Long Non-Coding RNAs Regulate Transcription of Lymphoma Oncogenes

Non-Hodgkin Lymphoma (NHL) is the most common blood cancer in the U.S. Our analysis of gene regulation in >100 NHL and normal B cell samples revealed a distinct profile of long non-coding RNA (lncRNA) expression. Few lncRNAs have been characterized, and there are no guidelines for functional prediction or categorization. Therefore, we developed a novel computational approach: Correlative Recurrent Expression of Predicted Elements (CREPE), which integrates -omics data to create a correlative regression model to predict lncRNA function. CREPE analysis revealed several NHL-associated lncRNAs that may regulate the expression of signaling proteins downstream of B-cell receptor activation. We highlight a multi-exon lncRNA that is highly expressed in NHL and has a top-ranked CREPE transcriptional regulatory score: AC074289.1. Consistent with a role in regulating transcription, qRT-PCR of subcellular fractions demonstrate nuclear localization and chromatin association (3.5–5X : cytoplasm). Expression of AC074289.1 is cell-type specific with 5–10X higher levels in B lymphoid compared to T or epithelial cell lines. AC074289.1 expression positively correlates with a neighboring gene, PELI1, which encodes Pellino 1, an E3 ubiquitin ligase that modulates NF-κb signaling in immune cells. NF-κb signaling also plays a significant role in NHL pathogenesis. Notably, high PELI1 expression is associated with more aggressive NHL. In summary, our global -omics study of normal and NHL samples identified new gene regulatory connections between lncRNAs and potential NHL oncogenes, including AC074289.1 and PELI1. This novel approach will accelerate our understanding of lncRNA function and may uncover new therapeutic targets in NHL.