Abstract PR13: CRISPRi screening with targeted therapeutics classifies functional long non-coding RNAs in DLBCL

While tens of thousands of lncRNAs have been detected in the human genome, the functional significance of the majority of these genes remain untested. Here, we use CRISPR interference (CRISPRi) loss-of-function screening combined with targeted drug treatment to identify oncogenic and tumor suppressive lncRNAs. Integrative analysis of 417 primary human tumor and cell line RNA-seq datasets from Diffuse Large B Cell Lymphoma (DLBCL) identified 1,276 intergenic lncRNA candidates, including 59 de novo assembled transcripts. CRISPRi screening in a genetically diverse panel of 4 DLBCL cell lines identified known ABC DLBCL protein-coding oncogenes (BTK, CD79A) and demonstrated oncogenic function of 247 lncRNAs including MIR155HG and MALAT1. To assign functionally-related pathways to unknown lncRNAs, we performed this CRISPRi screen in the context of drugs with known targets: Ibrutinib (BTK), JQ1 (BRD4), and Etoposide (TOP2A). Significant synergy or resistance to drug treatment was observed with 54 lncRNAs. This ongoing work demonstrates a high-throughput pipeline for functional classification of lncRNAs using synthetic lethality screening in cancer. Citation Format: Dan E. Webster, James D. Phelan, Monica Kasbekar, Arthur L. Shaffer, III, Louis M. Staudt. CRISPRi screening with targeted therapeutics classifies functional long non-coding RNAs in DLBCL [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR13.