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.
Carbone
A
A
Divisions of Pathology, Centro di Riferimento Oncologico, IRCCS, Istituto Nazionale Tumori, Aviano, Italy.
Cilia
A M
AM
Gloghini
A
A
Capello
D
D
Fassone
L
L
Perin
T
T
Rossi
D
D
Canzonieri
V
V
De Paoli
P
P
Vaccher
E
E
Tirelli
U
U
Volpe
R
R
Gaidano
G
G
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