Dynamic and nonspecific dispersal of human T-cell leukemia/lymphoma virus type-I integration in cultured lymphoma cells

Seigel, Leonard J.; Nash, William G.; Poiesz, Bernard J.; Moore, Janet; O’Brien, Stephen J.

doi:10.1016/0042-6822(86)90430-7

Cited by 16 publications

(13 citation statements)

References 34 publications

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“…Previous studies have shown that primary HTLV-1 induced T-cell tumors generally have a single integrated provirus but that during propagation in tissue culture, the number of integrations can increase significantly (50,51). Whether these extra integrations influence cell line evolution and/or cell growth in culture is unclear.…”

Section: Resultsmentioning

confidence: 97%

High-Throughput RNA Sequencing-Based Virome Analysis of 50 Lymphoma Cell Lines from the Cancer Cell Line Encyclopedia Project

Cao¹,

Strong²,

Wang³

et al. 2015

J Virol

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Using high-throughput RNA sequencing data from 50 common lymphoma cell culture models from the Cancer Cell Line Encyclopedia project, we performed an unbiased global interrogation for the presence of a panel of 740 viruses and strains known to infect human and other mammalian cells. This led to the findings of previously identified infections by Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), and human T-lymphotropic virus type 1 (HTLV-1). In addition, we also found a previously unreported infection of one cell line (DEL) with a murine leukemia virus. High expression of murine leukemia virus (MuLV) transcripts was observed in DEL cells, and we identified four transcriptionally active integration sites, one being in the TNFRSF6B gene. We also found low levels of MuLV reads in a number of other cell lines and provided evidence suggesting crosscontamination during sequencing. Analysis of HTLV-1 integrations in two cell lines, HuT 102 and MJ, identified 14 and 66 transcriptionally active integration sites with potentially activating integrations in immune regulatory genes, including interleukin-15 (IL-15), IL-6ST, STAT5B, HIVEP1, and IL-9R. Although KSHV and EBV do not typically integrate into the genome, we investigated a previously identified integration of EBV into the BACH2 locus in Raji cells. This analysis identified a BACH2 disruption mechanism involving splice donor sequestration. Through viral gene expression analysis, we detected expression of stable intronic RNAs from the EBV BamHI W repeats that may be part of long transcripts spanning the repeat region. We also observed transcripts at the EBV vIL-10 locus exclusively in the Hodgkin's lymphoma cell line, Hs 611.T, the expression of which were uncoupled from other lytic genes. Assessment of the KSHV viral transcriptome in BCP-1 cells showed expression of the viral immune regulators, K2/vIL-6, K4/vIL-8-like vCCL1, and K5/E2-ubiquitin ligase 1 that was significantly higher than expression of the latency-associated nuclear antigen. Together, this investigation sheds light into the virus composition across these lymphoma model systems and provides insights into common viral mechanistic principles. IMPORTANCEViruses cause cancer in humans. In lymphomas the Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV) and human T-lymphotropic virus type 1 are major contributors to oncogenesis. We assessed virus-host interactions using a high throughput sequencing method that facilitates the discovery of new virus-host associations and the investigation into how the viruses alter their host environment. We found a previously unknown murine leukemia virus infection in one cell line. We identified cellular genes, including cytokine regulators, that are disrupted by virus integration, and we determined mechanisms through which virus integration causes deregulation of cellular gene expression. Investigation into the KSHV transcriptome in the BCP-1 cell line revealed high-level expression of immune signaling genes. EBV transcriptome analysis sh...

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Section: Resultsmentioning

confidence: 97%

High-Throughput RNA Sequencing-Based Virome Analysis of 50 Lymphoma Cell Lines from the Cancer Cell Line Encyclopedia Project

Cao¹,

Strong²,

Wang³

et al. 2015

J Virol

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“…Combined with the recent reports of Kubota et al (1996) on HTLV-I LTR-driven expression of the IL-9 receptor in the MT-2 line and Bamford et al (1996) on the IL-15 gene in HuT-102 cells, our results suggest that a subset of HTLV-I-mediated transforming events may occur via a promoter insertion mechanism in which a retroviral LTR drives expression of a cellular gene. This hypothesis is supported by the fact that most ATL cells contain a HTLV-I provirus integrated in a monoclonal pattern (Kettman et al, 1982;Van den Broeke et al, 1988), even though proviruses in dierent individual tumors are found to be integrated in diverse regions of the host genome Seigel et al, 1986). Such insertional activation events might target a small but diverse group of cellular genes critical to cellular regulation in the mature T-lymphocyte, the general target for HTLV-I integration, and proposed precursor to HTLV-I-related malignancy (cutaneous T-cell lymphoma and adult T-cell leukemia-lymphoma).…”

Section: Discussionmentioning

confidence: 69%

“…Curiously, the pX region of the provirus, encoding the Tax transactivator is invariably retained (Korber et al, 1991), despite the fact that the end-stage tumor cells rarely express Tax RNA or protein, possibly due to methylation of the proviral LTR (Saggioro et al, 1990). Although the pX region and the downstream LTR are invariably conserved even in deleted proviruses, few studies have considered the possibility that this LTR might function to drive downstream cellular genes, probably because of early and in¯uential ®ndings failing to ®nd a common HTLV-I integration site in ATL tumor cells Seigel et al, 1986). Our results show that integration of the HTLV-I provirus into the PDGF b-receptor gene results in à proviral-cellular' hybrid gene whose expression is regulated by the 3'-LTR.…”

Section: Discussionmentioning

confidence: 99%

“…viral oncogene(s), with nucleic acid homology to normal cellular sequences, proto-oncogene(s) (Shimotohno et al, 1984). Moreover, the sites of proviral integration vary from tumor to tumor Seigel et al, 1986), and this has suggested that the transforming ability of HTLV-I is mediated by the viral transactivator protein Tax which can activate cellular genes involved in cell proliferation (Sodroski et al, 1984(Sodroski et al, , 1985Felber et al, 1985). One mechanism postulated to account for the transforming potential of HTLV-I on T-cells is an autocrine loop involving interleukin-2 (IL-2) and IL-2-receptor (IL-2R) expressed in cells cultured from ATL patients (Depper et al, 1984;Umadome et al, 1988;Marriott et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Integration of proviral DNA into the PDGF β-receptor gene in HTLV-I-infected T-cells results in a novel tyrosine kinase product with transforming activity

et al. 1997

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We have previously shown that noninfected human T-cell lines express the canonical 5.7 kb mRNA coding for the type b platelet-derived growth factor-receptor (PDGF breceptor), whereas HTLV-I-infected T-cell lines express a novel PDGF b-receptor mRNA of 3.8 kb. In this report, we have extended those studies to molecularly characterize the 3.8 kb PDGF b-receptor mRNA and show that it has resulted from integration of an apparently undeleted HTLV-I provirus into the PDGF b-receptor gene in an orientation enabling expression of a truncated PDGF b-receptor mRNA using the 3' HTLV-I long terminal repeat as a promoter. Further, NIH3T3 cells transfected with a plasmid containing the truncated PDGF b-receptor ORF plasmid generate colonies in soft agar with more cells per colony than untransfected cells, or cells transfected with the Tax 1 or PDGF-B (c-sis) plasmids. These results indicate that the truncated PDGF b-receptor protein acquires transforming capability and that HTLV-I-induced truncation of PDGF b-receptor may correlate with HTLV-I-associated neoplasia of human T-cells.

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“…The HTLV-1 virus integrates in the DNA genome of CD4-positive lymphocytes [2,3]. The locus of integration is variable from patient to patient and there may be multiple copies of integrated virus per cell [4,5]. The activation of the "tat" gene increases the production of the IL-2 receptor, which in turn increases the infected T-cell population within 4 to 6 weeks, initially in a polyclonal fashion.…”

mentioning

confidence: 99%

Prevalence of Anti-HTLV-1 Antibodies in Sera from 153 Cases of Non-Hodgkin's Lymphoma

et al. 1990

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Dynamic and nonspecific dispersal of human T-cell leukemia/lymphoma virus type-I integration in cultured lymphoma cells

Cited by 16 publications

References 34 publications

High-Throughput RNA Sequencing-Based Virome Analysis of 50 Lymphoma Cell Lines from the Cancer Cell Line Encyclopedia Project

High-Throughput RNA Sequencing-Based Virome Analysis of 50 Lymphoma Cell Lines from the Cancer Cell Line Encyclopedia Project

Integration of proviral DNA into the PDGF β-receptor gene in HTLV-I-infected T-cells results in a novel tyrosine kinase product with transforming activity

Prevalence of Anti-HTLV-1 Antibodies in Sera from 153 Cases of Non-Hodgkin's Lymphoma

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