%0 Journal Article %J Cell %D 2018 %T An Integrated Genome-wide CRISPRa Approach to Functionalize lncRNAs in Drug Resistance %A Assaf C. Bester %A Jonathan D. Lee %A Chavez, Alejandro %A Yu-Ru Lee %A Daphna Nachmani %A Vora, Suhani %A Joshua Victor %A Martin Sauvageau %A Emanuele Monteleone %A Rinn, John L %A Paolo Provero %A Church, George M %A Clohessy, John G %A Pier Paolo Pandofi %X Resistance to chemotherapy plays a significant role in cancer mortality. To identify genetic units affecting sensitivity to cytarabine, the mainstay of treatment for acute myeloid leukemia (AML), we developed a comprehensive and integrated genome-wide platform based on a dual protein-coding and non-coding integrated CRISPRa screening (DICaS). Putative resistance genes were initially identified using pharmacogenetic data from 760 human pan-cancer cell lines. Subsequently, genome scale functional characterization of both coding and long non-coding RNA (lncRNA) genes by CRISPR activation was performed. For lncRNA functional assessment, we developed a CRISPR activation of lncRNA (CaLR) strategy, targeting 14,701 lncRNA genes. Computational and functional analysis identified novel cell-cycle, survival/apoptosis, and cancer signaling genes. Furthermore, transcriptional activation of the GAS6-AS2 lncRNA, identified in our analysis, leads to hyperactivation of the GAS6/TAM pathway, a resistance mechanism in multiple cancers including AML. Thus, DICaS represents a novel and powerful approach to identify integrated coding and non-coding pathways of therapeutic relevance. %B Cell %V 173 %P 649-664 %G eng %U http://www.cell.com/cell/fulltext/S0092-8674(18)30384-2 %N 3