Multiple myeloma (MM) is a heterogenous disease. Although there have been several novel agents and combinations available for treatment, the genomic adaptability of the tumor cells lead to their continued growth and and adverse survival outcome. Therefore there is need for identification of novel target sand directed therapies. One of the emrging areas of research in this direction has been the recent advances highlighting the functional significance of long noncoding RNAs (lncRNAs) that span > 80% of human genome. These RNA molecules control variety of cellular and molecular functions via mechanisms that are as yet not well described. In our preliminary investigation we utilized our RNA- seq data from CD138+ MM cells from 308 newly diagnosed and uniformly treated patients, and 16 normal plasma cells and described the aberrant lncRNA landscape in MM. We identified 869 differentially expressed lncRNAs in MM compared to normal plasma cells. We identified 14 lncRNAs associated with PFS and calculated a risk score that stratified patients and report their significant role as an independent risk predictor for clinical outcome1. These results provided the rationale to further investigate biological and molecular activity of lncRNA in MM. We evaluated 913 expressed lncRNAs for impact on MM cell viability in a preliminary CRISPR interference (CRISPRi)-based screen. A primary screen in 3 MM cell lines identified 20 lncRNAs impacting MM cell viability. Evaluation using RNA-seq data showed a significant upregulation of these 20 lncRNAs. Of note, specific lncRNAs were found selectively upregulated in genetically-defined patient subsets, including high-risk MM carrying t(4;14). A secondary screen (of the most enriched or depleted sgRNAs) identified MIR17HG (RNA Regulator of Lipogenesis; RROL), as one of the top hits as a novel lncRNA in MM. In subsequent experiments, suppression of RROL significantly impaired MM cell growth and survival in vitro and in vivo. We also observed that Acetyl Co-A Carboxylase 1 (ACC1), the rate-limiting enzyme of de novo lipogenesis (DNL) pathway, is one of the primary targets of RROL. This metabolic pathway converts nutrients (glucose, glutamine, etc.) into fatty acids serving for energy storage or biosynthesis of membranes and signaling molecules. We have also begun to investigate inhibitors of both lncRNA RROL as well as ACC1 and observed anti-MM activity. Based on these observations, we hypothesize that dysregulated lncRNAs significantly impact the pathobiology of MM by their ability to control multiple genes, with potential to serve as therapeutic targets. To further understand the role of lncRNAs in MM and identify those associated with progression, and to evaluate their therapeutic potential, we will identify functional lncRNA dependencies in myeloma (Aim 1), validate the role of functional lncRNAs in MM (Aim 2) and evaluate inhibitors of MIR17HG (RROL) and its downstream target using small molecule and transgenic manipulati...