{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:57:33Z","timestamp":1790143053447,"version":"4.0.1"},"reference-count":51,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5320","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[1997,6,20]]},"abstract":"<jats:p>Kaposi's sarcoma\u2013associated herpesvirus (KSHV) was found in the bone marrow dendritic cells of multiple myeloma patients but not in malignant plasma cells or bone marrow dendritic cells from normal individuals or patients with other malignancies. In addition the virus was detected in the bone marrow dendritic cells from two out of eight patients with monoclonal gammopathy of undetermined significance (MGUS), a precursor to myeloma. Viral interleukin-6, the human homolog of which is a growth factor for myeloma, was found to be transcribed in the myeloma bone marrow dendritic cells. KSHV may be required for transformation from MGUS to myeloma and perpetuate the growth of malignant plasma cells.<\/jats:p>","DOI":"10.1126\/science.276.5320.1851","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T09:45:50Z","timestamp":1027763150000},"page":"1851-1854","source":"Crossref","is-referenced-by-count":369,"title":["Kaposi's Sarcoma-Associated Herpesvirus Infection of Bone Marrow Dendritic Cells from Multiple Myeloma Patients"],"prefix":"10.1126","volume":"276","author":[{"given":"M. B.","family":"Rettig","sequence":"first","affiliation":[{"name":"M. B. Rettig, R. A. Vescio, J. R. Berenson, Division of Hematology and Oncology, Veterans Affairs West Los Angeles Medical Center, 11301 Wilshire Boulevard, 111-H, Los Angeles, CA 90073, USA, and Jonsson Comprehensive Cancer Center and Division of Hematology and Oncology, University of California Los Angeles School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA."},{"name":"H. J. Ma, M. Po\u0303ld, D. Belson, C. Wu, Division of Hematology and Oncology, Veterans Affairs West Los Angeles Medical Center, 11301 Wilshire Boulevard, 111-H, Los Angeles, CA 90073, USA."},{"name":"G. Schiller, A. Savage, C. Nishikubo, J. Fraser, Jonsson Comprehensive Cancer Center and Division of Hematology and Oncology, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA."},{"name":"J. W. Said, Jonsson Comprehensive Cancer Center and Department of Pathology, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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Wu, Division of Hematology and Oncology, Veterans Affairs West Los Angeles Medical Center, 11301 Wilshire Boulevard, 111-H, Los Angeles, CA 90073, USA."},{"name":"G. Schiller, A. Savage, C. Nishikubo, J. Fraser, Jonsson Comprehensive Cancer Center and Division of Hematology and Oncology, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA."},{"name":"J. W. Said, Jonsson Comprehensive Cancer Center and Department of Pathology, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Schiller","sequence":"additional","affiliation":[{"name":"M. B. Rettig, R. A. Vescio, J. R. 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Fraser, Jonsson Comprehensive Cancer Center and Division of Hematology and Oncology, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA."},{"name":"J. W. Said, Jonsson Comprehensive Cancer Center and Department of Pathology, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Savage","sequence":"additional","affiliation":[{"name":"M. B. Rettig, R. A. Vescio, J. R. Berenson, Division of Hematology and Oncology, Veterans Affairs West Los Angeles Medical Center, 11301 Wilshire Boulevard, 111-H, Los Angeles, CA 90073, USA, and Jonsson Comprehensive Cancer Center and Division of Hematology and Oncology, University of California Los Angeles School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA."},{"name":"H. J. Ma, M. Po\u0303ld, D. Belson, C. Wu, Division of Hematology and Oncology, Veterans Affairs West Los Angeles Medical Center, 11301 Wilshire Boulevard, 111-H, Los Angeles, CA 90073, USA."},{"name":"G. Schiller, A. Savage, C. Nishikubo, J. Fraser, Jonsson Comprehensive Cancer Center and Division of Hematology and Oncology, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA."},{"name":"J. W. Said, Jonsson Comprehensive Cancer Center and Department of Pathology, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Nishikubo","sequence":"additional","affiliation":[{"name":"M. B. Rettig, R. A. Vescio, J. R. 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Wu, Division of Hematology and Oncology, Veterans Affairs West Los Angeles Medical Center, 11301 Wilshire Boulevard, 111-H, Los Angeles, CA 90073, USA."},{"name":"G. Schiller, A. Savage, C. Nishikubo, J. Fraser, Jonsson Comprehensive Cancer Center and Division of Hematology and Oncology, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA."},{"name":"J. W. Said, Jonsson Comprehensive Cancer Center and Department of Pathology, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. W.","family":"Said","sequence":"additional","affiliation":[{"name":"M. B. Rettig, R. A. Vescio, J. R. 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W., Knowles D. M., N. Engl. J. Med. 332, 1186 (1995).","journal-title":"N. Engl. J. Med."},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7997879"},{"key":"e_1_3_1_8_3","unstructured":". The KS330 233 sequence represents a 233-bp fragment of the KS330 Bam region of KSHV. The KS330 Bam region was a sequence that was originally isolated from KS genomic DNA by representational difference analysis."},{"key":"e_1_3_1_9_2","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1056\/NEJM199607253350403","volume":"335","author":"Gao S.-J.","year":"1996","unstructured":"Gao S.-J., et al., N. Engl. J. Med. 335, 233 (1996).","journal-title":"N. Engl. J. Med."},{"key":"e_1_3_1_10_2","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1111\/j.1365-2141.1995.tb05410.x","volume":"91","author":"Pastore C.","year":"1995","unstructured":"Pastore C., et al., Br. J. Haematol. 91, 918 (1995).","journal-title":"Br. J. Haematol."},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5293.1739"},{"key":"e_1_3_1_12_2","unstructured":"Bone marrow aspirates were obtained from 23 patients with active multiple myeloma 10 normal donors for allogeneic bone marrow transplantation 12 non-Hodgkin's lymphoma patients 1 acute myelogenous leukemia patient 1 metastatic adenocarcinoma patient and 2 Hodgkin's disease patients. All specimens were obtained after informed consent and in compliance with the Human Subjects Protection Committee. Cytospins of fresh bone marrow mononuclear cells from the 23 multiple myeloma patients which were separated by Ficoll-Hypaque density sedimentation demonstrated 11 to 90% malignant plasma cells. Bone marrow mononuclear cells separated by Ficoll-Hypaque density sedimentation were used to establish long-term bone marrow stromal cell cultures as described ["},{"key":"e_1_3_1_12_3","doi-asserted-by":"crossref","first-page":"4756","DOI":"10.1073\/pnas.77.8.4756","volume":"77","author":"Gartner S. M.","year":"1980","unstructured":"Gartner S. M., Kaplan H. S., Proc. Natl. Acad. Sci. U.S.A. 77, 4756 (1980);","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_1_12_4","unstructured":"]. Bone marrow mononuclear cells were suspended in 10 ml of Iscove's modified Dulbecco's medium (Irvine Scientific Santa Ana CA) supplemented with 10% fetal calf serum (Gemini Bio-Products Calabasas CA) 10% horse serum (Gemini Bio-Products) 200 mM l -glutamine (Gemini Bio-Products) penicillin (100 U\/ml Irvine Scientific) and streptomycin (100 \u03bcg\/ml Irvine Scientific) in 75-cm 2 flasks (CoStar Cambridge MA). Cells were incubated at 37\u00b0C in a CO 2 incubator. The growth medium was changed every week. Once a confluent adherent cell monolayer developed the monolayer was washed three times with phosphate-buffered saline (PBS). The adherent bone marrow stromal cells were harvested with 0.5% trypsin in Hanks' buffered saline solution (Irvine Scientific) washed with PBS and collected by centrifugation."},{"key":"e_1_3_1_13_2","unstructured":"PCR was performed with 100 ng (\u223c15 000 cells worth) of genomic DNA from bone marrow stromal cells (see below) or bone marrow mononuclear cells the component of bone marrow that contains the malignant plasma cells. A total of 45 cycles of PCR amplification was performed on all samples to detect the KS330 233 sequence as described (7). The positive control was genomic DNA from the pleural effusion lymphoma cell line KS-1 (6) and the negative control was placental DNA (Stratagene La Jolla CA). PCR product (10 \u03bcl) was electrophoresed on a 1% agarose gel impregnated with ethidium bromide and then photographed. PCR with vIL-6 primers was performed in a similar fashion (10). PCR with \u03b2-actin primers (forward primer 5\u2032-TGACGGGGTCACCCACACTGTGCCCATCTA-3\u2032; reverse primer 5\u2032-CTAGAAGCATTTGCGGTGGACGATGGAGGG-3\u2032) was performed on all samples that were PCR-negative with the KS330 233 primers. The PCR amplification was repeated up to three times to assure the reproducibility of the results. Samples were also evaluated in a blinded fashion (the source of bone marrow stromal cells was unknown by the technician)."},{"key":"e_1_3_1_14_2","unstructured":"Southern (DNA) blot transfer was performed from the gel obtained from the PCR products. A 32 P end-labeled probe internal to the KS330 233 sequence was used for hybridization as described (7)."},{"key":"e_1_3_1_15_2","unstructured":"The KS330 233 PCR product was cloned into the pCR 2.1 vector (Invitrogen San Diego CA) and sequenced with the Sequenase Version 2.0 Sequencing Kit (Amersham Life Science Cleveland OH) according to the manufacturers' instructions."},{"key":"e_1_3_1_16_2","unstructured":"M. B. Rettig et al. data not shown."},{"key":"e_1_3_1_17_2","unstructured":"Serial paraffin sections were mounted on glass slides deparaffinized and immersed in 3% hydrogen peroxide to quench endogenous peroxidase activity. After proteinase digestion for 30 min at 37\u00b0C slides were incubated sequentially with 10% paraformaldehyde solution for 5 min at room temperature and with glycine solution at 37\u00b0C for 5 min. The slides were then dehydrated and air-dried and a cover slip was applied and then heated at 95\u00b0C for 4 min to denature viral DNA. Sections were incubated for 18 hours at 37\u00b0C with a biotinylated probe diluted 1:100 to 1:300 in 50% formamide 2\u00d7 standard saline citrate (SSC) Denhardt's solution dextrose sulfate and salmon sperm DNA. The probe was in sense orientation with the following sequence: 5\u2032- T GCAGCAGC T GT T GGTG T ACCACATC T ACT-3\u2032; T denotes biotinylated thymidine. The sequence of this probe was identical to that of the probe used for Southern blotting except for the addition of 5 bp to the 3\u2032 end (7). Slides were then washed in tris-buffered saline and 0.02% SDS and incubated with a monoclonal mouse antibody to biotin (Dako Carpinteria CA) followed by horseradish peroxidase\u2013conjugated rabbit antibody to mouse and goat antibody to rabbit immunoglobulins (Dako). The reaction product was visualized by means of the diaminobenzidene reaction. To determine if in situ hybridization signals were from specific hybridization to DNA and RNA we pretreated slides with RNase (1 mg\/ml) (DNase-free Sigma St. Louis MO) and DNase (1 mg\/ml) (RNase-free Boehringer Mannheim Indianapolis IN)."},{"key":"e_1_3_1_18_2","unstructured":"After trypsinization bone marrow stromal cells were pelleted and fixed with formalin. Pellets were embedded in paraffin and then sectioned. Staining for CD31 CD34 CD68 CD1a CD83 vimentin and lysozyme was performed on deparaffinized sections with monoclonal antibodies (all antibodies were from Dako Carpinteria CA except antibody to CD83 which was from Immunotech Marseille France) by using immunoperoxidase methods as described [J. Ho et al. Appl. Immunohistochem. 2 282 (1994)]. Staining for fascin was performed as described ["},{"key":"e_1_3_1_18_3","first-page":"543","volume":"150","author":"Pinkus G. S.","year":"1997","unstructured":"Pinkus G. S., et al., Am. J. Pathol. 150, 543 (1997)].","journal-title":"Am. J. Pathol."},{"key":"e_1_3_1_19_2","first-page":"593","volume":"148","author":"Moseiglos G.","year":"1996","unstructured":"Moseiglos G., et al., Am. J. Pathol. 148, 593 (1996);","journal-title":"Am. J. Pathol."},{"key":"e_1_3_1_19_3","doi-asserted-by":"crossref","first-page":"3821","DOI":"10.4049\/jimmunol.154.8.3821","volume":"154","author":"Zhou L.-J.","year":"1995","unstructured":"Zhou L.-J., Tedder T. F., J. Immunol. 154, 3821 (1995).","journal-title":"J. Immunol."},{"key":"e_1_3_1_20_2","unstructured":"Cells were fixed in glutaraldehyde pelleted and embedded for electron microscopy as described ["},{"key":"e_1_3_1_20_3","doi-asserted-by":"crossref","first-page":"4937","DOI":"10.1182\/blood.V87.12.4937.bloodjournal87124937","volume":"87","author":"Said J. W.","year":"1996","unstructured":"Said J. W., et al., Blood 87, 4937 (1996);","journal-title":"Blood"},{"key":"e_1_3_1_20_4","unstructured":"]. Ultrathin sections were stained with uranyl acetate and lead citrate and examined in a transmission electron microscope (JEOL Peabody MA)."},{"key":"e_1_3_1_21_2","unstructured":"Total RNA was prepared with RNAzol (TelTest Friendswood TX) according to the manufacturer's instructions. First-strand synthesis was performed at 42\u00b0C for 1 hour with 5 \u03bcg of total RNA. PCR was done in 200 \u03bcM for each deoxynucleotide triphosphate and 5 pmol of each vIL-6 primer (7). The PCR sequence was as follows: 44 cycles at 58\u00b0C for 1 min 72\u00b0C for 1.5 min 94\u00b0C for 1 min with a 5-min initial denaturation at 95\u00b0C and a final 5-min elongation step. PCR product (10 \u03bcl) was electrophoresed on a 1% agarose gel impregnated with ethidium bromide and then photographed. The expected PCR product is 695 bp. RT-PCR with \u03b2-actin primers (12) was performed on samples (3 \u03bcg of total RNA) that were RT-PCR negative with the vIL-6 primers."},{"key":"e_1_3_1_22_2","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/0002-9343(78)90522-3","volume":"64","author":"Kyle R. A.","year":"1978","unstructured":"Kyle R. A., Am. J. Med. 64, 814 (1978);","journal-title":"Am. J. Med."},{"key":"e_1_3_1_22_3","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1111\/j.1365-2141.1992.tb08245.x","volume":"81","author":"Blade J.","year":"1992","unstructured":"Blade J., et al., Br. J. Haematol. 81, 391 (1992);","journal-title":"Br. J. Haematol."},{"key":"e_1_3_1_22_4","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/0090-1229(78)90024-7","volume":"10","author":"Lindstr\u00f6m F. D.","year":"1978","unstructured":"Lindstr\u00f6m F. D., Dahlstr\u00f6m U., Clin. Immunol. Immunopathol. 10, 168 (1978);","journal-title":"Clin. Immunol. Immunopathol."},{"key":"e_1_3_1_22_5","first-page":"123","volume":"80","author":"Paladini G.","year":"1989","unstructured":"Paladini G., et al., Recenti Prog. Med. 80, 123 (1989).","journal-title":"Recenti Prog. Med."},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.185.5.941"},{"key":"e_1_3_1_24_2","unstructured":"We thank A. Lichtenstein for critical comments G. S. Pinkus and J. L. Pinkus for assistance with fascin staining and T. Moss (BIS Laboratories Reseda CA) for providing relevant samples. Supported by funds from the Veterans Administration."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.276.5320.1851","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T06:12:19Z","timestamp":1705126339000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.276.5320.1851"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,6,20]]},"references-count":51,"journal-issue":{"issue":"5320","published-print":{"date-parts":[[1997,6,20]]}},"alternative-id":["10.1126\/science.276.5320.1851"],"URL":"https:\/\/doi.org\/10.1126\/science.276.5320.1851","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,6,20]]}}}