The missing piece: Long noncoding RNAs in cancer cell biology

While RNA was long thought to act as a mere intermediary between DNA and protein, we now know RNA transcripts can have diverse cellular functions themselves. The major class of long noncoding (lncRNAs) thus represent a missing piece in the puzzle of human cell biology. A variety of transcriptional as well as posttranscriptional regulatory mechanisms have been described for lncRNAs. This thesis addresses the relevance of lncRNAs in normal B cell development and B cell malignancies. Specifically, we study lncRNA expression changes in normal B cells before, during and after the maturation process using naive, germinal center [GC] and memory B cells, respectively. Vast lncRNA expression changes are observed in the highly proliferative GC B cells, indicating significant lncRNA involvement in the B cell maturation process. Furthermore we identify multiple lncRNAs overexpressed in Hodgkin lymphoma cell lines compared to their cell-of-origin, which show cancer cell specific expression in primary patient tissue. We defined lncRNAs regulated by the oncogenic transcription factor Myc and putatively involved in its proliferation-supportive effects. We observe deregulation of hundreds of lncRNAs in response to Myc, thus identifying lncRNAs as a major component of the Myc transcriptional network. Myc-induced lncRNA KTN1-AS1 is studied in more detail and shown to affect Burkitt lymphoma cell growth by reinforcing high Myc expression. In summary, our studies provide novel insights into the role of lncRNAs in normal B cells and B cell malignancies. The individual lncRNAs we identified can potentially serve as biomarkers or therapeutic targets for lymphoma detection and treatment.