[PDF][PDF] An integrated genome-wide CRISPRa approach to functionalize lncRNAs in drug resistance
Cell, 2018•cell.com
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 …
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 …
Summary
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.
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