Abstract 1181: Expression studies from the PVT1 region of 8q24

Several SNPs in the area surrounding the PVT1 noncoding gene region on human chromosome 8q24 have recently been found by Genome Wide Association (GWA) to be associated with susceptibility to a number of malignancies including Hodgkin9s Lymphoma and other diseases including Type II Diabetes and End Stage Renal Disease in Type I Diabetes. This genetically unstable region is one of the most frequent targets of retroviral integration of the Human Papilloma Virus Type 18 (HPV18 in Cervical Carcinoma) and is the frequent target of chromosomal translocation in lymphoid malignancies such as Non-Hodgkin9s Lymphoma [incl. Burkitt9s Lymphoma (BL) and Diffuse Large B Cell Lymphoma (DLBL)]. Gene amplification in carcinomas such as breast, prostate, ovarian, colon, pancreatic, esophageal, as well as osteogenic sarcoma usually encompasses the proximal region of PVT1 along with its well-known neighboring transcript, MYC, whereas chromosomal deletion (in hematodermic NK lymphoma) affects the distal segment of PVT1. In a search for functionality to PVT1, many laboratories (including our own) have cloned and sequenced transcripts from the PVT1 region from many species in addition to human, with the conclusion that PVT1 is a noncoding or lincRNA with many alternatively spliced isoforms. We have systematically documented these isoforms with a particular focus on promoter and regulatory elements that are found in the region. Our laboratory has also identified a cluster of at least 6 miRNAs (miR-1204∼1208) that span the PVT1 region adding yet another level of complexity to the locus. To begin to assign some function to PVT1 based transcripts in these disease phenotypes, we have made 4th generation (CMV promoter with WPE enhancer) over-expressing lentiviral constructs containing either a large segment of PVT1 (Exons 1b-10) or the most proximal and abundant miRNA, miR-1204. These constructs follow earlier studies with a 3rd generation lentivirus (CMV promoter) containing miR-1204 that rapidly generated DLBL in cooperation with MYC or IL6 transgenes (∼16 days or 82 days respectively). While these results pointed to over-expression of miR-1204 playing a specific role in the development of B cell malignancy, additional studies with the LentiCMV-miR-1204 construct in other tumor cell lines (prostate and breast) also revealed potential phenotypic changes in cell proliferation and migration. With the new 4th generation constructs, experiments are now underway in cell lines and mouse models to determine if over-expression of miR-1204 or PVT1 alone is sufficient to induce phenotypic changes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1181. doi:10.1158/1538-7445.AM2011-1181