Characterization of a novel HHV-8-positive cell line reveals implications for the pathogenesis and cell cycle control of primary effusion lymphoma.
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 CROAP/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.
Divisions of Pathology, Centro di Riferimento Oncologico, IRCCS, Istituto Nazionale Tumori, Aviano, Italy.
A
A
Carbone
A M
AM
Cilia
A
A
Gloghini
D
D
Capello
L
L
Fassone
T
T
Perin
D
D
Rossi
V
V
Canzonieri
P
P
De Paoli
E
E
Vaccher
U
U
Tirelli
R
R
Volpe
G
G
Gaidano
D000328:Adult; D000956:Antigens, Viral / Q000096:biosynthesis / Q000235:genetics; D002453:Cell Cycle; D002869:Chromosome Aberrations; D002999:Clone Cells / Q000473:pathology / Q000821:virology; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D019175:DNA Methylation; D004789:Enzyme Activation; D020031:Epstein-Barr Virus Infections / Q000473:pathology / Q000821:virology; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D016147:Genes, Tumor Suppressor; D006566:Herpesviridae Infections / Q000235:genetics / Q000473:pathology* / Q000821:virology; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000302:isolation & purification / Q000472:pathogenicity; D019288:Herpesvirus 8, Human / Q000276:immunology / Q000302:isolation & purification / Q000472:pathogenicity*; D006801:Humans; D016130:Immunophenotyping; D016483:Lymphoma, AIDS-Related / Q000209:etiology / Q000235:genetics / Q000473:pathology* / Q000821:virology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000473:pathology / Q000821:virology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016066:Pleural Effusion, Malignant / Q000235:genetics / Q000473:pathology* / Q000821:virology; D011401:Promoter Regions, Genetic; D011519:Proto-Oncogenes; D014407:Tumor Cells, Cultured / Q000821:virology*; D014412:Tumor Virus Infections / Q000235:genetics / Q000473:pathology* / Q000821:virology; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics; D017735:Virus Latency
D000956:Antigens, Viral; D016213:Cyclins; D009363:Neoplasm Proteins; D014764:Viral Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase