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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1482-1486
RAPID COMMUNICATION
Detection of Kaposi's Sarcoma Herpesvirus DNA Sequences in Multiple
Myeloma Bone Marrow Stromal Cells
By
Dharminder Chauhan,
Ajit Bharti,
Noopur Raje,
Eric Gustafson,
Geraldine S. Pinkus,
Jack L. Pinkus,
Gerrard Teoh,
Teru Hideshima,
Steve P. Treon,
Joyce D. Fingeroth, and
Kenneth C. Anderson
From the Department of Adult Oncology, Dana-Farber Cancer Institute
and the Department of Medicine, Harvard Medical School; the Department
of Pathology, Brigham and Womens Hospital, and the Department of
Pathology, Harvard Medical School, Boston, MA.
 |
ABSTRACT |
Whether Kaposi's sarcoma herpesvirus (KSHV) is associated with
multiple myeloma (MM) remains controversial. We assayed for KSHV DNA
sequences in long-term bone marrow stromal cells (BMSCs) from 26 patients with MM and 4 normal donors. Polymerase chain reaction (PCR)
using primers which amplify a KSHV gene sequence to yield a 233-bp
fragment (KS330233 within open reading frame 26) was
negative in all cases. Aliquots of these PCR products were used as
templates in subsequent nested PCR, with primers that amplify a 186-bp
product internal to KS330233. BMSCs from 24 of 26 (92%)
patients with MM and 1 of 4 normal donors were KSHV PCR+.
DNA sequence analyses showed interpatient specific mutations (2 to 3 bp). Both Southern blot and sequence analyses confirmed the specificity
of PCR results. The presence of the KSHV gene sequences was further
confirmed by amplifying T 1.1 (open reading frame [ORF]
K7) and viral cyclin D (ORF 72), two other domains within the KSHV
genome. Immunohistochemical studies of KSHV PCR+ MM BMSCs
demonstrate expression of dendritic cell (DC) lineage markers (CD68,
CD83, and fascin). Serological studies for the presence of KSHV lytic
or latent antibodies were performed using sera from 53 MM patients, 12 normal donors, and 5 human immunodeficiency virus
(HIV)/KSHV+ patients. No lytic or latent antibodies were
present in sera from either MM patients or normal donors. Taken
together, these findings show that KSHV DNA sequences are detectable in
BMSCs from the majority of MM patients, but that serologic responses to
KSHV are not present. Ongoing studies are defining whether the lack of
antibody response is caused by the absence of ongoing infection, the
presence of a novel viral strain associated with MM, or underlying
immunodeficiency in these patients.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
WHETHER KAPOSI'S SARCOMA herpesvirus
(KSHV) is associated with multiple myeloma (MM), and if present,
whether it is of pathophysiologic significance or merely an
epiphenomenon, remains controversial. Although early studies did not
detect KSHV in MM cells,1 Rettig et al2 showed
that bone marrow stromal cells (BMSCs), but not MM cells themselves,
are infected with KSHV.2 These studies are consistent with
prior observations that MM cells themselves are not infected with
KSHV,1 and suggest the possibility that KSHV may promote
the growth and/or survival of tumor cells in a paracrine
mechanism by secretion of cytokines, ie, viral interleukin-6
(vIL-6),3 from infected BMSCs. However, to date only three
groups have shown KSHV DNA within BM biopsy specimens from MM
patients,4-6 whereas multiple other groups have not
confirmed an association of KSHV with MM. Specifically, investigators
from France, England, Italy, and the United States have not found
antibodies to KSHV in sera from MM patients despite humoral responses
to other herpesviruses,7-12 and other investigators using
polymerase chain reaction (PCR) have failed to detect KSHV DNA in
either freshly isolated bone marrow mononuclear cells
(BMMCs),9,13 BMSCs,10 or BM biopsy
samples14 from patients with MM.
In the present study, we assayed for KSHV DNA sequences in long-term
BMSCs from 26 patients with MM and 4 normal donors. PCR using primers
that detect KSHV gene sequence (KS330233)15 was negative; however, subsequent nested PCR using primers that amplify sequences internal to KS330233 to yield a final PCR product
of 186 bp was positive in 24 of 26 (92%) patients with MM and 1 of 4 normal donors. Southern blotting analyses and gene sequence analysis
confirmed specificity of PCR results. Moreover, PCR amplification of T
1.1 and viral cyclin D regions in the KSHV genome further confirmed the
presence of KSHV gene sequences in MM BMSCs. However, serological
analyses showed lack of either KSHV lytic or latent antibodies in MM
patients as well as normal donors. Therefore, our studies demonstrate
that KSHV gene sequences are detectable in MM BMSCs in the absence of a
serological response.
| |
MATERIALS AND METHODS |
Preparation of long-term BMSC cultures.
After appropriate informed consent and under the auspices of an
Insitutional Review Board approved protocol, Ficoll Hypaque (Pharmacia
Biotech, Inc, Piscataway, NJ) BMMCs were freshly obtained from 26 patients with MM and 4 normal donors, obtained at the time of BM
harvest for allografting. BMMCs were cultured for 2 to 6 weeks in
Iscove's media (Sigma Diagnostics, St Louis, MO) with 10% fetal
bovine serum (FBS, Sigma), 10% horse serum (Sigma), and
penicillin/streptomycin (pen/strep; GIBCO-BRL, Gaithersburg, MD) to
generate long-term BMSC cultures, as previously described.2 Adherent layers were trypsinized and assayed for presence of KSHV DNA,
as well as cell-surface phenotype.
PCR assays for KSHV sequences.
DNA was prepared using the Easy-DNA kit per manufacturer's
instructions (Invitrogen, Carlsbad, CA). Genomic DNA was extracted from
freshly isolated MM BMMCs and normal BMMCs, from 3- to 6-week-old MM
BMSC and normal BMSC cultures. To increase the specificity of PCR, the
DNA was amplified in a two-step PCR, first with outer primers and then
with inner primers nested within the first primers.16,17 PCR with nested primers has been used to detect HIV-1 in tumor cell
lines and in clinical samples.16,18 We first performed PCR
using primers that recognize and amplify a region within the KSHV gene
sequence to yield a 233-bp fragment (KS330233), as
previously described.15 An aliquot from the first PCR
amplification product was used as template in a subsequent nested PCR
using primers (forward primer, 5'-CTC GAA TCC AAC GGA TTT GA-3';
reverse primer, 5'-ATA TGT GCG CCC CAT AAA TG-3') that recognize
sequences internal to this 233-bp fragment to yield a final PCR product
of 186 bp. The thermal cycling conditions, similar for both the initial
and nested PCR reactions, were as follows: 95°C for 3 minutes (1 cycle); 94°C for 1 minute, 60°C for 1 minute, 72°C for 1 minute
(45 cycles); 72°C extension for 5 minutes (1 cycle). Each PCR
reaction uses 500 ng to 800 ng of genomic DNA, and 30 pmol of each
primer. The PCR reactions were performed in Ready-To-Go PCR beads
(Pharmacia Biotech AB, Uppsala, Sweden) with a final volume of 25 µL
reaction mixture, and amplifications performed in a Perkin-Elmer 480 Thermocycler (Applied Biosystems, Foster City, CA). Fifteen microliters
of the PCR product was analyzed on 1.5% agarose gels containing
ethidium bromide and photographed under UV light. Genomic DNA from body cavity-based lymphoma (BCBL)-1 cell line infected with
KSHV19 served as a positive control for the detection of
KSHV gene sequences. PCR with  -actin primers was
performed on all samples to assure quality of genomic DNA.
A similar nested PCR approach was used to amplify viral cyclin D (open
reading frame [ORF] 72) with previously described primer sets and
thermal cycling conditions.20 In addition, genomic DNA from
MM patients was also assayed for another gene unique to KSHV,
designated ORF K7 or T1.1. For T1.1 (ORF K7), the outer primer set was
5' CTT GCC GCT TCT GGT TTT CA 3' as forward primer and 5' CAC CAG TGG
GCG CTG CTT CTT TC 3' as backward primer; the inner primer set was 5'
CTT GCC GCT TCT GGT TTT CA 3' as forward primer and 5' GGC GCT GCT TTC
CTT TCA CA 3' as backward primer.21-23 The thermal cycling
conditions were as follows: 95°C for 3 minutes (1 cycle); 94°C for
1 minute, 62°C for 1 minute, and 72°C for 1 minute (45 cycles); and
72°C extension for 5 minutes (1 cycle).
Southern blot analyses and DNA sequencing of PCR products.
Southern blot analyses were performed to confirm the specificity of
PCR. The PCR products observed in the agarose gels were transferred
onto nitrocellulose filter membranes which were then hybridized to a
32P end-labeled 25-bp oligomer probe internal to the
KS330233 sequence (5' TGC AGC AGC TGT TGG TGT ACC ACA T),
as previously described.15 Filters were washed and exposed
to Kodak X-O mat XAR film (Eastman Kodak, Rochester, NY) using an
intensifying screen. The autoradiograms were scanned using the LKB
Produkter (LKB, Bromma, Sweden) ultrascan XL laser densitometer and
analyzed with a Gelscan XL software package (LKB). DNA
sequencing of the 186-bp nested PCR product was performed on 7 KSHV+ MM samples. The nested PCR products obtained after
amplification of viral cyclin D and T1.1 regions were also purified and
sequenced from 4 and 2 MM patients, respectively.
Phenotypic analysis.
Immunohistochemical staining was performed on cytosmears prepared from
long-term MM BMSCs using monoclonal antibodies (MoAbs) reactive with B
(CD20  ,  , and CD38), T (CD3), monocytoid (CD14 and CD68),
hematopoietic progenitor (CD34), as well as dendritic (CD83 and
fascin)24,25 cell lineage.
Serologic assays.
Serological studies for KSHV lytic and latent antibodies were performed
by using KSHV enzyme-linked immunosorbent assay (ELISA) and
immunofluorescent assay (IFA), as previously
described.26,27 Sera from patients with classic KS served
as a positive control.
| |
RESULTS AND DISCUSSION |
KSHV DNA sequence is detectable in MM BMSCs.
Ficol-Hypaque BMMCs were freshly obtained from 26 patients with MM and
4 normal donors and cultured for 2 to 6 weeks in Iscove's media.
Adherent layers were trypsinized and assayed for presence of KSHV DNA
sequence by PCR amplification of extracted DNA with primers that detect
KSHV gene sequences (KS330233).15 No
KS330233 was detectable in these samples. Aliquots from
these PCR amplification products were used as templates for nested PCR
with a second set of primers that recognize sequences internal to
KS330233 to yield a final PCR product of 186 bp.
KSHV-specific amplicons were demonstrable in BMSCs from 24 of 26 (92%)
patients with MM and 1 of 4 normal donors, but were not detected in
freshly isolated BMMCs from 4 MM patients. Representative results in
BMSCs from 12 MM patients and 2 normal donors are shown in Fig
1A. Genomic DNA from BCBL-1 cell line
infected with KSHV19 served as a positive control for the
detection of KSHV gene sequences (Fig 1A, lane 1). KSHV DNA was evident
in long-term BMSCs from 10 of 12 patients with MM (lanes 4 through 13),
including those 4 cases (lanes 7, 8, 12, and 13) in which fresh MM
BMMCs were negative for KSHV by nested PCR. In contrast, KSHV DNA was
absent in BMSCs from 2 MM patients (lanes 14 and 15) and 2 normal
donors (lanes 2 and 3). Amplification with -actin-specific primers
confirmed DNA in each lane (Fig 1B).
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| Fig 1.
KSHV DNA sequence (ORF 26) is detectable in MM BMSCs.
Ficoll Hypaque BMMCs were freshly obtained from 26 patients with MM and
4 normal donors and cultured for 2 to 6 weeks in Iscove's media with
10% FBS, 10% horse serum, and penicillin/streptomycin to generate
long-term BMSC cultures. Adherent layers were trypsinized and assayed
for presence of KSHV DNA sequence. (A) DNA from long-term BMSCs from 12 patients with MM and 2 normal donors were assayed by PCR using primers
that amplify KSHV gene sequences (KS330233) followed by
nested PCR using primers designed to recognize sequences internal to
KS330233 to yield a final PCR product of 186 bp. DNA from
BCBL-1 cell line (lane 1) served as a positive control for the
detection of KSHV gene sequences and DNA obtained from normal BMSCs
(lanes 2 and 3) as a negative control; MM patient BMSCs are shown in
lanes 4 through 15. (B) Amplification with -actin specific primers
confirmed DNA in each lane. (C) To confirm the specificty of PCR,
nested PCR products were transferred onto nitrocellulose filters.
Southern blot analysis was performed by hybridizing the filters with a
32P end-labeled 25-bp oligomer probe internal to the
KS330233 sequence.
|
|
The specificty of nested PCR product was determined by Southern blot
analyses. The results showed reactivity in lanes 4 through 13 and lack
of reactivity in lanes 2, 3, 14, and 15, confirming our PCR results
(Fig 1C). To confirm KSHV gene sequences, we purified the 186-bp nested
PCR product from 7 MM patient samples and performed DNA sequencing,
using either forward or reverse primers. The DNA sequences from all 7 patients demonstrated 92% to 96% homology to sequences (1030 bp to
1177 bp) present within the KS330 Bam fragment of KSHV
genome.15 Interpatient specific mutations were observed
among these patients, which reaffirms the lack of PCR contamination. In
addition, two different regions of the KSHV genome, ORF 72 (viral cylin
D) and ORF K7 (T 1.1), were also amplified by nested PCR in DNA of
BMSCs from MM patients and normal donors (Fig 2A and 2B,
respectively). ORF 72 encodes
for a functional cyclin D homolog with 31% identity to cellular cyclin
D which is also found in Herpesvirus saimiri. Viral cyclin D is capable of phosphorylating the retinoblastoma protein and is known to be
expressed in latency. ORF K7 or T1.1 is among the 15 different genes
(K1-15) that are unique to KSHV. The results showed PCR positivity for
both of these genes in MM patient DNA samples, whereas normal BMSCs
were PCR negative. Moreover, sequence analyses of PCR products showed
97% homology to known KSHV sequence and demonstrated patient specific
mutations.
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| Fig 2.
KSHV DNA sequences viral cyclin D (ORF 72) and T1.1 (ORF
K7) are detectable in MM BMSCs. (A) DNA from long-term BMSCs from 4 patients with MM (lanes 2 through 5) and 2 normal donors (lanes 6 and
7) were assayed by nested PCR to amplify viral cyclin D (ORF 72) KSHV
gene sequence. DNA from BCBL-1 cell line (lane 1) served as a positive
control and water (H2O) (lane 8) served as control for
nested PCR contamination. (B) DNA from long-term BMSCS from 2 patients
with MM (lanes 2 and 3) and 2 normal donors (lanes 5 and 6) were
assayed by nested PCR to amplify T1.1 (ORF K7). DNA from BCBL-1 cell
line (lane 1) served as a positive control and water (H2O)
(lane 4) served as a control for nested PCR contamination.
|
|
Our data are consistent with the prior reports2,4,5 that MM
BMSCs are KSHV PCR+. Moreover, our results are in concert
with other studies showing that MM cells themselves are not infected
with KSHV,1,2,9 since KSHV DNA was not detected in freshly
isolated MM BMMCs. In contrast, our results differ from those of Masood
et al,10 who failed to detect KSHV DNA in long-term BMSCs
from patients with MM. It is possible that MM BMSCs examined in this
study were uninfected, or alternatively, that negative PCR results were
due to a lack of sensitivity of the single-step PCR methodology. In the
present study, we also did not detect KSHV DNA by PCR using primers to
amplify KS330233,15 and therefore used aliquots
from the first PCR amplification product as templates for nested PCR with internal primers. With this nested PCR strategy, KSHV sequences were demonstrable in the majority (24 of 26) of MM BMSCs.
Morphologic and phenotypic profile of MM BMSCs with detectable KSHV
gene sequences.
To identify the lineage of the KSHV PCR+ cell within BMSCs,
immunohistochemical staining was performed on cytosmears prepared from
these long-term MM BMSCs using MoAbs reactive with B (CD20, ,
, and CD38), T (CD3), monocytoid (CD14 and CD68),
hematopoietic progenitor (CD34), and dendritic (CD83 and fascin)
lineage cells. Immunohistochemical studies (indirect immunoperoxidase
or immunoalkaline phosphatase techniques) of the dominant large BMSCs
are summarized in Table 1. These cells
strongly expressed CD68, CD83, and fascin, but lacked and chain, CD20, CD3, CD14, and CD34 expression. Ill-defined cytoplasmic
staining for CD38 of uncertain significance was observed. The
population of smaller mononuclear cells, generally less than 5% to
10% of the cell population, included rare cells reactive for CD3 or
CD14 and rare or small numbers of cells reactive for or light
chains, CD20, and CD38; these cells lacked CD68, CD83, and fascin.
Double-marker studies for CD20 and fascin verified the presence of two
distinct cell populations: a dominant fascin-positive population
consistent with DCs, and a very minor population of cells of B lineage
by virtue of CD20 staining. However, it is important to note that
fascin is expressed on Reed-Sternberg cells25 and can be
induced by EBV on B cells.28 These findings are in concert
with prior reports2 that KSHV PCR+ MM BMSCs are
of DC lineage.
Although MM cells do not appear to be infected in the present and
previous studies,1,2 it is nonetheless of interest to note
that KSHV has been isolated from CD19+ B cells of normal
blood donors.29 In MM, several lines of evidence show the
existence of CD19+ clonotypic B cells30;
however, these CD19+ cells comprise a minor population in
which detection of viral infection may be difficult. Importantly, we
and others have shown in prior studies that CD40 ligand (CD40L)
stimulation of MM cells expands these CD19+ MM cells and
triggers IL-6 secretion.31-33 Therefore, in ongoing studies
we are activating MM cells in vitro using CD40L to facilitate assay of
CD19+ malignant cells for the presence of KSHV sequences by
nested PCR. Moreover, because human IL-6 was previously used to
activate normal CD19+ B cells and thereby enhance
sensitivity of KSHV detection,29 induction of IL-6 related
to CD40 activation of MM cells may also aid in detection of virus in
tumor cells. Thus, the precise lineage(s) of cells with detectable KSHV
sequences within MM BMSCs remains under investigation.
Seroprevalence of KSHV antibodies in MM patient and normal donor
sera.
Serological studies were performed by using KSHV ELISA and
immunofluorescent assay to latent antigens (LANA), as previously described.26,27 The ELISA studies for the presence of KSHV lytic antibodies were performed in the laboratory of Dr D.V.
Ablashi (Advanced Biotechnologies, Columbia, MD) and the
LANA in the laboratory of Dr C. Boshoff (Chester Beatty Laboratory
Cancer Research Institute, London, UK) on sera from 53 MM patients, 12 normal donors, and 5 HIV/KSHV+ patients. No lytic or latent
antibodies were detectable in sera of MM patients or normal donors,
whereas sera from HIV/KSHV patients showed detectable antibody titers
to KSHV. Multiple groups have failed to demonstrate a serological
response to KSHV in patients with MM, as is true in our studies, and
concluded on this basis that KSHV is not associated with
MM.7-12 Based on the lack of serological response to KSHV
and the absence of an epidemiological link between MM and KS, these
investigators have concluded that there is no association between KSHV
and MM. However, given the studies demonstrating KSHV gene sequences in
MM BMSCs now emanating from UCLA,2,4 France,5,6
and our laboratory, this conclusion may be premature. First, the
absence of humoral response to KSHV may truly reflect a lack of
infection in some MM patients. Secondly, it may be that assays used in
our and other negative studies do not adequately detect antibodies. In
this regard, a recent report used ORF 65 and latent nuclear antigen
(LNA) immunoblotting to show antibodies to ORF 65 and to LNA in 81%
and 52% of MM patients, respectively.34 These results need
to be confirmed using these assays to study larger numbers of MM
patients. Alternatively, a specific lack of humoral response to KSHV
with preserved response to other herpesviruses in KSHV may occur in
KSHV infected MM patients. Finally and most likely, it may be that
epitopes on KSHV which are immunogenic in other settings, ie, KS
patients, do not trigger detectable immune response in MM due to the
presence of different strains of KSHV in these clinical settings. In
this regard, a recent report has amplified ORF 26 in MM BMSCs and some
normal donor BMSCs using nested PCR, but failed to amplify ORF 72 and ORF 75, suggesting the presence of a related (KS330-containing) virus.35
In summary, the present results show (1) that KSHV gene sequences are
detectable in the majority of MM BMSCs; (2) that KSHV+ MM
BMSCs express DC lineage antigens, and (3) a lack of KSHV seropostivity
despite the presence of KSHV gene sequences in MM patient BMSCs.
Although these data show that KSHV gene sequences are evident in the
majority of MM BMSCs and less commonly in normal BMSCs, whether there
is infection with BMSC in MM, and whether biologically active KSHV gene
products play a role in MM pathogenesis, is presently unknown and the
object of ongoing studies.
| |
FOOTNOTES |
Submitted October 2, 1998; accepted November 24, 1998.
Supported by National Institutes of Health Grants No. CA50947 and
CA78378, and the Kraft Family Research Fund.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Kenneth C. Anderson, MD, Dana-Farber Cancer
Institute, 44 Binney St, Boston, MA 02215;
e-mail:kenneth_anderson{at}dfci.harvard.edu.
| |
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Abstract
Introduction