A novel latent membrane 2 transcript expressed in Epstein-Barr virus-positive NK- and T-cell lymphoproliferative disease encodes a target for cellular immunotherapy
- PMID: 20671118
- PMCID: PMC2981530
- DOI: 10.1182/blood-2010-06-292268
A novel latent membrane 2 transcript expressed in Epstein-Barr virus-positive NK- and T-cell lymphoproliferative disease encodes a target for cellular immunotherapy
Abstract
Therapeutic targeting of virus-encoded proteins using cellular immunotherapy has proved successful for Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease. However, the more limited repertoire and immunogenicity of EBV-encoded proteins in other malignancies such as Hodgkin lymphoma and extranodal natural killer (NK)/T lymphoma has been more challenging to target. The immunosubdominant latent membrane protein 2 (LMP2) is considered the optimal target in such Latency II tumors, although data relating to its expression in T/NK malignancies are limited. In addressing the validity of LMP2 as an immunotherapeutic target we found that LMP2-specific effector CD8(+) T cells recognized and killed EBV-positive NK- and T-cell tumor lines, despite an apparent absence of LMP2A protein and barely detectable levels of LMP2 transcripts from the conventional LMP2A and LMP2B promoters. We resolved this paradox by identifying in these lines a novel LMP2 mRNA, initiated from within the EBV terminal repeats and containing downstream, epitope-encoding exons. This same mRNA was also highly expressed in primary (extra-nodal) NK/T lymphoma tissue, with virtually undetectable levels of conventional LMP2A/B transcripts. Expression of this novel transcript in T/NK-cell lymphoproliferative diseases validates LMP2 as an attractive target for cellular immunotherapy and implicates this truncated LMP2 protein in NK- and T-cell lymphomagenesis. This study is registered at clinicaltrials.gov as NCT00062868.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2981530/bin/zh89991059920001.gif)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2981530/bin/zh89991059920002.gif)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2981530/bin/zh89991059920003.gif)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2981530/bin/zh89991059920004.gif)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2981530/bin/zh89991059920005.gif)
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2981530/bin/zh89991059920006.gif)
![Figure 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2981530/bin/zh89991059920007.gif)
Comment in
-
Mystery of the missing target.Blood. 2010 Nov 11;116(19):3691-2. doi: 10.1182/blood-2010-09-300590. Blood. 2010. PMID: 21071613 No abstract available.
Similar articles
-
Extranodal NK/T-Cell Lymphomas: The Role of Natural Killer Cells and EBV in Lymphomagenesis.Int J Mol Sci. 2020 Feb 22;21(4):1501. doi: 10.3390/ijms21041501. Int J Mol Sci. 2020. PMID: 32098335 Free PMC article. Review.
-
Epstein-Barr virus-associated T- and NK-cell lymphoproliferative diseases: an update and diagnostic approach.Pathology. 2020 Jan;52(1):111-127. doi: 10.1016/j.pathol.2019.09.011. Epub 2019 Nov 22. Pathology. 2020. PMID: 31767131 Review.
-
Epstein-Barr Virus (EBV)-derived BARF1 encodes CD4- and CD8-restricted epitopes as targets for T-cell immunotherapy.Cytotherapy. 2019 Feb;21(2):212-223. doi: 10.1016/j.jcyt.2018.08.001. Epub 2018 Nov 2. Cytotherapy. 2019. PMID: 30396848 Free PMC article.
-
Epstein-Barr virus-positive nodal T/NK-cell lymphoma: an analysis of 15 cases with distinct clinicopathological features.Hum Pathol. 2015 Jul;46(7):981-90. doi: 10.1016/j.humpath.2015.03.002. Epub 2015 Mar 25. Hum Pathol. 2015. PMID: 25907865
-
Epstein-Barr virus (EBV) latent membrane protein-1-specific cytotoxic T lymphocytes targeting EBV-carrying natural killer cell malignancies.Eur J Immunol. 2006 Mar;36(3):593-602. doi: 10.1002/eji.200535485. Eur J Immunol. 2006. PMID: 16479544
Cited by
-
A differential diagnosis method for systemic CAEBV and the prospect of EBV-related immune cell markers via flow cytometry.Ann Med. 2024 Dec;56(1):2329136. doi: 10.1080/07853890.2024.2329136. Epub 2024 Mar 19. Ann Med. 2024. PMID: 38502913 Free PMC article. Review.
-
EBV-induced T-cell responses in EBV-specific and nonspecific cancers.Front Immunol. 2023 Sep 29;14:1250946. doi: 10.3389/fimmu.2023.1250946. eCollection 2023. Front Immunol. 2023. PMID: 37841280 Free PMC article. Review.
-
Novel target and treatment agents for natural killer/T-cell lymphoma.J Hematol Oncol. 2023 Jul 22;16(1):78. doi: 10.1186/s13045-023-01483-9. J Hematol Oncol. 2023. PMID: 37480137 Free PMC article. Review.
-
Extranodal Natural Killer/T-Cell Lymphomas: Current Approaches and Future Directions.J Clin Med. 2022 May 10;11(10):2699. doi: 10.3390/jcm11102699. J Clin Med. 2022. PMID: 35628826 Free PMC article. Review.
-
Expression of the Chemokine Receptor CCR1 in Burkitt Lymphoma Cell Lines Is Linked to the CD10-Negative Cell Phenotype and Co-Expression of the EBV Latent Genes EBNA2, LMP1, and LMP2.Int J Mol Sci. 2022 Mar 22;23(7):3434. doi: 10.3390/ijms23073434. Int J Mol Sci. 2022. PMID: 35408790 Free PMC article.
References
-
- Rickinson AB, Kieff E. Epstein-Barr virus. In: Knipe DM, Howley PM, editors. Fields Virology. 5th Ed. Vol 2. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2007. pp. 2655–2700.
-
- Roskrow MA, Suzuki N, Gan YJ, et al. Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the treatment of patients with EBV-positiye relapsed Hodgkin's disease. Blood. 1998;91(8):2925–2934. - PubMed
-
- Bollard CM, Straathof KC, Huls MH, et al. The generation and characterization of LMP2-specific CTLs for use as adoptive transfer from patients with relapsed EBV-positive Hodgkin disease. J Immunother. 2004;27(4):317–327. - PubMed
Publication types
MeSH terms
Substances
Associated data
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials