Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4281-4288 ◽  
Author(s):  
Andreas Höglund ◽  
Lisa M. Nilsson ◽  
Linus Plym Forshell ◽  
Kirsteen H. Maclean ◽  
Jonas A. Nilsson
Keyword(s):  
Tumor Cells ◽  
Dna Methyltransferase ◽  
Epstein Barr Virus ◽  
Caspase Activation ◽  
Myc Oncogene ◽  
Barr Virus ◽  
Mouse Embryo Fibroblasts ◽  
G2 Block ◽  
Epstein Barr

Abstract Decitabine (also referred to as 5-aza-2′-deoxycytidine) is a drug that has recently been approved by the Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome (MDS). The mechanism of action is believed to be the blocking of DNA methylation and thereby reactivating silenced genes involved in harnessing MDS. When analyzing reactivation of genes involved in Burkitt lymphoma (BL), we discovered that decitabine also sensitizes tumor cells by inducing DNA damage. This sensitization is grossly augmented by the MYC oncogene, which is overexpressed in BL, and occurs in cells lacking a functional p53 tumor suppressor pathway. In p53-deficient BL cells and p53−/− mouse embryo fibroblasts, Myc overrides a transient G2-block exerted by decitabine via activation of Chk1. This triggers aneuploidy and cell death that correlates with, but can occur in the absence of, Epstein-Barr virus (EBV) reactivation, caspase activation, and/or expression of the BH3-only protein Puma. In vivo modeling of Myc-induced lymphoma suggests that decitabine constitutes a potential new drug against lymphoma that would selectively sensitize tumor cells but spare normal tissue.

scholarly journals Epstein-Barr Virus (EBV)-Specific Cytotoxic T Lymphocytes for the Treatment of Patients With EBV-Positive Relapsed Hodgkin's Disease

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2925-2934 ◽  
Author(s):  
Marie A. Roskrow ◽  
Nobuhiro Suzuki ◽  
Yan-jun Gan ◽  
John W. Sixbey ◽  
Catherine Y.C. Ng ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cytotoxic T Lymphocytes ◽  
Hodgkin's Disease ◽  
Epstein Barr Virus ◽  
Hodgkin’S Disease ◽  
Barr Virus ◽  
Specific Ctls ◽  
Epstein Barr ◽  
Relapsed Disease

Adoptive transfer of Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) is effective prophylaxis and treatment of EBV-positive immunoblastic lymphoma in immunocompromised patients. In 50% of patients with Hodgkin's disease, the tumor cells are EBV antigen-positive and may therefore also be suitable targets for treatment with virus-specific CTLs. However, Hodgkin's disease may produce several inhibitory effects on immune induction and effector function in vivo, which may preclude the generation or effector function of CTLs reactive against EBV viral proteins, including those expressed by the tumor cells. We have investigated whether EBV-specific CTLs could be generated ex vivo from 13 patients with Hodgkin's disease: nine with active relapsed disease and four who were in clinical remission after a first or subsequent relapse. CTL lines were successfully generated from nine of 13 patients (five active disease, four remission). Although these lines had an abnormal pattern of expansion comparable to EBV-specific CTLs generated from normal donors, their phenotype was normal except for reduced expression of the zeta chain of the T-cell receptor (TCR). Their cytotoxicity was also compared to EBV-specific lines generated from normal donors and included activity against LMP2a, one of the three weakly immunogenic viral antigens expressed by Hodgkin's tumor cells. To assess the activity of the CTLs in vivo, they were gene-marked and infused into three patients with multiply relapsed disease. The CTLs persisted for more than 13 weeks postinfusion and retained their potent antiviral effects in vivo, thereby enhancing the patient immune response to EBV. This approach may therefore have value in the treatment of EBV-positive Hodgkin's disease.

scholarly journals Heterogeneous expression of Epstein-Barr virus latent proteins in endemic Burkitt's lymphoma

Blood ◽  
1995 ◽  
Vol 86 (2) ◽  
pp. 659-665 ◽  
Author(s):  
G Niedobitek ◽  
A Agathanggelou ◽  
M Rowe ◽  
EL Jones ◽  
DB Jones ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Burkitt’S Lymphoma ◽  
Operational Definition ◽  
Lytic Cycle ◽  
Burkitt's Lymphoma ◽  
Barr Virus ◽  
Epstein Barr

Epstein-Barr virus (EBV)-infected cells may sustain three distinct forms of virus latency. In lymphoblastoid cell lines, six EBV-encoded nuclear antigens (EBNA1, 2, 3A, 3B, 3C, -LP), three latent membrane proteins (LMP1, 2A, 2B), and two nuclear RNAs (EBERs) are expressed. This form of latency, termed latency III, is also encountered in some posttransplant lymphoproliferative disorders. In EBV-positive cases of Hodgkin's disease, the EBERs, EBNA1, and the LMPs are expressed (latency II), whereas in Burkitt's lymphoma (BL) only the EBERs and EBNA1 have been detected (latency I). We have studied the expression of EBV proteins in 17 cases of EBV-positive endemic BL by immunohistology. Expression of LMP1 was seen in variable proportions of tumor cells in two cases and EBNA2 was detected in some tumor cells in three other cases. Also, the BZLF1 trans-activator protein was expressed in a few tumor cells in 6 cases, indicating entry into the lytic cycle. A phenotypic drift from latency I to latency III has been observed previously in some BL cell lines. Our results suggest that a similar phenomenon may occur in BL in vivo and indicate that the operational definition of EBV latencies is not easily applied to human tumors.

scholarly journals EBV-LMP1 promotes radioresistance by inducing protective autophagy through BNIP3 in nasopharyngeal carcinoma

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
San Xu ◽  
Zhuan Zhou ◽  
Xingzhi Peng ◽  
Xuxiu Tao ◽  
Peijun Zhou ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Crucial Role ◽  
Epstein Barr Virus ◽  
Interacting Protein ◽  
Multiple Tumors ◽  
Barr Virus ◽  
Signaling Axis ◽  
Epstein Barr ◽  
Adenovirus E1b

AbstractStudies have indicated that dysfunction of autophagy is involved in the initiation and progression of multiple tumors and their chemoradiotherapy. Epstein–Barr virus (EBV) is a lymphotropic human gamma herpes virus that has been implicated in the pathogenesis of nasopharyngeal carcinoma (NPC). EBV encoded latent membrane protein1 (LMP1) exhibits the properties of a classical oncoprotein. In previous studies, we experimentally demonstrated that LMP1 could increase the radioresistance of NPC. However, how LMP1 contributes to the radioresistance in NPC is still not clear. In the present study, we found that LMP1 could enhance autophagy by upregulating the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3). Knockdown of BNIP3 could increase the apoptosis and decrease the radioresistance mediated by protective autophagy in LMP1-positive NPC cells. The data showed that increased BNIP3 expression is mediated by LMP1 through the ERK/HIF1α signaling axis, and LMP1 promotes the binding of BNIP3 to Beclin1 and competitively reduces the binding of Bcl-2 to Beclin1, thus upregulating autophagy. Furthermore, knockdown of BNIP3 can reduce the radioresistance promoted by protective autophagy in vivo. These data clearly indicated that, through BNIP3, LMP1 induced autophagy, which has a crucial role in the protection of LMP1-positive NPC cells against irradiation. It provides a new basis and potential target for elucidating LMP1-mediated radioresistance.

scholarly journals Epstein–Barr Virus (EBV) Viral Load in Tumor Cells Did Not Predict Tumor Extensiveness in Nasopharyngeal Cancer

2021 ◽  
Vol 12 (1) ◽  
pp. 150-156
Author(s):  
Soehartati A. Gondhowiardjo ◽  
Handoko ◽  
Marlinda Adham ◽  
Lisnawati Rachmadi ◽  
Henry Kodrat ◽  
...  
Keyword(s):  
Viral Load ◽  
Tumor Cells ◽  
Epstein Barr Virus ◽  
Tumor Volume ◽  
Nasopharyngeal Cancer ◽  
Dna Quantification ◽  
Barr Virus ◽  
Nasopharyngeal Biopsy ◽  
Ebv Dna ◽  
Epstein Barr

Background: Nasopharyngeal cancer is commonly associated with Epstein–Barr virus (EBV) infection, especially undifferentiated non-keratinized histology. EBV DNA quantification through nasopharyngeal brushing was previously reported to be not related to disease stage. This study aimed to reinvestigate the relationship of EBV viral load in tumor tissue with tumor extensiveness by more accurate EBV DNA quantification through microscopically confirmed tumor cells from nasopharyngeal biopsy. Method: The specimens for EBV DNA quantification were derived from histopathology slides which were pre-treated following the QIAsymphony® SP protocol for tissue DNA extraction. Then, the extracted DNA underwent real-time polymerase chain reaction (RT-PCR) using the artus® EBV RG PCR Kit for EBV DNA quantification. The tumor volume was determined by delineating the gross tumor based on 3D imaging of the patient’s nasopharynx. Result: Twenty-four subjects were included in this study. All subjects were stage III and above, with more males (75%) than females. EBV viral load in tumor cells was found to have no correlation to tumor volume both in local and nodal regions. The median local tumor volume was 81.3 cm3 ± 80 cm3. The median EBV viral load in tumor cells was 95,644.8 ± 224,758.4 copies/100 ng of DNA. The median nodal or regional tumor volume was 35.7 ± 73.63 cm3. Conclusion: EBV viral load from tumor cells from nasopharyngeal biopsy has no relationship with tumor extensiveness in nasopharyngeal cancer. The presence and amount of EBV in tumor cells did not translate into larger or smaller tumors. The EBV viral proteins and RNAs were perhaps more likely to confer some prognostic information due to the fact that those molecules were related to carcinogenesis.

scholarly journals Quantitative multi-target RNA profiling in Epstein-Barr virus infected tumor cells

2017 ◽  
Vol 241 ◽  
pp. 24-33 ◽  
Author(s):  
A.E. Greijer ◽  
O. Ramayanti ◽  
S.A.W.M. Verkuijlen ◽  
Z. Novalić ◽  
H. Juwana ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Epstein Barr Virus ◽  
Rna Profiling ◽  
Barr Virus ◽  
Epstein Barr ◽  
Target Rna ◽  
Infected Tumor

scholarly journals Epstein-Barr virus, B cell lymphoproliferative disease, and SCID mice: Modeling T cell immunotherapy in vivo

2011 ◽  
Vol 83 (9) ◽  
pp. 1585-1596 ◽  
Author(s):  
I. Johannessen ◽  
L. Bieleski ◽  
G. Urquhart ◽  
S.L. Watson ◽  
P. Wingate ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Lymphoproliferative Disease ◽  
Scid Mice ◽  
Barr Virus ◽  
Cell Immunotherapy ◽  
Epstein Barr ◽  
T Cell Immunotherapy

scholarly journals Expression of the Epstein-Barr virus BamHI A fragment in nasopharyngeal carcinoma: evidence for a viral protein expressed in vivo.

1991 ◽  
Vol 65 (11) ◽  
pp. 6252-6259 ◽  
Author(s):  
K J Gilligan ◽  
P Rajadurai ◽  
J C Lin ◽  
P Busson ◽  
M Abdel-Hamid ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Viral Protein ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Acyclovir Improves the Efficacy of Chemoradiation in Nasopharyngeal Cancer Containing the Epstein Barr Virus Genome

2020 ◽  
Author(s):  
Aditya Thandoni ◽  
Andrew Zloza ◽  
Devora Schiff ◽  
Malay Rao ◽  
Kwok-wai Lo ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Treatment Options ◽  
Immune Surveillance ◽  
Nasopharyngeal Cancer ◽  
Standard Of Care ◽  
Virus Genome ◽  
Barr Virus ◽  
Standard Of Care Treatment ◽  
Epstein Barr

AbstractNasopharyngeal carcinoma (NPC) is a malignancy endemic to East Asia and is caused by Epstein-Barr Virus (EBV)-mediated cancerous transformation of epithelial cells. The standard of care treatment for NPC involves radiation and chemotherapy. While treatment outcomes continue to improve, up to 50% of patients can be expected to recur by five years, and additional innovative treatment options are needed. We posit that a potential way to do this is by targeting the underlying cause of malignant transformation, namely EBV. One method by which EBV escapes immune surveillance is by undergoing latent phase replication, during which EBV expression of immunogenic proteins is reduced. However, chemoradiation is known to drive conversion of EBV from a latent to a lytic phase. This creates an opportunity for the targeting of EBV-infected cells utilizing anti-viral drugs. Indeed, we found that combining acyclovir with cisplatin and radiation significantly decreases the viability of the EBV-infected C666-1 cell line. Western blot quantification revealed a resultant increase of thymidine kinase (TK) and apoptosis-inducing mediators, cleaved PARP (cPARP) and phosphorylated ERK (pERK). These studies suggest that the addition of anti-viral drugs to frontline chemoradiation may improve outcomes in patients treated for EBV-related NPC and future in vivo and clinical studies are needed.

Sign in / Sign up

Export Citation Format

Share Document