715A Mary Ellen Jones, CB #7290
Dittmer Lab Pages: https://www.med.unc.edu/microimm/dittmerlab;
Approximately 1/3 of all human cancers is of viral origin or requires viral infection as an essential cofactor. The goal of our research is to understand viral cancers; specifically, cancers that are caused by Kaposi sarcoma-associated herpesvirus (KSHV). KSHV is a double-stranded DNA virus with about 80 open reading frames, which belongs to human herpesviruses. It was discovered in 1994 by Patrick Moore and Yuan Change, and is associated with Kaposi sarcoma (KS) as well as a B-cell lymphoma (PEL) and multicentric Castleman’s disease (MCD). These diseases are ultimately fatal as they affect internal organs and, in the U.S., are seen in the context of immune suppression such as HIV-positive individuals or transplant patients. Our lab is focused on four areas:
- Transcriptional profiling (mRNA and microRNA) - To determine the contribution of genes in AIDS-associated cancers we have developed real-time quantitative PCR-based arrays. These allow us to analyze patterns of all KSHV transcripts in PEL and KS. Using this technology, we have designed qPCR arrays for all human herpesviruses and established the UNC Vironomics core (http://www.med.unc.edu/vironomics). We also use this technology in conjunction with NextGen sequencing to study microRNAs in Kaposi sarcoma and AIDS lymphoma.
- Identification of new viruses - Based on our expertise in high-throughput PCR, we are trying to identify novel viruses in the human population. To date, have identified a novel primate KSHV homolog in primates as well as a novel SV40 homolog. We have since established the bioinformatics and robotics infrastructure for rapid screening, NextGen sequencing and quantification of known and unknown viruses.
- Regulation of KSHV latency - We initially demonstrated that the KSHV latency associated nuclear antigen (LANA) is transcribed in every single KS tumor cell. LANA is required for latent viral replication and proper episome segregation. LANA also binds to the p53 and other proteins, which suggests that LANA might be a putative viral oncogene and may contribute to KSHV pathogenesis. Since the LANA promoter is the major latency promoter of KSHV, we are engaged in a detailed investigation of its architecture and regulation by cellular factors, such as p53, Sp1 as well as LANA itself.
- Mouse models of KSHV oncogenesis and pre-clinical drug development - We have developed transgenic mice, which express the LANA protein under the control of its own promoter and had previously shown that the LANA promoter exhibits B-lineage specificity in transgenic mice. We use this model in conjunction with specific ko-mice to study the immune regulation by KSHV. Building upon or initial studies of SCID-human mouse models for primary KSHV infection, we established a xenograft model for KSHV-associated lymphomas and KS. Using this model we are investigating the anti-lymphoma properties of established and novel anti-viral drugs.
Roy D, Dittmer DP (2011). PTEN on Chromosome 10 Is Phosphorylated in Primary Effusion Lymphoma and Kaposi's Sarcoma. Am J Pathol.
Ramos JC, Sin SH, Staudt MR, Roy D, Vahrson W, Dezube BJ, Harrington W Jr, Dittmer DP (2011). Nuclear factor kappa B (NFkB) pathway associated biomarkers in AIDS defining malignancies. Int J Cancer. doi: 10.1002/ijc.26302.
Chen W, Dittmer DP (2011). Ribosomal Protein S6 Interacts with the Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus.
J Virol. 85(18):9495-505.
Roy D, Sin SH, Damania B, Dittmer DP (2011). Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines. Blood. 118(7):e32-9.
Chugh P, Tamburro K, Dittmer DP (2010). Profiling of pre-micro RNAs and microRNAs using quantitative real-time PCR (qPCR) arrays. J Vis Exp. (46). pii: 2210. doi: 10.3791/2210.
Dittmer DP (2010). The flu vaccine in cancer patients: insights from other immune-suppressed populations. Oncology (Williston Park). 24(12):1171.
Dittmer DP (2010). An appraisal of non-AIDS-defining cancers: comment on "Spectrum of cancer risk late after AIDS onset in the United States". Arch Intern Med. 170(15):1345-6.
Sin SH, Fakhari FD, Dittmer DP (2010). The Viral Latency-Associated Nuclear Antigen Augments the B-Cell Response to Antigen In Vivo. J. Virol. 2010 Oct. 84(20):10653-10660.
Chen W, Hilton IB, Staudt MR, Burd CE, Dittmer DP (2010). Distinct p53, p53:LANA, and LANA Complexes in Kaposi’s Sarcoma-Associated Herpesvirus Lymphomas. J. Virol. 2010 Apr. 84(8):3898-3908.
Bhatt AP, Bhende PM, Sin SH, Roy D, Dittmer DP, Damania B (2010). Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood. 2010 June. 115(22):4455-4463.
O’Hara AJ, Chugh P, Wang L, Netto EM, Luz E, Harrington Jr. WJ, Dezube BJ, Damania B, Dittmer DP (2009). Pre-Micro RNA Signatures Delineate Stages of Endothelial Cell Transformation in Kaposi Sarcoma. PLoS Pathogens. 2009 Apr. 5(4):1-14.
Gregory SM, West JA, Dillon PJ, Hilscher C, Dittmer DP, Damania B. Toll-like receptor signaling controls reactivation of KSHV from latency. Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11725-30.
O'Hara AJ, Vahrson W, Dittmer DP. Gene alteration and precursor and mature microRNA transcription changes contribute to the miRNA signature of primary effusion lymphoma. Blood. 2008 Feb 15;111(4):2347-53.
Krown SE, Lee JY, Dittmer DP; AIDS Malignancy Consortium (2008) More on HIV-associated Kaposi's sarcoma. N Engl J Med. 2008 358(5):535-6
A.D. Mutlu, L.E. Cavallin, L. Vincent, C. Chiozzini, P. Eroles, E.M. Duran, Z. Asgari, A.T. Hooper, K.M. LaPerle, C. Hilsher, S.J. Gao, D.P. Dittmer, S. Rafii, E. Mesri “In Vivo-Restricted and Reversible Malignancy Induced by Human Herpesvirus-8 KSHV: A Cell and Animal Model of Virally Induced Kaposi's Sarcoma” Cancer Cell 11(3): 245-58 (2007)
F.D. Fakhari, J.H. Jeong, Y. Kanan, and D.P. Dittmer, “The latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma”, J. Clinical Investigation, 116(3): 1-8 (2006)