Abstract
Primary effusion lymphoma (PEL) represents a peculiar type of B cell lymphoma which associates with HHV-8 infection and preferentially grows in liquid phase in the serous body cavities. In this report, we provide the detailed characterization of a newly established PEL cell line, termed CRO-AP/6. The cell line was obtained from the pleural effusion of a HIV-positive patient with PEL. Its derivation from the tumor clone was established by immunogenotypic analysis. Detailed phenotypic investigations defined that CRO-AP/6 reflects pre-terminally differentiated B cells expressing the CD138/syndecan-1 antigen. Karyotypic studies of CRO-AP/6 identified several chromosomal abnormalities, whereas genotypic studies ruled out the involvement of molecular lesions associated with other types of B cell lymphoma. Both CRO-AP/6 and the parental tumor sample harbored infection by HHV-8. Conversely, EBV infection was present in the parental tumor sample although not in CRO-AP/6, indicating that CRO-AP/6 originated from the selection of an EBV-negative tumor subclone. The pattern of viral (HHV-8 v-cyclin) and cellular (p27Kip1) regulators of cell cycle expressed by CRO-AP/6, together with the results of growth fraction analysis, point to abrogation of the physiological inverse relationship between proliferation and p27Kip1 expression. Also, both CRO-AP/6 and the parental tumor sample display biallelic inactivation of the DNA repair enzyme gene O6-methylguanine-DNA methyltransferase (MGMT) by promoter methylation. Overall, the CRO-AP/6 cell line may help understand cell cycle control of PEL cells, may clarify the relative contribution of HHV-8 and EBV to the disease growth and development and may facilitate the identification of recurrent cytogenetic abnormalities highlighting putative novel cancer related loci relevant to PEL.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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 New Engl J Med 1995 332: 1186–1191
Jaffe ES . Primary body cavity-based AIDS-related lymphomas. Evolution of a new disease entity Am J Clin Pathol 1996 105: 141–143
Nador R, Cesarman E, Chadburn A, Dawson DB, Ansari MQ, Said J, Knowles DM . Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus Blood 1996 88: 645–656
Carbone A, Gaidano G . HHV-8 positive body cavity-based lymphoma: a novel lymphoma entity Br J Haematol 1997 97: 515–522
Karcher DS, Alkan S . Human herpesvirus-8-associated body cavity-based lymphoma in human immunodeficiency virus-infected patients: a unique B cell neoplasm Hum Pathol 1997 28: 801–808
Komanduri KV, Luce JA, McGrath MS, Herndier BG, Ng VL . The natural history and molecular heterogeneity of HIV-associated primary malignant lymphomatous effusions J Acq Imm Def Syn 1996 13: 215–226
Morassut S, Vaccher E, Balestreri L, Gloghini A, Gaidano G, Volpe R, Tirelli, U, Carbone A . HIV-associated HHV-8 positive primary lymphomatous effusions: radiological findings in six patients Radiology 1997 205: 459–463
Gaidano G, Pastore C, Gloghini A, Cusini M, Nomdedeu J, Volpe G, Capello D, Vaccher E, Bordes R, Tirelli U, Saglio G, Carbone A . Distribution of human herpesvirus-8 sequences throughout the spectrum of AIDS-related neoplasia AIDS 1996 10: 941–949
Otsuki T, Kumar S, Ensoli B, Kingma DW, Yano T, Stetler-Stevenson M, Jaffe ES, Raffeld M . Detection of HHV-8/KSHV DNA sequences in AIDS-associated extranodal lymphoid malignancies Leukemia 1996 10: 1358–1362
Gessain A, Briere J, Angelin-Duclos C, Valensi F, Beral HM, Davi F, Nicola MA, Sudaka A, Fouchard N, Babarre J, Troussard X, Dulmet E, Audouin J, Diebold J, de The G . Human herpes virus 8 (Kaposi's sarcoma herpesvirus) and malignant lymphoproliferations in France: a molecular study of 250 cases including two AIDS-associated body cavity based lymphomas Leukemia 1997 11: 266–272
Uphoff CC, Habig S, Carbone A, Gaidano G, Drexler HG . HHV-8 infection is specific for cell lines derived from primary effusion (body cavity-based) lymphomas Leukemia 1998 12: 1806–1809
Dotti G, Fiocchi R, Motta T, Facchinetti B, Chiodini B, Borleri GM, Gavazzeni G, Barbui T, Rambaldi A . Primary effusion lymphoma after heart transplantation: a new entity associated with human herpesvirus-8 Leukemia 1999 13: 664–670
Chang Y, Moore PS, Talbot SJ, Boshoff C, Zarkowska T, Godden-Kent D, Paterson H, Weiss RA, Mittnacht S . Cyclin encoded by KS herpesvirus Nature 1996 382: 410
Davis MA, Stürzl M, Blasig C, Schreier A, Guo H-G, Reitz M, Opalenik SR, Browning PJ . Expression of human herpesvirus 8-encoded cyclin D in Kaposi's sarcoma spindle cells J Natl Cancer Inst 1997 24: 1868–1874
Boshoff C . Kaposi's sarcoma associated herspesvirus Cancer Surveys, Volume 33: Infections and Human Cancer Imperial Cancer Research Fund: London 1998 pp 157–190
Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A . p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest Genes Dev 1994 8: 9–22
Toyoshima H, Hunter T . p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21 Cell 1994 78: 67–74
Sherr CJ . Cancer cell cycles Science 1996 274: 1672–1677
Ansari MQ, Dawson DB, Nador R, Rutherford C, Schneider NR, Latimer, MJ, Picker L, Knowles DM, Mckenna RW . Primary body cavity-based AIDS-related lymphomas Am J Clin Pathol 1996 105: 221–229
Gaidano G, Capello D, Cilia AM, Gloghini A, Perin T, Quattrone S, Migliazza A, Lo Coco F, Saglio G, Ascoli A, Carbone A . Genetic characterization of HHV-8/KSHV-positive primary effusion lymphoma reveals frequent mutations of BCL6: implications for disease pathogenesis and histogenesis Gene Chromosome Cancer 1999 24: 16–23
Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG . Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia Cancer Res 1999 59: 793–797
Singal R, Ginder GD . DNA methylation Blood 1999 93: 4059–4070
Horenstein MG, Nador RG, Chadburn A, Hyjek EM, Inghirami G, Knowles DM, Cesarman E . Epstein–Barr virus latent gene expression in primary effusion lymphomas containing Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 Blood 1997 90: 1186–1191
Carbone A, Gaidano G, Gloghini A, Larocca LM, Capello D, Canzonieri V, Antinori A, Tirelli U, Falini B, Dalla-Favera R . Differential expression of BCL-6, CD138/syndecan-1 and EBV-encoded latent membrane protein-1 identifies distinct histogenetic subsets of acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas Blood 1998 91: 747–755
Drexler HG, Uphoff CC, Gaidano G, Carbone A . Lymphoma cell lines: in vitro models for the study of HHV-8 primary effusion lymphomas (body cavity-based lymphomas) Leukemia 1998 12: 1507–1517
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 1997 73: 562–569
Carbone A, Cilia AM, Gloghini A, Capello D, Todesco M, Quattrone S, Volpe R, Gaidano G . Establishment and characterization of EBV-positive and EBV-negative primary effusion lymphoma cell lines harbouring human herpesvirus type-8 Br J Haematol 1998 102: 1081–1089
Drexler HG, Meyer C, Gaidano G, Carbone A . Constitutive cytokine production by primary effusion (body cavity-based) lymphoma-derived cell lines Leukemia 1999 13: 634–640
De Paoli P, Cozzi M, Tedeschi RM, Gloghini A, Cilia AM, van Kooten C, Gaidano G, Carbone A . High CD40 membrane expression in AIDS-related lymphoma B cell lines is associated with the CD45RA+, CD45RO+, CD95+ phenotype and high levels of its soluble form in culture supernatans Cytometry 1997 30: 33–38
ISCN . An International System for Human Cytogenetic Nomenclature. Mitelman F (ed) S Karger: Basel 1995
Pinkel D, Straume T, Gray JW . Cytogenetic analysis using quantitative, high-sensitivity, fluorescence hybridization Proc Natl Acad Sci USA 1986 83: 2934–2938
Miller SA, Dykes, DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells Nucleic Acids Res 1988 16: 1215
Boshoff C, Schulz TF, Kennedy MM, Graham AK, Fisher C, Thomas A, McGee JO'D, Weiss RA, O'Leary JJ . Kaposi's sarcoma-associated herpesvirus infects endothelial and spindle cells Nature Med 1995 1: 1274–1278
Gaidano G, Parsa NZ, Tassi V, Della-Latta P, Chaganti RSK, Knowles DM, Dalla-Favera R . In vitro establishment of AIDS-related lymphoma cell lines: phenotypic characterization, oncogene and tumor suppressor gene lesions, and heterogeneity in Epstein–Barr virus infection Leukemia 1993 7: 1621–1629
Fassone L, Bhatia K, Gutierrez M, Capello D, Gloghini A, Dolcetti R, Vivenza D, Ascoli V, Lo Coco F, Pagani L, Dotti G, Rambaldi A, Raphael M, Tirelli U, Saglio G, Magrath IT, Carbone A, Gaidano G . Molecular profile of Epstein–Barr virus infection in HHV-8 positive primary effusion lymphoma Leukemia 2000 14: 271–277
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 1981 75: 734–738
Drexler HG, Matsuo Y . Guidelines for the characterization and publication of human malignant hematopoietic cell lines Leukemia 1999 13: 853–842
Gaidano, G, Gloghini A, Gattei V, Rossi MF, Cilia AM, Godeas C, Degan M, Perin T, Canzonieri V, Aldinucci D, Saglio G, Carbone A, Pinto A . Association of KSHV positive primary effusion lymphoma with expression of the CD138/syndecan-1 antigen Blood 1997 90: 4894–4900
Sánchez-Beato M, Sáez AI, Martínez-Montero JC, Mateo MS, Sánchez-Verde L, Villuendas R, Troncone G, Piris MA . Cyclin dependent kinase inhibitor p27KIP1 in lymphoid tissue. p27KIP1 expression is inversely proportional to the proliferative index Am J Pathol 1997 151: 151–160
Erlanson M, Portin C, Linderholm B, Lindh J, Roos G, Landberg G . Expression of cyclin E and the cyclin-dependent kinase inhibitor p27 in malignant lymphomas. Prognostic implications Blood 1998 92: 770–777
Quintanilla-Martinez L, Thieblemont C, Fend F, Kumar S, Pinyol M, Campo E, Jaffe ES, Raffeld M . Mantle cell lymphomas lack expression of p27Kip1 a cyclin-dependent kinase inhibitor Am J Pathol 1998 153: 175–182
Sánchez-Beato M, Camacho FI, Martínez-Montero JC, Sáez AI, Villuendas R, Sánchez-Verde L, García JF, Piris MA . Anomalous high p27/KIP1 expression in a subset of aggressive B cell lymphomas is associated with cyclin D3 overexpressison. p27/KIP1-cyclin D3 colocalization in tumor cells Blood 1999 94: 765–772
Carbone A, Gloghini A, Bontempo D, Monini P, Tirelli U, Volpe R, Browning PJ, Gaidano G . Proliferation in HHV-8 positive primary effusion lymphoma is associated with expression of HHV-8 cyclin but independent of p27Kip1 Am J Pathol 2000 156: 1209–1215
Swanton C, Mann DJ, Fleckenstein B, Neipel F, Peters G, Jones N . Herpes viral cyclin/cdk6 complexes evade inhibition by CDK inhibitor proteins Nature 1997 390: 184–187
Katano H, Hoshino Y, Morishita Y, Nakamura T, Satoh H, Iwamoto A, Herndier B, Mori S . Establishing and characterizing a CD30-positive cell line harboring HHV-8 from a primary effusion lymphoma J Med Virol 1999 58: 394–401
Sakumi K, Shiraishi A, Shimizu S, Tsuzuki T, Ishikawa T, Sekiguchi M . Methylnitrosourea-induced tumorigenesis in MGMT gene knockout mice Cancer Res 1997 57: 2415–2418
Acknowledgements
We wish to thank Fulvio Coletto for photographic assistance and Barbara Canal, Paola Ceolin and Ivana Zanette for excellent technical assistance in immunohistochemistry experiments and in situ hybridization studies. This work was supported by Istituto Superiore di Sanità, II Programma Nazionale di Ricerca sull'AIDS – Progetto Patologia, Clinica e Terapia dell'AIDS, Rome, Italy, Fondazione ‘Piera Pietro e Giovanni Ferrero’, Alba, Italy, and ‘Fondazione CRT’, Torino, Italy. DC is being supported by a fellowship from FIRC, Milan, Italy. LF is being supported by the PhD program in Molecular Medicine of the Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
Note
CRO-AP/6 cell line is available upon request.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Carbone, A., Cilia, A., Gloghini, A. et al. Characterization of a novel HHV-8-positive cell line reveals implications for the pathogenesis and cell cycle control of primary effusion lymphoma. Leukemia 14, 1301–1309 (2000). https://doi.org/10.1038/sj.leu.2401802
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2401802
Keywords
This article is cited by
-
Recruitment of the tumour suppressor protein p73 by Kaposi’s Sarcoma Herpesvirus latent nuclear antigen contributes to the survival of primary effusion lymphoma cells
Oncogene (2013)
-
Malignant lymphomas (ML) and HIV infection in Tanzania
Journal of Experimental & Clinical Cancer Research (2008)
-
A requirement for NF-κB induction in the production of replication-competent HHV-8 virions
Oncogene (2004)
-
Disruption of the B-cell specific transcriptional program in HHV-8 associated primary effusion lymphoma cell lines
Oncogene (2003)
-
Point mutations of the BCL-6 gene: clinical and prognostic correlation in B-diffuse large cell lymphoma
Leukemia (2002)