期刊
CELL
卷 173, 期 3, 页码 649-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.03.052
关键词
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资金
- EMBO Long-Term Fellowship [ALTF 318-2013]
- Fulbright awards
- NCI [5T32CA009216-34]
- Burroughs Wellcome Fund Career Award for Medical Scientists
- NIH [RM1 HG008525, P50 HG005550]
- NIH NCI R35 grant [CA197529]
- Ludwig Center at Harvard
- Common Fund of the Office of the Director of the NIH
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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