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https://www.readbyqxmd.com/read/28098136/exome-and-genome-sequencing-of-nasopharynx-cancer-identifies-nf-%C3%AE%C2%BAb-pathway-activating-mutations
#1
Yvonne Y Li, Grace T Y Chung, Vivian W Y Lui, Ka-Fai To, Brigette B Y Ma, Chit Chow, John K S Woo, Kevin Y Yip, Jeongsun Seo, Edwin P Hui, Michael K F Mak, Maria Rusan, Nicole G Chau, Yvonne Y Y Or, Marcus H N Law, Peggy P Y Law, Zoey W Y Liu, Hoi-Lam Ngan, Pok-Man Hau, Krista R Verhoeft, Peony H Y Poon, Seong-Keun Yoo, Jong-Yeon Shin, Sau-Dan Lee, Samantha W M Lun, Lin Jia, Anthony W H Chan, Jason Y K Chan, Paul B S Lai, Choi-Yi Fung, Suet-Ting Hung, Lin Wang, Ann Margaret V Chang, Simion I Chiosea, Matthew L Hedberg, Sai-Wah Tsao, Andrew C van Hasselt, Anthony T C Chan, Jennifer R Grandis, Peter S Hammerman, Kwok-Wai Lo
Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases...
January 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28077657/lmp1-and-lmp2a-collaborate-to-promote-epstein-barr-virus-ebv-induced-b-cell-lymphomas-in-a-cord-blood-humanized-mouse-model-but-are-not-essential
#2
Shi-Dong Ma, Ming-Han Tsai, James C Romero-Masters, Erik A Ranheim, Shane M Huebner, Jillian Bristol, Henri-Jacques Delecluse, Shannon C Kenney
: Epstein-Barr virus (EBV) infection is associated with B cell lymphomas in humans. The ability of EBV to convert human B cells into long-lived lymphoblastoid cell lines (LCLs) in vitro requires the collaborative effects of EBNA2 (which hijacks notch signaling), LMP1 (which mimics CD40 signaling), and EBNA 3A/3C (which inhibit oncogene-induced senescence and apoptosis). However, we recently showed that an LMP1-deleted EBV mutant induces B cell lymphomas in a newly developed cord blood-humanized mouse model that allows EBV-infected B cells to interact with CD4 T cells (the major source of CD40 ligand)...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28056887/therapeutic-vaccine-targeting-epstein-barr-virus-latent-protein-lmp1-suppresses-lmp1-expressing-tumor-growth-and-metastasis-in-vivo
#3
Mei-Chun Lin, Yong-Chong Lin, Syue-Ting Chen, Tai-Horng Young, Pei-Jen Lou
BACKGROUND: In endemic area, nasopharyngeal carcinoma (NPC) tumor cells harbor EBV latent infection and expresses viral antigens such as EBNA1, LMP1 and LMP2. In this study, we established a NPC-mimicry animal model and assessed the therapeutic potential of LMP1 vaccine. METHODS: Animal models were established by injection of LMP1-expressing TC-1 cells in C57BL6/J mice subcutaneously or through tail veins. pcDNA3.1 empty vector or LMP1/pcDNA3.1 vaccine was delivered by a helium-driven gene gun...
January 5, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28053105/epstein-barr-virus-encoded-latent-membrane-protein-1-upregulates-glucose-transporter-1-transcription-via-the-mtorc1-nf-%C3%AE%C2%BAb-signaling-pathways
#4
Jun Zhang, Lin Jia, Weitao Lin, Yim Ling Yip, Kwok Wai Lo, Victoria Ming Yi Lau, Dandan Zhu, Chi Man Tsang, Yuan Zhou, Wen Deng, Hong Lok Lung, Maria Li Lung, Lai Man Cheung, Sai Wah Tsao
: Accumulating evidence indicates that oncogenic viral protein exerts a crucial role in activating aerobic glycolysis during tumorigenesis, but the underlying mechanisms are largely undefined. The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a trans-membrane protein with potent cell signaling properties and has tumorigenic transformation property. Activation of NF-κB is a major signaling pathway mediating many downstream transformation properties of LMP1. Here we report that activation of mTORC1 by LMP1 is a key modulator for activation of NF-κB signaling to mediate aerobic glycolysis...
January 4, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28009988/a-neutralized-human-lmp1-igg-inhibits-enktl-growth-by-suppressing-the-jak3-stat3-signaling-pathway
#5
Yuan Mao, Jun Wang, Mingzhi Zhang, Weifei Fan, Qi Tang, Siping Xiong, Xiaojun Tang, Juqing Xu, Lin Wang, Shu Yang, Suyao Liu, Li Xu, Yan Chen, Lin Xu, Rong Yin, Jin Zhu
Latent membrane protein 1 (LMP1), which is associated with the development of different types of Epstein-Barr virus (EBV) related lymphoma, has been suggested to be an important oncoprotein. In this study, a human anti-LMP1 IgG antibody (LMP1-IgG) was constructed and characterized by ELISA, western blotting (WB), affinity and immunohistochemistry (IHC) analyses. CCK-8, MTT, apoptosis assays, antibody-dependent cell-mediated cytotoxicity (ADCC) and CDC (complement-dependent cytotoxicity) assays were performed to evaluate the inhibitory effects of LMP1-IgG on extranodal nasal-type natural killer (NK)/T-cell lymphoma (ENKTL)...
December 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27993616/quantitative-multi-target-rna-profiling-in-epstein-barr-virus-infected-tumor-cells
#6
A E Greijer, O Ramayanti, S A W M Verkuijlen, Z Novalić, H Juwana, J M Middeldorp
Epstein-Barr virus (EBV) is etiologically linked to multiple acute, chronic and malignant diseases. Detection of EBV-RNA transcripts in tissues or biofluids besides EBV-DNA can help in diagnosing EBV related syndromes. Sensitive EBV transcription profiling yields new insights on its pathogenic role and may be useful for monitoring virus targeted therapy. Here we describe a multi-gene quantitative RT-PCR profiling method that simultaneously detects a broad spectrum (n=16) of crucial latent and lytic EBV transcripts...
December 16, 2016: Journal of Virological Methods
https://www.readbyqxmd.com/read/27982024/epstein-barr-virus-positive-follicular-lymphoma
#7
Nicholas Mackrides, German Campuzano-Zuluaga, Yvan Maque-Acosta, Adrienne Moul, Nouf Hijazi, Francis Offiong Ikpatt, Ronald Levy, Ramiro E Verdun, Kranthi Kunkalla, Yasodha Natkunam, Izidore S Lossos, Francisco Vega, Jennifer Chapman
Epstein-Barr virus (EBV) -associated follicular lymphoma is only rarely reported. Herein, we report the largest series analyzing prevalence and clinicopathologic characteristics of EBV-associated follicular lymphoma occurring in unselected cases. Out of 382 analyzed cases, 10 EBV-positive follicular lymphomas were identified (prevalence=2.6%, 95% confidence interval 1.3-4.0%). All EBV-positive follicular lymphomas showed EBV-encoded small RNA-positive lymphoma cells present in a follicular distribution. Of these, eight also had tissue available for testing of expression of latent membrane protein 1 (LMP1), out of which six (75%) were positive...
December 16, 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/27974566/cd63-regulates-epstein-barr-virus-lmp1-exosomal-packaging-enhancement-of-vesicle-production-and-non-canonical-nf-%C3%AE%C2%BAb-signaling
#8
Stephanie N Hurwitz, Dingani Nkosi, Meghan M Conlon, Sara B York, Xia Liu, Deanna C Tremblay, David G Meckes
: Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) encoded oncoprotein that is packaged into small extracellular vesicles (EVs) called exosomes. Trafficking of LMP1 into multivesicular bodies (MVBs) alters the content and function of exosomes. LMP1-modified exosomes enhance the growth, migration, and invasion of malignant cells, demonstrating the capacity to manipulate the tumor microenvironment and enhance the progression of EBV-associated cancers. Despite the growing evidence surrounding the significance of LMP1-modified exosomes in cancer, very little is understood about the mechanisms that orchestrate LMP1 incorporation into these vesicles...
December 14, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27926490/positive-regulation-of-taz-expression-by-ebv-lmp1-contributes-to-cell-proliferation-and-epithelial-mesenchymal-transition-in-nasopharyngeal-carcinoma
#9
Jiang He, Feiyu Tang, Liyu Liu, Lin Chen, Jiang Li, Danming Ou, Lu Zhang, Zhi Li, Deyun Feng, Wenzheng Li, Lun-Quan Sun
The Epstein-Barr virus latent membrane protein 1 (LMP1) is an integral membrane protein. LMP1 has been reported to activate the NF-κB and mitogen-activated protein kinase pathways. However, these effects alone are unable to account for the profound oncogenic properties of LMP1. TAZ is one of the nuclear effectors of Hippo-related pathways and highly expressed in many human tumors. Here, we reported that TAZ was frequently expressed in LMP1-positive nasopharyngeal carcinoma. In NPC cell lines, we showed that LMP1 promoted TAZ expression...
December 2, 2016: Oncotarget
https://www.readbyqxmd.com/read/27903798/lubac-modulates-lmp1-activation-of-nf%C3%AE%C2%BAb-and-irf7
#10
Ling Wang, Yujia Wang, Juan Zhao, Junping Ren, Kenton H Hall, Jonathan P Moorman, Zhi Q Yao, Shunbin Ning
: Recently, Linear Ubiquitin Assembly Complex (LUBAC)-mediated linear ubiquitination has come into focus due to its emerging role in activation of NFκB in different biological contexts. However, the role of LUBAC in LMP1 signaling leading to NFκB and IRF7 activation has not been investigated. We have shown here that RNF31, the key component of LUBAC complex, interacts with LMP1 and IRF7 in EBV-transformed cells, and that LUBAC stimualtes linear ubiquitination of NEMO and IRF7. Consequently, LUBAC is required for LMP1 signaling to full activation of NFκB, but inhibits LMP1-stimulated IRF7 transcriptional activity...
November 30, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27900085/id1-upregulation-and-foxo3a-downregulation-by-epstein-barr-virus-encoded-lmp1-in-hodgkin-s-lymphoma
#11
Jun-Ichiro Ikeda, Naoki Wada, Satoshi Nojima, Shinichiro Tahara, Yoko Tsuruta, Kaori Oya, Eiichi Morii
Cancer-initiating cells (CICs) are specialized cells that have the ability to self-renew and are multipotent. We recently demonstrated that Forkhead box O3a (FoxO3a)-expressing cells exhibited a CIC-like potential in Hodgkin's lymphoma (HL). A proportion of HL patients are infected with Epstein-Barr virus (EBV). EBV-encoded latent membrane protein (LMP) 1 downregulates FoxO3a, suggesting that FoxO3a expression may be abolished in EBV-positive HL. Inhibitors of DNA-binding (ID) proteins are highly conserved transcription factors mediating stem cell functions...
November 2016: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/27873282/ebv-directed-t-cell-therapeutics-for-ebv-associated-lymphomas
#12
Lauren P McLaughlin, Stephen Gottschalk, Cliona M Rooney, Catherine M Bollard
Epstein Barr virus (EBV) is a human gamma herpes virus that establishes latency in B cells after primary infection. EBV generally only causes a mild, self-limiting viral illness but is also associated with several malignancies including posttransplantation lymphoproliferative disorder in the immunosuppressed host as well as Hodgkin and non-Hodgkin lymphoma in the immune competent host. The expression of EBV antigens by lymphoma has important applications as targets for adoptive T cell therapy. However, as many lymphomas only express subdominant EBV antigens that are less immunogenic, novel strategies are needed to manufacture EBV-specific T cell products specific for Latent Membrane Protein 1 (LMP1) and LMP2, which are expressed in lymphomas with type II and III latency...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27873269/the-use-of-3d-telomere-fish-for-the-characterization-of-the-nuclear-architecture-in-ebv-positive-hodgkin-s-lymphoma
#13
Hans Knecht, Sabine Mai
The 3D nuclear architecture is closely related to cellular functions and chromosomes are organized in distinct territories. Quantitative 3D telomere FISH analysis (3D Q-FISH) and 3D super-resolution imaging (3D-SIM) at a resolution up to 80 nm as well as the recently developed combined quantitative 3D TRF2-telomere immune FISH technique (3D TRF2/Telo-Q-FISH) have substantially contributed to elucidate molecular pathogenic mechanisms of hematological diseases. Here we report the methods we applied to uncover major molecular steps involved in the pathogenesis of EBV-associated Hodgkin's lymphoma...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27856754/mouse-model-for-acute-epstein-barr-virus-infection
#14
Tristan Wirtz, Timm Weber, Sven Kracker, Thomas Sommermann, Klaus Rajewsky, Tomoharu Yasuda
Epstein-Barr Virus (EBV) infects human B cells and drives them into continuous proliferation. Two key viral factors in this process are the latent membrane proteins LMP1 and LMP2A, which mimic constitutively activated CD40 receptor and B-cell receptor signaling, respectively. EBV-infected B cells elicit a powerful T-cell response that clears the infected B cells and leads to life-long immunity. Insufficient immune surveillance of EBV-infected B cells causes life-threatening lymphoproliferative disorders, including mostly germinal center (GC)-derived B-cell lymphomas...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27819673/lmp1-signaling-pathway-activates-irf4-in-latent-ebv-infection-and-a-positive-circuit-between-pi3k-and-src-is-required
#15
L Wang, J Ren, G Li, J P Moorman, Z Q Yao, S Ning
Interferon (IFN) regulatory factors (IRFs) have crucial roles in immune regulation and oncogenesis. We have recently shown that IRF4 is activated through c-Src-mediated tyrosine phosphorylation in virus-transformed cells. However, the intracellular signaling pathway triggering Src activation of IRF4 remains unknown. In this study, we provide evidence that Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) promotes IRF4 phosphorylation and markedly stimulates IRF4 transcriptional activity, and that Src mediates LMP1 activation of IRF4...
November 7, 2016: Oncogene
https://www.readbyqxmd.com/read/27813134/establishment-and-characterization-of-a-novel-hodgkin-lymphoma-cell-line-am-hlh-carrying-the-epstein-barr-virus-genome-integrated-into-the-host-chromosome
#16
Masahiko Hayashida, Masanori Daibata, Erika Tagami, Takahiro Taguchi, Fumiyo Maekawa, Kayo Takeoka, Katsuhiro Fukutsuka, Daiki Shimomura, Takamasa Hayashi, Yoshinori Iwatani, Hitoshi Ohno
We describe the establishment and characterization of a cell line, AM-HLH, obtained from a patient with Epstein-Barr virus-positive (EBV(+) ) nodular sclerosis-type Hodgkin lymphoma (HL). The cells were positive for CD2 and CD30 and negative for CD15. The immunoglobulin heavy- and κ light-chain genes were rearranged. The karyotype was of the triploid range. Southern blotting using the EBV terminal repeat probe detected 3 hybridizing bands that were identical to those of the parental HL material. The cells expressed EBV-encoded RNAs as well as latent genes (EBNA1, EBNA2, LMP1, and LMP2A) and lytic genes (BZLF1 and BALF2)...
November 4, 2016: Hematological Oncology
https://www.readbyqxmd.com/read/27793268/spontaneous-metastases-in-immunocompetent-mice-harboring-a-primary-tumor-driven-by-oncogene-latent-membrane-protein-1-from-epstein-barr-virus
#17
Pu-Yuan Chang, Yenlin Huang, Tzu-Yuan Hung, Kowit-Yu Chong, Yu-Sun Chang, Chuck C-K Chao, Kai-Ping N Chow
BACKGROUND: In vitro and clinical studies suggest that the oncogene LMP1 (latent membrane protein 1) encoded by Epstein-Barr virus (EBV) plays a role in the development of nasopharyngeal carcinoma (NPC) and the formation of metastases in immunocompetent individuals. However, whether LMP1 itself is sufficient to drive these events in immunocompetent hosts remains elusive due to the lack of appropriate experimental models. The aim of this study was to study LMP1-dependent tumorigenesis and metastasis in BALB/c mice inoculated with BALB/c-3T3 cells expressing N-LMP1 (a Taiwanese NPC variant)...
August 2016: Biomedical Journal
https://www.readbyqxmd.com/read/27737703/pd-l1-is-upregulated-by-ebv-driven-lmp1-through-nf-%C3%AE%C2%BAb-pathway-and-correlates-with-poor-prognosis-in-natural-killer-t-cell-lymphoma
#18
Xi-Wen Bi, Hua Wang, Wen-Wen Zhang, Jing-Hua Wang, Wen-Jian Liu, Zhong-Jun Xia, Hui-Qiang Huang, Wen-Qi Jiang, Yu-Jing Zhang, Liang Wang
BACKGROUND: Natural killer/T-cell lymphoma (NKTCL) is an Epstein-Barr virus (EBV)-associated, highly aggressive lymphoma. Treatment outcome remains sub-optimal, especially for advanced-stage or relapsed diseases. Programmed cell death receptor 1 (PD-1) and PD ligand 1 (PD-L1) have become promising therapeutic targets for various malignancies, but their role in the pathogenesis and their interactions with EBV in NKTCL remains to be investigated. METHODS: Expression of PD-L1 was measured in NK-92 (EBV-negative) and SNK-6 (EBV-positive) cells by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay, and flow cytometry, respectively...
October 13, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27732937/tofacitinib-induces-g1-cell-cycle-arrest-and-inhibits-tumor-growth-in-epstein-barr-virus-associated-t-and-natural-killer-cell-lymphoma-cells
#19
Shotaro Ando, Jun-Ichi Kawada, Takahiro Watanabe, Michio Suzuki, Yoshitaka Sato, Yuka Torii, Masato Asai, Fumi Goshima, Takayuki Murata, Norio Shimizu, Yoshinori Ito, Hiroshi Kimura
Epstein-Barr virus (EBV) infects not only B cells, but also T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoma. These lymphoid malignancies are refractory to conventional chemotherapy. We examined the activation of the JAK3/STAT5 pathway in EBV-positive and -negative B, T and NK cell lines and in cell samples from patients with EBV-associated T cell lymphoma. We then evaluated the antitumor effects of the selective JAK3 inhibitor, tofacitinib, against these cell lines in vitro and in a murine xenograft model...
October 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27686857/ganetespib-an-hsp90-inhibitor-kills-epstein-barr-virus-ebv-infected-b-and-t-cells-and-reduces-the-percentage-of-ebv-infected-cells-in-the-blood
#20
Amber Shatzer, Mir A Ali, Mayra Chavez, Kennichi Dowdell, Min-Jung Lee, Yusuke Tomita, Iman El-Hariry, Jane B Trepel, David A Proia, Jeffrey I Cohen
HSP90 inhibitors have been shown to kill Epstein-Barr virus (EBV)-infected cells by reducing the level of EBV EBNA-1 and/or LMP1. We treated virus-infected cells with ganetespib, an HSP90 inhibitor currently being evaluated in multiple clinical trials for cancer and found that the drug killed EBV-positive B and T cells and reduced the level of both EBV EBNA-1 and LMP1. Treatment of cells with ganetespib also reduced the level of pAkt. Ganetespib delayed the onset of EBV-positive lymphomas and prolonged survival in SCID mice inoculated with one EBV-transformed B-cell line, but not another B-cell line...
August 11, 2016: Leukemia & Lymphoma
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