Here, we report that the bioactivity of antcin H, an analog of the JAK2 inhibitor zhankuic acid A (ZAA), inhibits LMP1-induced JAK/STAT related signaling and induces lymphoma cell line apoptosis.
Together, these results point to a second mechanism by which LMP1 dysregulates sumoylation processes and adds EBV-associated lymphomas to the list of malignancies associated with increased SUMO expression.
These data suggest new functions of the N terminus and transmembrane domains in LMP1 intra- and extracellular trafficking that are likely downstream of an interaction with CD63.<b>IMPORTANCE</b> EBV infection contributes to the development of cancers, such as nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin's disease, and posttransplant lymphomas, in immunocompromised or genetically susceptible individuals.
EBV, a human gamma herpesvirus that contributes to the progression of a multitude of lymphomas and carcinomas in immunocompromised or genetically susceptible populations, packages its major oncoprotein, LMP1, into vesicles for secretion.
Epstein-Barr virus latent membrane protein 1 (LMP1) is expressed in multiple human malignancies, including nasopharyngeal carcinoma and Hodgkin and immunosuppression-associated lymphomas.
Thus, the expression of either LMP1 or LMP2A may be sufficient to promote early-onset EBV-induced tumors in this model.<b>IMPORTANCE</b> EBV causes human lymphomas, but few models are available for dissecting how EBV causes lymphomas <i>in vivo</i> in the context of a host immune response.
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.
Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is crucial for B cell transformation and oncogenesis of other EBV-related malignancies, such as nasopharyngeal carcinoma and T/NK lymphoma.
Gene expression levels of LMP-1, LMP-2A, and LMP-2B and EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C and EBNA-LP were monitored by real-time quantitative-polymerase chain reaction (qRT-PCR) in cells from nine EBV-induced lymphomas and in matched lymphocytes from healthy subjects.
Thus, EBV may contribute to the development and maintenance of human lymphomas even in the absence of LMP1.Here, we found that i.p. injection of human cord blood mononuclear cells infected with a LMP1-deficient EBV into immunodeficient mice induces B cell lymphomas.
Because T cells specific for these antigens are present with low frequency and may be rendered anergic by the tumors that express them, we expanded LMP-cytotoxic T lymphocytes (CTLs) from patients with lymphoma using autologous dendritic cells and EBV-transformed B-lymphoblastoid cell lines transduced with an adenoviral vector expressing either LMP2 alone (n = 17) or both LMP2 and ΔLMP1 (n = 33).
The oncogenic latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is involved in the pathogenesis of human nasopharyngeal carcinoma (NPC) and lymphoma.
Using a panel of transfected sublines of the B-lymphoma line BJAB expressing the viral genes associated with latent infection, we show that the EBV nuclear antigens, EBNA-1 and EBNA-3C, and the latent membrane protein 1, LMP-1, independently promote genomic instability, as detected by nonclonal chromosomal aberrations, DNA breaks and phosphorylation of histone H2AX.
Although the latent membrane protein-1 (LMP1) of the Epstein-Barr virus (EBV) is believed to be important for the transformation of germinal centre (GC) B cells, the precise contribution of this viral oncogene to lymphoma development is poorly understood.
The latency II program is limited to the expression of the nonimmunodominant antigens EBNA1, LMP1 and LMP2 and is seen in EBV-positive Hodgkin disease, nasopharyngeal carcinomas, and peripheral T/NK-cell lymphomas.
Overall, these data suggest that immunotherapy targeting LMP1 in EBV-associated NK lymphomas and CAEBV might serve as an alternative treatment modality.
Moreover, IL-10 could induce the expression of LMP-1 in tonsillar B cells infected with the nontransforming, EBNA-2-deficient EBV strain P3HR1 and enhance LMP-1 expression in 2 EBV-positive NK lymphoma lines.
EBV encodes several latent genes, among them latent membrane protein 1 (LMP1) and LMP2A, which are regularly expressed in EBV-positive Hodgkin lymphoma and posttransplantation lymphomas.
In all four patients, the lymphoma was associated with Epstein-Barr virus infection, detected by EBER in situ hybridization and the latency I phenotype as defined by lack of expression of LMP1.