majority of
tumor cells show strong cytoplasmic and membrane staining for B-B4 antibody, that recognizes the plasma cell specific CD138/syndecan-1 antigen. Cytospin preparation, APAAP immunostaining, hematoxylin counterstain. Original magnification ×400.
|
|
All AIDS-PEL scored negative for BCL-6 protein expression (Tables 2 and
3). Conversely, all samples of AIDS-PEL were found to express the syn-1
antigen (Tables 2 and 3). Out of the 7 AIDS-PEL carrying EBV infection,
3 cases displayed a small proportion of cells expressing the LMP-1
antigen (Table 3).
Expression of BCL-6 and syn-1 in PGL.
A panel of 7 PGL samples was used to define the expression pattern of
BCL-6 and syn-1 in nonneoplastic lymph nodes. In all PGL samples
tested, a strong and specific reactivity for BCL-6 was detectable
within the follicular GC (see Fig 4 for
representative results). The mantle and paracortical zones were mostly
negative with the exception of several small lymphoid cells and rare
isolated large cells, presumably represented by T cells.21
In the same lymph node samples, the anti-syn-1 MoAb showed a strong
cytoplasmic and membrane staining of plasma cells, but no reactivity in
other cell populations. Syn-1+ plasma cells were
consistently present in the interfollicular areas. In addition, a
variable number of plasma cells was also found in follicular GC and
their surrounding mantle zones. Thus, in the context of PGL, individual
lymphoid cells expressed selectively either BCL-6 or syn-1. In
particular, when considering PGL areas in which BCL-6+
cells and syn-1+ cells were simultaneously detectable,
double-labelling experiments ruled out the co-expression of BCL-6 and
syn-1 by the same cell (Fig 4).
View larger version (86K):
[in this window]
[in a new window]
| Fig 4.
Hyperplastic lymph node from an HIV-infected
person with persistent generalized lymphadenopathy (PGL). (A) Two-color
staining. Within a follicle numerous germinal center (GC)
cells exhibit nuclear staining (blue) for BCL-6. In the same follicle,
large cells with a plasma cell morphology show a strong cytoplasmic and
membrane staining (reddish) with the anti-CD138/syndecan-1 MoAb. They
are present within the GC and in the perifollicular (PF) zone. No
co-expression of both markers by the same GC cell is detectable.
Paraffin-embedded tissue section, no counterstain. (B) EBER in situ
hybridization. EBER+ cells are localized around the
hyperplastic follicle (right) and within the expanded germinal center
(left). Paraffin-embedded tissue section, nuclear fast red
counterstain. (C) Immunostaining for LMP-1. No LMP-1 expression by
lymph node cells is detectable. Paraffin-embedded tissue section, APAAP
method, hematoxylin counterstain. Original magnification ×250 (A),
×100 (B) and (C).
|
|
EBV-infected cells were detected in all PGL samples by EBER ISH studies
(see Fig 4 for representative results) and Southern blot analysis (not
shown). EBV-carrying cells were usually restricted to the
interfollicular zone. However, in 2 of 7 PGL samples they were also
present within the follicular GC (Fig 4). EBER+ B cells
within the GC were consistently negative for LMP-1 expression (Fig 4).
| |
DISCUSSION |
The results presented in this study indicate that expression of BCL-6
and syn-1 segregates two major phenotypic subsets of AIDS-NHL, ie,
BCL-6+/syn-1 and
BCL-6/syn-1+ (Fig
5). These two phenotypic patterns were
confirmed in nonneoplastic B cells, indicating that they correspond to
two distinct differentiation programs of normal B cells. These findings
bear implications for the histogenesis and diagnosis of AIDS-NHL.
View larger version (27K):
[in this window]
[in a new window]
| Fig 5.
Model of systemic AIDS-NHL histogenesis. The proposed
model is based on the expression pattern of BCL-6 and
CD138/syndecan-1 (syn-1) throughout physiologic B-cell
differentiation. B cells within the germinal center (GC) display
the BCL-6+/syn-1 phenotype,
whereas B cells that have exited the GC and have undergone further maturation toward the plasma cell stage exhibit the
BCL-6/syn-1+ phenotype. On these
bases, systemic AIDS-NHL displaying the
BCL-6+/syn-1 phenotype, ie, AIDS-SNCCL and
AIDS-LNCCL, are postulated to originate from GC B cells. Conversely,
systemic AIDS-NHL displaying the BCL-6/syn-1+ phenotype, ie, AIDS-IBLP, are
postulated to derive from preterminally differentiated B cells.
In the case of AIDS-NHL infected by EBV, the
BCL-6/syn-1+ phenotype is permissive for
expression of the EBV encoded LMP-1 antigen. Conversely, LMP-1
expression is consistently absent among AIDS-NHL displaying the
BCL-6+/syn-1 phenotype.
|
|
In normal lymphoid tissues, the phenotypic patterns identified by BCL-6
and syn-1 map to lymph node areas that are populated by B cells at
different stages of differentiation21,26-28 (and this
report). In particular, B cells within the GC are
BCL-6+/syn-1, whereas plasma cells, which
predominate in interfollicular areas, are
BCL-6/syn-1+. This pattern of expression
confirms that post-GC terminal differentiation of B cells is coupled to
downregulation of BCL-6 and upregulation of syn-1 (Fig 5).
These observations suggest a histogenetic model for AIDS-NHL
development (Fig 5). AIDS-NHL displaying the
BCL-6+/syn-1 phenotype originate from
GC-related B cells, whereas cases displaying the
BCL-6/syn-1+ phenotype derive from B cells
which have exited from the GC and are maturing toward the plasma cell
stage. Because AIDS-NHL categories that are pathologically and
molecularly distinct (eg, AIDS-SNCCL and AIDS-LNCCL) share the same
phenotypic pattern (eg, BCL-6+/syn-1), it is
conceivable that the same progenitor cell may give rise to different
types of AIDS-NHL depending on the molecular pathway that is being
activated.
Among EBV-infected AIDS-NHL, expression of the EBV-encoded LMP-1
antigen can be found only in BCL-6/syn-1+
cases. Furthermore, all AIDS-DLCL expressing LMP-1 exhibit
morphological (IBPL) and/or phenotypic
(BCL-6/syn-1+) features consistent with an
advanced stage of B-cell maturation. This suggests that the GC stage is
not permissive for LMP-1 expression and that maturation beyond the GC
is required for successful LMP-1 expression in B cells.
This hypothesis was previously suggested based on the pattern of LMP-1
expression in an in vitro model of EBV-infected Burkitt's lymphoma
(BL).40-44 Expression of LMP-1 is absent in EBV-infected BL
cell lines retaining the GC phenotype characteristic of BL in vivo
(conventionally denominated as group I BL cell lines), whereas it is
upregulated in EBV+ BL cell lines which have acquired
immunoblastic features after in vitro culture (conventionally
denominated as group III BL cell lines). Once the cell becomes
permissive for LMP-1 expression, LMP-1 may directly downregulate the
level of BCL-6 protein. In fact, recent results indicate that the
genetically induced expression of LMP-1, as well as activation of CD40,
induces downregulation of BCL-6 expression, suggesting that it may be
associated with a critical step of post-GC differentiation of B
cells.45
Finally, the expression pattern of BCL-6 and syn-1 bears implications
for AIDS-NHL diagnosis. In fact, distinct pathologic and molecular
categories of AIDS-NHL selectively associate with different patterns of
BCL-6 and syn-1 expression. Remarkably, the association between
phenotype and histology appears to be independent of the primary site
of the disease, as exemplified by the fact that both systemic
AIDS-LNCCL and AIDS-PCNSL with LNCCL morphology share the same
BCL-6+/syn-1 phenotype. On these bases, it
is conceivable that the expression pattern of BCL-6 and syn-1 may
contribute to the morphological diagnosis of these lymphomas.
| |
FOOTNOTES |
Submitted October 2, 1997;
accepted October 28, 1997.
Supported in part by the Instituto Superiore di Sanità, AIDS
project 1996 and 1997, Rome, Italy; by the Associazione Italiana per la
Ricerca sul Cancro, Milan, Italy; by Fondazione "Piera Pietro e
Giovanni Ferrero," Alba, Italy; and by National Institutes of Health
Grant No. CA-37295
Address reprint requests to Antonino Carbone, MD, Division of
Pathology, Centro di Riferimento Oncologico, IRCCS, via Pedemontana Occidentale, Aviano I-33081, Italy.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be here-by marked
"advertisement" in accordance with 18 U.S.C. section 17.34 solely
to indicate this fact.
| |
ACKNOWLEDGMENT |
The following reagent was obtained through the AIDS Research and
reference Reagent Program, Division of AIDS, NIAID, NIH, Bethesda, MD:
BCBL-1 SP from Drs Michael McGrath and Don Ganem. BC-3 was the kind
gift of Dr E. Cesarman (Cornell University, New York, NY). LAM
C3+ was the kind gift of Dr S. Roncella (IST, Genova,
Italy).
| |
REFERENCES |
1.
Levine AM:
AIDS-related malignancies: The emerging epidemic.
J Natl Cancer Inst
85:1382,
1993[Abstract/Free Full Text]
2.
Gaidano G,
Carbone A:
AIDS-related lymphomas: From pathogenesis to pathology.
Br J Haematol
90:235,
1995[Medline]
[Order article via Infotrieve]
3.
Knowles DM:
Molecular pathology of acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma.
Semin Diagn Pathol
14:67,
1997[Medline]
[Order article via Infotrieve]
4.
Harris NL,
Jaffe ES,
Stein H,
Banks PM,
Chan JKC,
Cleary ML,
Delsol G,
De Wolf-Peters C,
Falini B,
Gatter KC,
Grogan TM,
Isaacson PG,
Knowles DM,
Mason DY,
Muller-Hermelink H-K,
Pileri S,
Piris MA,
Ralfkiaer E,
Warnke RA:
A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group.
Blood
84:1361,
1994[Free Full Text]
5. Camilleri-Broèt S, Davi F, Feuillard J, Seilhean D,
Michiels JF, Brousset P, Epardeau B, Navratil E, Mokhtari K, Bourgeois
C, Marelle L, Raphaèl M, Hauw J-J, and the French Study Group for
HIV-Associated Tumors: AIDS-related primary brain lymphomas: Histopathologic and immunohistochemical study of 51 cases. Hum Pathol
28:367, 1997
6.
Cesarman E,
Chang Y,
Moore PS,
Said JW,
Knowles DM:
Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas.
N Engl J Med
332:1186,
1995[Abstract/Free Full Text]
7.
Carbone A,
Gloghini A,
Vaccher E,
Zagonel V,
Pastore C,
Dalla Palma P,
Branz F,
Saglio G,
Volpe R,
Tirelli U,
Gaidano G:
Kaposi's sarcoma-associated herpesvirus DNA sequences in AIDS-related and AIDS-unrelated lymphomatous effusions.
Br J Haematol
94:533,
1996[Medline]
[Order article via Infotrieve]
8. IARC Monographs on the Evaluation of Carcinogenic Risks to
Humans, Vol 67: Human Immunodeficiency Viruses and Human T-Cell
Lymphotropic Viruses. International Agency for Research on
Cancer/World Health Organization, Lyon, France, 1996
9.
Ballerini P,
Gaidano G,
Gong JZ,
Tassi V,
Saglio G,
Knowles DM,
Dalla-Favera R:
Multiple genetic lesions in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma.
Blood
81:166,
1993[Abstract/Free Full Text]
10.
Gaidano G,
Lo Coco F,
Ye BH,
Shibata D,
Levine A,
Knowles DM,
Dalla-Favera R:
Rearrangements of the BCL-6 gene in acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma: Association with diffuse large-cell subtype.
Blood
84:397,
1994[Abstract/Free Full Text]
11.
Gaidano G,
Carbone A,
Pastore C,
Capello D,
Migliazza A,
Gloghini A,
Roncella S,
Ferrarini M,
Saglio G,
Dalla-Favera R:
Frequent mutation of the 5 noncoding region of the BCL-6 gene in acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas.
Blood
89:3755,
1997[Abstract/Free Full Text]
12.
Carbone A,
Tirelli U,
Gloghini A,
Volpe R,
Boiocchi M:
Human immunodeficiency virus-associated systemic lymphomas may be subdivided into two main groups according to Epstein-Barr viral latent gene expression.
J Clin Oncol
11:1674,
1993[Abstract/Free Full Text]
13.
Hamilton-Dutoit SJ,
Pallesen G,
Franzmann MB,
Karkov J,
Black F,
Skinhøj P,
Pedersen C:
AIDS-related lymphoma. Histopathology, immunophenotype, and association with Epstein-Barr virus as demonstrated by in situ nucleic acid hybridization.
Am J Pathol
138:149,
1991[Abstract]
14.
MacMahon EME,
Glass JD,
Hayward SD,
Mann RB,
Becker PS,
Charache P,
McArthur JC,
Ambinder RF:
Epstein-Barr virus in AIDS-related primary central nervous system lymphoma.
Lancet
338:969,
1991[Medline]
[Order article via Infotrieve]
15.
Hamilton-Dutoit SJ,
Rea D,
Raphael M,
Sandvej K,
Delecluse HJ,
Gisselbrecht C,
Marelle L,
van Krieken JHJM,
Pallesen G:
Epstein-Barr virus-latent gene expression and tumor cell phenotype in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. Correlation of lymphoma phenotype with three distinct patterns of viral latency.
Am J Pathol
143:1072,
1993[Abstract]
16.
Carbone A,
Gaidano G,
Gloghini A,
Pastore C,
Saglio G,
Tirelli U,
Dalla-Favera R,
Falini B:
BCL-6 protein expression in AIDS-related non-Hodgkin's lymphomas.
Am J Pathol
150:155,
1997[Abstract]
17.
Ye BH,
Rao PH,
Chaganti RSK,
Dalla-Favera R:
Cloning of BCL-6, the locus involved in chromosome translocations affecting band 3q27 in B-cell lymphoma.
Cancer Res
53:2732,
1993[Abstract/Free Full Text]
18.
Ye BH,
Lista F,
Lo Coco F,
Knowles DM,
Chaganti RSK,
Dalla-Favera R:
Alterations of BCL-6, a novel zinc-finger gene, in diffuse large cell lymphoma.
Science
262:747,
1993[Abstract/Free Full Text]
19.
Baron BW,
Nucifora G,
McNabe N,
Espinosa R III,
Le Beau MM,
McKeithan TW:
Identification of the gene associated with the recurrent chromosomal translocations t(3;14)(q27;q32) and t(3;22)(q27;q11) in B-cell lymphomas.
Proc Natl Acad Sci USA
90:5262,
1993[Abstract/Free Full Text]
20.
Kerckaert J-P,
Deweindt C,
Tilly H,
Quief S,
Lecocq G,
Bastard C:
LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphoma.
Nature Genet
5:66,
1993[Medline]
[Order article via Infotrieve]
21.
Cattoretti G,
Chang CC,
Cechova K,
Zhang J,
Ye BH,
Falini B,
Louie DC,
Offit K,
Chaganti RS,
Dalla-Favera R:
BCL-6 protein is expressed in germinal-center B cells.
Blood
86:45,
1995[Abstract/Free Full Text]
22.
Dent AL,
Shaffer AL,
Yu X,
Allman D,
Staudt LM:
Control of inflammation, cytokine expression, and germinal center formation by BCL-6.
Science
276:589,
1997[Abstract/Free Full Text]
23.
Ye BH,
Cattoretti G,
Shen Q,
Zhang J,
Hawe N,
de Waard R,
Leung C,
Nouri-Shirazi M,
Orazi A,
Chaganti RS,
Rothman P,
Stall AM,
Pandolfi PP,
Dalla-Favera R:
The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation.
Nature Genet
16:161,
1997[Medline]
[Order article via Infotrieve]
24.
Bernfield M,
Kokenyesi R,
Kato M,
Spring J,
Gallo RL,
Lose EJ:
Biology of the syndecans: A family of transmembrane heparan sulfate proteoglycans.
Annu Rev Cell Biol
8:365,
1992
25.
Jalkanen M,
Elenius K,
Rapraeger A:
Syndecan: Regulator of cell morphology and growth factor action at the cell-matrix interface.
Trends Glycosci Glycotechnol
5:107,
1993
26.
Sanderson RD,
Lalor P,
Bernfield M:
B lymphocytes express and loose syndecan-1 at specific stages of differentiation.
Cell Regul
1:27,
1989[Medline]
[Order article via Infotrieve]
27.
Ridley RC,
Xiao H,
Hata H,
Woodliff J,
Epstein J,
Sanderson RD:
Expression of syndecan regulates human myeloma plasma cell adhesion to type I collagen.
Blood
81:767,
1993[Abstract/Free Full Text]
28.
Wijdenes J,
Voojis WC,
Clément C,
Post J,
Morard P,
Vita N,
Laurent P,
Sun R-X,
Klein B,
Dore J-M:
A plasmocyte selective monoclonal antibody (B-B4) recognizes syndecan-1.
Br J Haematol
94:318,
1996[Medline]
[Order article via Infotrieve]
29.
Carbone A,
Cilia AM,
Gloghini A,
Canzonieri V,
Pastore C,
Todesco M,
Cozzi M,
Perin T,
Volpe R,
Pinto A,
Gaidano G:
Establishment of HHV-8 positive and HHV-8 negative lymphoma cell lines from primary lymphomatous effusions.
Int J Cancer
73:562,
1997[Medline]
[Order article via Infotrieve]
30.
Cesarman E,
Moore PS,
Rao PH,
Inghirami G,
Knowles DM,
Chang Y:
In vitro establishment and characterization of two acquired immunodeficiency syndrome-related lymphoma cell lines (BC-1 and BC-2) containing Kaposi's sarcoma-associated herpesvirus-like (KSHV) DNA sequences.
Blood
86:2708,
1995[Abstract/Free Full Text]
31.
Gaidano G,
Cechova K,
Chang Y,
Moore PS,
Knowles DM,
Dalla-Favera R:
Establishment of AIDS-related lymphoma cell lines from lymphomatous effusions.
Leukemia
10:1237,
1996[Medline]
[Order article via Infotrieve]
32.
Renne R,
Zhong W,
Herndier B,
Kedes D,
McGrath M,
Ganem D:
Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in B cell lymphoma cells in culture.
Nature Med
2:342,
1996[Medline]
[Order article via Infotrieve]
33.
Arvanitakis L,
Mesri EA,
Nador RG,
Said JW,
Asch AS,
Knowles DM,
Cesarman E:
Establishment and characterization of primary effusion (body cavity-based) lymphoma cell line (BC-3) harboring Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) in the absence of Epstein-Barr virus.
Blood
88:2648,
1996[Abstract/Free Full Text]
34.
Hsu S-M,
Raine L,
Fanger H:
A comparative study of the peroxidase-antiperoxidase method and an avidin-biotin complex method for studying polypeptide hormones with radioimmunoassay antibodies.
Am J Clin Pathol
75:734,
1981[Medline]
[Order article via Infotrieve]
35.
Cordell JL,
Falini B,
Erber WN,
Ghosh AK,
Abdulaziz Z,
Macdonald S,
Pulford KAF,
Stein H,
Mason DY:
Immunoenzymatic labelling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal antialkaline phosphatase (APAAP complexes).
J Histochem Cytochem
32:219,
1984[Abstract]
36.
Flenghi L,
Ye BH,
Fizzotti M,
Bigerna B,
Cattoretti G,
Venturi S,
Pacini R,
Pileri S,
Lo Coco P,
Pescarmona E,
Pelicci P-G,
Dalla-Favera R,
Falini B:
A specific monoclonal antibody (PG-B6) detects expression of the BCL-6 protein in germinal center B cells.
Am J Pathol
147:405,
1995[Abstract]
37.
Falini B,
Bigerna B,
Pasqualucci L,
Fizzotti M,
Martelli MF,
Pileri S,
Pinto A,
Carbone A,
Venturi S,
Pacini R,
Cattoretti G,
Pescarmona E,
Lo Coco F,
Pelicci P-G,
Anagnastopoulos I,
Dalla-Favera R,
Flenghi L:
Distinctive expression pattern of the BCL-6 protein in nodular lymphocyte predominance Hodgkin's disease.
Blood
87:465,
1996[Abstract/Free Full Text]
38.
Miller SA,
Dykes DD,
Polesky HF:
A simple salting out procedure for extracting DNA from human nucleated cells.
Nucleic Acid Res
16:1215,
1988[Free Full Text]
39.
Migliazza A,
Martinotti S,
Chen W,
Fusco C,
Ye BY,
Knowles DM,
Offit K,
Chaganti RSK,
Dalla-Favera R:
Frequent somatic hypermutation of the 5 noncoding region of the bcl-6 gene in B-cell lymphoma.
Proc Natl Acad Sci USA
92:12520,
1995[Abstract/Free Full Text]
40.
Contreras-Broding BA,
Anvert M,
Imre S,
Altiok E,
Klein G,
Masucci MG:
B-cell phenotype dependent expression of the Epstein-Barr virus nuclear antigens EBNA-2 to EBNA-6: Studies with somatic cell hybrids.
J Gen Virol
72:3025,
1991[Abstract/Free Full Text]
41.
Sample J,
Brooks L,
Sample C,
Young L,
Rowe M,
Gregory C,
Rickinson A,
Kieff E:
Restricted Epstein-Barr virus protein expression in Burkitt lymphoma is reflected in a novel EBNA1 mRNA and transcriptional initiation site.
Proc Natl Acad Sci USA
88:6343,
1991[Abstract/Free Full Text]
42.
Schaefer BC,
Woisetschlager M,
Strominger JL,
Speck SH:
Exclusive expression of Epstein-Barr virus nuclear antigen 1 in Burkitt's lymphoma arises from a third promoter distinct from the promoters utilized in latently infected lymphocytes.
Proc Natl Acad Sci USA
88:6550,
1991[Abstract/Free Full Text]
43.
Rowe M,
Lear AL,
Croom-Carter D,
Davies AH,
Rickinson AB:
Three pathways of Epstein-Barr virus gene activation from EBNA-1 positive latency in B-lymphocytes.
J Virol
66:122,
1992[Abstract/Free Full Text]
44.
Klein G:
Role of EBV and Ig/myc translocation in Burkitt lymphoma.
Antibiot Chemother
46:110,
1994[Medline]
[Order article via Infotrieve]
45. (abstr)
Cattoretti G,
Zhang J,
Cleary AM,
Lederman S,
Gaidano G,
Carbone A,
Choganti RSK,
Dalla-Favera R:
Downregulation of BCL-6 gene expression by CD40 and EBV latent membrane protein-1 (LMP-1) and its block in lymphoma carrying BCL-6 rearrangements.
Blood
90:175a,
1997
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
A. Duverger, J. Jones, J. May, F. Bibollet-Ruche, F. A. Wagner, R. Q. Cron, and O. Kutsch
Determinants of the Establishment of Human Immunodeficiency Virus Type 1 Latency
J. Virol.,
April 1, 2009;
83(7):
3078 - 3093.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Gasperini, S. Sakakibara, and G. Tosato
Contribution of viral and cellular cytokines to Kaposi's sarcoma-associated herpesvirus pathogenesis
J. Leukoc. Biol.,
October 1, 2008;
84(4):
994 - 1000.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Shore, P. C. White, R. C.-Y. Hui, A. Essafi, E. W.-F. Lam, M. Rowe, and P. Brennan
Epstein-Barr Virus Represses the FoxO1 Transcription Factor through Latent Membrane Protein 1 and Latent Membrane Protein 2A
J. Virol.,
November 15, 2006;
80(22):
11191 - 11199.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Hoffmann, M. Tiemann, C. Schrader, D. Janssen, E. Wolf, M. Vierbuchen, R. Parwaresch, K. Ernestus, A. Plettenberg, A. Stoehr, et al.
AIDS-related B-cell lymphoma (ARL): correlation of prognosis with differentiation profiles assessed by immunophenotyping
Blood,
September 1, 2005;
106(5):
1762 - 1769.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Guidoboni, M. Ponzoni, L. Caggiari, A. A. Lettini, L. Vago, V. De Re, A. Gloghini, P. Zancai, A. Carbone, M. Boiocchi, et al.
Latent Membrane Protein 1 Deletion Mutants Accumulate in Reed-Sternberg Cells of Human Immunodeficiency Virus-Related Hodgkin's Lymphoma
J. Virol.,
February 15, 2005;
79(4):
2643 - 2649.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. T. Batchelor, B. R. Buchbinder, and N. L. Harris
Case 1-2005 - A 35-Year-Old Woman with Difficulty Walking, Headache, and Nausea
N. Engl. J. Med.,
January 13, 2005;
352(2):
185 - 194.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Panagopoulos, P. Victoratos, M. Alexiou, G. Kollias, and G. Mosialos
Comparative Analysis of Signal Transduction by CD40 and the Epstein-Barr Virus Oncoprotein LMP1 In Vivo
J. Virol.,
December 1, 2004;
78(23):
13253 - 13261.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. F. Little, S. Pittaluga, N. Grant, S. M. Steinberg, M. F. Kavlick, H. Mitsuya, G. Franchini, M. Gutierrez, M. Raffeld, E. S. Jaffe, et al.
Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology
Blood,
June 15, 2003;
101(12):
4653 - 4659.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Gyory, G. Fejer, N. Ghosh, E. Seto, and K. L. Wright
Identification of a Functionally Impaired Positive Regulatory Domain I Binding Factor 1 Transcription Repressor in Myeloma Cell Lines
J. Immunol.,
March 15, 2003;
170(6):
3125 - 3133.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Colomo, A. Lopez-Guillermo, M. Perales, S. Rives, A. Martinez, F. Bosch, D. Colomer, B. Falini, E. Montserrat, and E. Campo
Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma
Blood,
January 1, 2003;
101(1):
78 - 84.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Wang, Z. Li, A. Naganuma, and B. H. Ye
Negative autoregulation of BCL-6 is bypassed by genetic alterations in diffuse large B cell lymphomas
PNAS,
November 12, 2002;
99(23):
15018 - 15023.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. L. Carter, E. Cahir-McFarland, and E. Kieff
Epstein-Barr Virus-Induced Changes in B-Lymphocyte Gene Expression
J. Virol.,
September 11, 2002;
76(20):
10427 - 10436.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. V. Ablashi, L. G. Chatlynne, J. E. Whitman Jr., and E. Cesarman
Spectrum of Kaposi's Sarcoma-Associated Herpesvirus, or Human Herpesvirus 8, Diseases
Clin. Microbiol. Rev.,
July 1, 2002;
15(3):
439 - 464.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Gloghini, G. Gaidano, L. M. Larocca, F. Pierconti, A. Cingolani, L. Dal Maso, D. Capello, S. Franceschi, U. Tirelli, M. Libra, et al.
Expression of Cyclin-Dependent Kinase Inhibitor p27Kip1 in AIDS-Related Diffuse Large-Cell Lymphomas Is Associated with Epstein-Barr Virus-Encoded Latent Membrane Protein 1
Am. J. Pathol.,
July 1, 2002;
161(1):
163 - 171.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. W. B. Derksen, R. M. J. Keehnen, L. M. Evers, M. H. J. van Oers, M. Spaargaren, and S. T. Pals
Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma
Blood,
February 15, 2002;
99(4):
1405 - 1410.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Carbone, A. Gloghini, L. M. Larocca, D. Capello, F. Pierconti, V. Canzonieri, U. Tirelli, R. Dalla-Favera, and G. Gaidano
Expression profile of MUM1/IRF4, BCL-6, and CD138/syndecan-1 defines novel histogenetic subsets of human immunodeficiency virus-related lymphomas
Blood,
February 1, 2001;
97(3):
744 - 751.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Levine, L. Seneviratne, B. M. Espina, A. R. Wohl, A. Tulpule, B. N. Nathwani, and P. S. Gill
Evolving characteristics of AIDS-related lymphoma
Blood,
December 15, 2000;
96(13):
4084 - 4090.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Teitell, M. A. Damore, G. G. Sulur, D. E. Turner, M.-H. Stern, J. W. Said, C. T. Denny, and R. Wall
TCL1 oncogene expression in AIDS-related lymphomas and lymphoid tissues
PNAS,
August 17, 1999;
96(17):
9809 - 9814.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Carbone, A. Gloghini, L. M. Larocca, A. Antinori, B. Falini, U. Tirelli, R. Dalla-Favera, and G. Gaidano
Human Immunodeficiency Virus-Associated Hodgkin's Disease Derives From Post-Germinal Center B Cells
Blood,
April 1, 1999;
93(7):
2319 - 2326.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Carbone, A. Gloghini, G. Gaidano, S. Franceschi, D. Capello, H. G. Drexler, B. Falini, and R. Dalla-Favera
Expression Status of BCL-6 and Syndecan-1 Identifies Distinct Histogenetic Subtypes of Hodgkin's Disease
Blood,
October 1, 1998;
92(7):
2220 - 2228.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Larocca, D. Capello, A. Rinelli, S. Nori, A. Antinori, A. Gloghini, A. Cingolani, A. Migliazza, G. Saglio, S. Cammilleri-Broet, et al.
The Molecular and Phenotypic Profile of Primary Central Nervous System Lymphoma Identifies Distinct Categories of the Disease and Is Consistent With Histogenetic Derivation From Germinal Center-Related B Cells
Blood,
August 1, 1998;
92(3):
1011 - 1019.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract