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- W2197777720 abstract "Acquired or de novo resistance to established (e.g. proteasome inhibitors) or investigational therapies represents a major clinical challenge and mechanistic conundrum in multiple myeloma (MM). To comprehensively characterize these treatment resistance mechanisms, we applied the CRISPR (clustered regularly interspaced short palindromic repeats)–associated nuclease Cas9 system and libraries of single-guide RNAs (sgRNAs). Briefly, we transduced RPMI8226 cells with lentiviral constructs for the Cas9 nuclease and for a genome-scale library (GeCKO v2) of 64,751 unique sgRNA sequences. The latter target Cas9 to the 5 constitutive exons of 18,080 genes (average coverage of 3- 4 sgRNAs per gene), causing double-stranded cleavage and loss of function for the respective gene. Pools of sgRNA-transduced MM cells were treated with anti-MM agents (e.g. Bortezomib, bromodomain inhibitor JQ1) and the distribution of sgRNAs (quantified by next-generation sequencing) in the cells surviving each treatment identified candidate regulators of resistance. A repeat genomewide screen was performed and a larger set of cell lines were lentivirally transduced with focused libraries of sgRNAs against candidate resistance genes with concordant results in the 2 screens. The identified candidate bortezomib-resistance genes have documented or presumed functions in regulation of apoptosis, autophagy, Toll-like receptor and NF-kappaB signaling, aggresome function, heat shock protein expression, chromatin remodeling, etc. These genes were also deleted, downregulated, or mutated less frequently in patients with newly diagnosed MM compared to other, bortezomib-unresponsive, neoplasias; while transcriptional signatures of low expression of these resistance genes correlated with shorter time-to-progression in bortezomib- but not dexamethasone-treated MM patients. The validation studies with focused sgRNA libraries identified both genes with concordant role in resistance across several MM cell lines (e.g. PMAIP1); as well as other genes with cell line-specific impact on resistance. These results indicate the power of CRISPR/Cas9-based technologies to interrogate gene function on a genome-wide scale, characterize the heterogeneous and complex nature of molecular mechanisms mediating drug resistance, and identify groups of pathophysiologically and clinically relevant molecular markers of this resistance." @default.
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- W2197777720 date "2015-09-01" @default.
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- W2197777720 title "Genome-scale CRISPR-Cas9 knockout studies to characterize the mechanisms of myeloma cell treatment resistance." @default.
- W2197777720 doi "https://doi.org/10.1016/j.clml.2015.07.172" @default.
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