Elucidating the mechanism and consequences of aberrant cyclin D1 gene expression

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ABSTRACT Some genes take drastic measures to force their aberrant expression. As an example, the gene cyclin D1 which is not normally present in B-cell lymphocytes is expressed in the blood cancer Mantle Cell Lymphoma (MCL). MCL is the most aggressive of all B-cell malignancies and a chromosomal translocation event, that pre-dates the disease, activates the cyclin D1 promoter is the initiating lesion in the transformation of normal B-cells. Once expressed, the transcribed cyclin D1 message (pre-mRNA) undergoes further processing which enables it to shorten it's 3'untraslated region (3'UTR) thus increasing the half-life of the transcript. The expression of cyclin D1 in MCL facilitates a hyper-proliferative phenotype and increases the genetic instability and chromosomal abnormalities of B-cells. In our prior work we identified a novel fusion gene in MCL cell lines and patient samples where cyclin D1 is joined to another gene thus resulting in a truncated 3'UTR. The goal of this project is to determine the molecular mechanisms that drive the shortening of the 3'UTR of cyclin D1 as well as the effects of the cyclin D1 driven chromosomal translocation events. In this proposal we will determine how the sequences found in the pre-mRNA of cyclin D1 as well as proteins involved in 3'end processing play a role in optimizing the expression of cyclin D1 in MCL (Aim 1). We will also systematically identify fusion genes, which result from chromosomal translocation events, using third generation sequencing technology which allows us to get full length gene transcripts (Aim 2). Although chromosomal translocations are known to occur with a high degree of frequency in MCL, apart from serendipity discovery in individual case studies, little effort has been put into identifying fusion genes on a global scale making this type of research innovative. Furthermore, our study will determine the molecular basis of abnormal 3'end formation will answer a basic question in the field. This will have a positive impact by establishing better understanding of disease causing genes are expressed in human cells and will allow for more effective strategies to detect and treat disease.