A hallmark event in the formation of Mantle Cell Lymphoma (MCL) is the translocation of the cyclin D1 gene downstream of the Ig Enhancer resulting in an upregulation of transcription. In the most proliferative cases of MCL in patients with the lowest survival the cyclin D1 3'UTR is shortened through alternative cleavage and polyadenylation (APA) resulting in a more stable mRNA that is resistant to microRNA. We will also using the newly developed 3P-Seq Deep Sequencing technology to define a global polyA site selection signature for MCL. Also, we will systematically deplete the known members of the cleavage and polyadenylation machinery and test for changes in cyclin D1 poly(A) site selection. Collectively, the information gathered from this proposal will provide a clearer picture of APA events both at the cyclin D1 locus and throughout the genome. This will provide further diagnostic markers and may aid in early cancer detection.
Recent observations demonstrate that as cells undergo tumorigenesis they shorten the length of their mRNA through the process of alternative cleavage and polyadenylation (APA). This proposal aims to employ 3P-Seq technology to identify APA events specific for Mantle Cell Lymphoma (MCL) and to identify candidate factors involved in this process. Successful completion of this research will generate potential biomarkers for MCL and will produce data for more detailed long-term studies leading to a better understanding of how APA is altered during tumorigenesis.
