Control of Cell Cycle Entry and Apoptosis in B Lymphocytes Infected by Epstein-Barr Virus

Spender, Lindsay C.; Cannell, Emma; Hollyoake, Martine; Wensing, Barbara; Gawn, Jonathan M.; Brimmell, Matthew; Packham, Graham; Farrell, Paul J.

doi:10.1128/jvi.73.6.4678-4688.1999

Cited by 62 publications

(18 citation statements)

References 77 publications

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“…However, some patterns seem to emerge as to the impact of EBV infection on cellular gene expression, which are congruent with our results. EBNA2 is the first EBV gene to be detected after infection and at 72 hr postinfection we previously measured expression of most latency‐associated EBV genes, in good agreement with that we found differential expression of validated EBNA2 targets such as CDK2, 4 and 6, and EBNA1 target genes such as BIRC5 . The fact that we find no EBNA3 or LMP1 target genes suggests that the impact of these proteins on cellular gene expression is less pronounced at 72 hr after infection.…”

Section: Discussionsupporting

confidence: 90%

Early gene expression changes by Epstein‐Barr virus infection of B‐cells indicate CDKs and survivin as therapeutic targets for post‐transplant lymphoproliferative diseases

Bernasconi

Ueda

Krukowski

et al. 2013

Intl Journal of Cancer

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Lymphoproliferative diseases (LPDs) associated with Epstein-Barr virus (EBV) infection cause significant morbidity and mortality in bone marrow and solid organ transplant recipients. To gain insight into LPD pathogenesis and to identify potential effective therapeutic approaches, we investigated early molecular events leading to B-cell transformation by gene expression profiling of EBV-infected B-cells from tonsils by Affymetrix microarray 72 hr postinfection when the B-cells hyperproliferation phase starts. Cell cycle and apoptosis were the most significantly affected pathways and enriched gene sets. In particular, we found significantly increased expression of cyclin-dependent kinase (CDK)1 and CCNB1 (cyclin B1) and of one of their downstream targets BIRC5 (survivin). Importantly, the strong upregulation of the antiapoptotic protein survivin was confirmed in lymphoblastoid cell lines (LCLs) and 71% of EBV-positive post-transplant EBV-LPD lesions scored positive for survivin. The validity of early transforming events for the identification of therapeutic targets for EBV-LPD was confirmed by the marked antiproliferative effect of the CDK inhibitor flavopiridol on LCLs and by the strong induction of apoptosis by survivin inhibition with YM155 or terameprocol. Our results suggest that targeting of CDKs and/or survivin in post-transplant EBV-LPD by specific inhibitors might be an important approach to control and eliminate EBV-transformed B-cells that should be further considered.Lymphoproliferative disease (LPD) associated with the B-cell tropic Epstein-Barr virus (EBV) causes significant morbidity and mortality in solid organ transplant (SOT) 1 or bone marrow transplant (BMT) 2 recipients. The risk to develop EBV-LPD is greatest in EBV-seronegative transplant recipients, i.e., upon primary EBV infection, and in patients with extensive iatrogenic immunosuppression. 3 EBV-associated B-cell lymphoma in the setting of post-transplant LPD (PTLD) is

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Section: Discussionsupporting

confidence: 90%

Early gene expression changes by Epstein‐Barr virus infection of B‐cells indicate CDKs and survivin as therapeutic targets for post‐transplant lymphoproliferative diseases

Bernasconi

Ueda

Krukowski

et al. 2013

Intl Journal of Cancer

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“…Although Gutierrez et al (1999) suggested that defects in Bax might contribute to FAS resistance in BL, and we and others have identified Bax mutations in BL cell lines (Brimmell et al, 1998;Meijerink et al, 1998;Gutierrez et al, 1999), the expression of Bax and other Bcl-2 family proteins did not correlate with TRAIL sensitivity (Spender et al, 1999). Other potential mechanisms of resistance that might account for TRAIL resistance include altered expression of other regulatory molecules, such as death-associated protein 3 (DAP3) (Miyazaki & Reed, 2001).…”

Section: Discussionmentioning

confidence: 63%

Regulation of tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced apoptosis in Burkitt's lymphoma cell lines

Mouzakiti

Packham

2003

Br J Haematol

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Summary. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in sensitive cells and may be suitable for novel anti-cancer therapies aimed at inducing apoptosis via the activation of TRAIL receptors on malignant cells. Here we have characterized the TRAIL sensitivity of a panel of Burkitt's lymphoma (BL) cell lines. Overall, 5/12 BL cell lines and 1/2 lymphoblastoid cell lines were sensitive to TRAIL-induced apoptosis, although only one BL cell line approached the sensitivity of Jurkat cells, a widely used model for TRAILinduced apoptosis. Whereas, 4/5 of the Epstein-Barr virus (EBV)-negative cell lines were TRAIL sensitive, only 1/7 EBV-positive BL cell lines were TRAIL sensitive. However, isogenic BL cell lines with different EBV status were not differently sensitive to TRAIL, indicating that EBV is not a major determinant of TRAIL sensitivity. All cell lines expressed the death receptor (DR)5 TRAIL receptor, whereas expression of DR4 was more variable. Differences in the expression of downstream signalling molecules [Fasassociated death domain protein (FADD), caspase 8] and inhibitors [decoy receptor 1 (DcR1), cellular FLICE-like inhibitory protein (c-FLIP)] did not correlate with TRAIL sensitivity. Therefore, a subset of BL cell lines are sensitive to TRAIL-induced apoptosis, however, the molecular mechanism that determines responsiveness remains to be identified.

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“…Cell isolation, culture and infection with EBV. Primary B cells were isolated from mixed-donor platelet-depleted buffy coat residues (North London Blood Transfusion Service) by positive selection, using anti-CD19 monoclonal antibody (mAb)-coated magnetic beads (M450 pan-B Dynabeads and Detachabeads (Dynal)) as described previously (Cannell et al, 1996;Spender et al, 1999). Flow cytometric analysis was performed using fluorescein isothiocyanate (FITC)-conjugated anti-CD20 mAbs (Dako) to monitor cell purity.…”

Section: Methodsmentioning

confidence: 99%

Proliferation and differentiation in isogenic populations of peripheral B cells activated by Epstein–Barr virus or T cell-derived mitogens

O’Nions

Allday

2004

Journal of General Virology

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Human B cells isolated from peripheral blood were activated and induced to proliferate by either Epstein-Barr virus (EBV) or the T cell-derived mitogens CD40 ligand (CD40L) plus interleukin (IL)-4. Although both populations initially proliferated as B-blasts, significant differences were revealed over a longer period. EBV infection resulted in continuously proliferating lymphoblastoid cell lines (LCLs), whereas most of the CD40L/IL-4-stimulated B cells had a finite proliferative lifespan of 3-4 weeks. Cell cycle analysis, trypan blue staining and Western blot analysis for cleavage of poly(ADP-ribose) polymerase (PARP) all demonstrated that the decrease in proliferation in CD40L/IL-4-stimulated B cells is not due to cell death. Instead, these cells arrest, accumulate in G 0 /G 1 and undergo alterations in cell surface marker expression, cellular morphology and immunoglobulin production, all consistent with plasmacytoid differentiation. In contrast, B cells infected with EBV continued to proliferate and retained a blast-like phenotype. Differences in both cytokine production and the expression of cell cycle regulators were identified between the two B-cell populations, which might contribute to the differentiation of the CD40L/IL-4-stimulated B cells and suggest potential mechanisms by which EBV may overcome this. The study has also identified a window of opportunity during which a comparison of isogenic populations of EBV-and mitogen-driven B blasts can be made. INTRODUCTIONThe B-cell compartment in peripheral blood consists of quiescent naïve (70-80 %) and memory (20-30 %) B cells (Agematsu, 2000;Klein et al., 1997Klein et al., , 1998. In vitro, EpsteinBarr virus (EBV) has the ability to infect resting primary B cells, driving them into the cell cycle and sustaining their proliferation as continuously growing, B-blast-like, lymphoblastoid cell lines (LCLs) (Henle et al., 1967;Kieff & Rickinson, 2001;Pope, 1967). LCLs have been extensively studied to identify the mechanisms utilized by EBV in B-cell transformation; however, comparison with proliferating normal B cells is required to dissect EBV-specific effects on cell cycle entry and proliferation. In vivo, CD4+ T cells, activated by specific antigen, express CD40 ligand (CD40L/CD154) (Armitage et al., 1992;Casamayor-Palleja et al., 1995; Lane et al., 1992;Noelle et al., 1992), which binds to CD40 on B cells. This interaction, in concert with B cell receptor (BCR) cross-linking and the action of T cell-derived cytokines interleukin (IL)-2, IL-5 and particularly IL-4, stimulates B-cell activation and proliferation (Croft & Swain, 1991;Gordon & Pound, 2000;Lohoff et al., 1992). CD40L is also a critical mediator of B-cell differentiation (Gordon & Pound, 2000;Schonbeck & Libby, 2001;van Kooten & Banchereau, 2000), which either involves formation of a germinal centre, producing either plasma cells (PCs) or memory cells, or direct differentiation of naïve B cells into PCs (Staudt & Brown, 2000). EBV is thought to mimic T cell-derived signals to stimulate B-cell proli...

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Control of Cell Cycle Entry and Apoptosis in B Lymphocytes Infected by Epstein-Barr Virus

Cited by 62 publications

References 77 publications

Early gene expression changes by Epstein‐Barr virus infection of B‐cells indicate CDKs and survivin as therapeutic targets for post‐transplant lymphoproliferative diseases

Early gene expression changes by Epstein‐Barr virus infection of B‐cells indicate CDKs and survivin as therapeutic targets for post‐transplant lymphoproliferative diseases

Regulation of tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced apoptosis in Burkitt's lymphoma cell lines

Proliferation and differentiation in isogenic populations of peripheral B cells activated by Epstein–Barr virus or T cell-derived mitogens

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