Long Noncoding RNAs in Viral Lymphomas
Abstract
This project will address the Peer Reviewed Cancer Research Program (PRCRP) Topic Area Lymphoma, with the Military Relevance Focus Area Gaps in cancer prevention, early detection/diagnosis, prognosis, and/or treatment in Mission Readiness. Specifically, we will establish a missing link between host lncRNAs and Epstein-Barr Virus (EBV) latent infection. Several viruses are well-known to cause different cancers in the people living with HIV/AIDS (PLWHA) with an estimate of approximate 40 million by the end of 2021 in the world, which will likely become significantly more prevalent in the U.S. The World Health Organization has defined the first discovered carcinogenic virus EBV (discovered in the year 1964) as a Class I carcinogen, contributing to ~200,000 new cancer cases and 140,000 deaths yearly worldwide, and substantially (>50%) contributes to AIDS-related lymphomas (ARLs), a leading cause of AIDS-related cancer deaths even in the combined antiviral therapy (ART) era. LncRNAs represent an emerging category of cancer therapeutic targets; however, their roles in virus-caused cancers are just emerging. Interferon Regulatory Factor 4 (IRF4, also known as MUM1, multiple myeloma oncogene 1) is a lymphocyte-specific gene with potent carcinogenic properties in certain lymphoid malignancies, and its expression is induced in 100% of EBV-driven lymphomas in mouse models. In clinical practice, IRF4 serves as an important prognostic and diagnostic marker for certain types of blood malignancies. However, the lack of necessary mechanistic studies is a major barrier that prevents the development of therapeutic strategies to target the IRF4 regulatory network for clinical applications. To gain insights into the role of lncRNAs in EBV-mediated lymphomagenesis, we performed transcriptome-wide lncRNA array analyses, and identified a pool of lncRNAs that are deregulated by EBV latent infection, in which a novel EBV-induced lncRNA G069094 is a natural antisense (NAT) lncRNA for IRF4 and thus we named it IRF4-AS1. In this pilot project, we have proposed sophisticated strategies to test the hypothesis that EBV-deregulated host natural antisense lncRNAs play crucial roles in EBV-mediated lymphomagenesis, with the focus on IRF4-AS1 as an example to outline our experimental plan. This pilot project is of paradigm-shifting innovation by introducing lncRNAs as novel players in viral cancers, exemplified by the novel lncRNA, IRF4-AS1, which was identified as a natural antisense lncRNA of IRF4 in our lncRNA array. This pilot study has broader significance in other cancers, including HTLV1-associated adult T-cell leukemia (ATLL), multiple myeloma (MM), melanoma, squamous cell carcinoma, basal cell carcinoma, etc., in which IRF4 is frequently overexpressed and shows potent oncogenic activity. However, the lack of necessary mechanistic studies is the major barrier to target the IRF4 regulatory network for therapeutic interventions. This study will thus broaden our knowledge of and provide novel mechanistic insights into the IRF4 regulatory network in these settings, and may identify IRF4-AS1 as a potential therapeutic target in the IRF4 regulatory network. Long-term follow-up studies with translational approaches will provide clinical relevance for potential therapeutic applications. In this regard, our team includes both basic and clinical scientists who have established a well- characterized patient cohort from two clinical sites at Mountain Home VA and East Tennessee State University, which allow us to translate findings from these long-term studies into clinical applications with greater feasibility. We are indeed developing nanoparticles and exosomes as vehicles to pack lncRNAs or miRNAs for targeted delivery in patients. Veterans comprise a remarkable rate of the HIV-infected population in the U.S., and AIDS-related cancer deaths remain a threat to the Department of Defense (DOD). There is an appreciable impact on mi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311037
Entities
People
- Shunbin Ning
Organizations
- United States Army