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Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition [CRISPR mini screen]

ABSTRACT: CRISPR/Cas9 screens identified unexpected hits in human AML cell lines whose loss of function causes resistance to SHP2 inhibition

ORGANISM(S): Homo sapiens

PROVIDER: GSE218489 | GEO | 2023/02/20

REPOSITORIES: GEO

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Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition [CRISPR genomic screen]

Project description:CRISPR/Cas9 screens identified unexpected hits in human AML cell lines whose loss of function causes resistance to SHP2 inhibition

2023-02-20 | GSE218488 | GEO

Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 Inhibition [RNA-seq]

Project description:CRISPR/Cas9 screens identified unexpected hits in human AML cell lines whose loss of function causes resistance to SHP2 inhibition.

2023-02-20 | GSE212231 | GEO

Genome-wide CRISPR-Cas9 screens reveal loss of redundancy between PKMYT1 and WEE1 in Glioblastoma stem-like cells

Project description:To identify new therapeutic targets for Glioblastoma (GBM), we performed genome-wide CRISPR-Cas9 "knockout" (KO) screens in patient-derived GBM stem-like cells (GSCs) and human neural stem/progenitors (NSCs), non-neoplastic stem cell controls, for genes required for their in vitro growth. Surprisingly, the vast majority GSC-lethal hits were found outside of molecular networks commonly altered in GBM and GSCs (e.g., oncogenic drivers). In vitro and in vivo validation of GSC-specific targets revealed several strong hits, including the wee1-like kinase, PKMYT1/Myt1. Mechanistic studies demonstrated that PKMYT1 acts redundantly with WEE1 to inhibit Cyclin B-CDK1 activity via CDK1-Tyr15 phosphorylation and to promote timely completion of mitosis in NSCs. However, in GSCs, this redundancy is lost, likely as a result of oncogenic signaling, causing GBM-specific lethality. A whole-genome CRISPR-Cas9 knockout screens targeting over 18,000 genes using the all-in-one LV-sgRNA:Cas9 platform system were performed using a âshot gunâ approach by transducing 2 GBM patient-derived isolates and 2 human neural stem cell isolates with the pool library (2 biological replicates), and cultures were outgrown for ~3 weeks. The end time point of each screen was compared to day 0 in order to determine which sgRNAs were overrepresented or underrepresented in the population.

2016-02-15 | E-GEOD-70038 | biostudies-arrayexpress

CRISPR Cas9 screens for drug resistance in AML cell lines

Project description:Acute myeloid leukaemia (AML) continues to have a very high mortality and its treatment hasnot changed for more than 20 years.Here, we propose to apply genomic-wide screens to directly identify therapeutic vulnerabilitiesof AML using AML cells lines with pre-defined somatic mutations. Our studies will be basedon genome-wide CRISPR/CAs9 gRNA screens and will be used to identify drivers of drugresistance to standard chemotherapies.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

2015-02-03 | E-ERAD-335 | biostudies-arrayexpress

Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 Inhibition

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-02-20 | GSE218491 | GEO

Parallel CRISPR-Cas9 screens clarify impacts of p53 on screen performance.

Project description: Not available

| S-EPMC7244323 | biostudies-literature

CRISPR/Cas9 Screens Reveal Epstein-Barr virus Synthetic Lethal Targets

Project description:Epstein-Barr virus (EBV) causes endemic Burkitt lymphoma and immunosuppression-related lymphomas. These B-cell malignancies arise by distinct transformation pathways and utilize divergent viral and host expression programs. To identify host dependency factors elicited by EBV latent-infection states, we performed parallel genome-wide CRISPR/Cas9 screens in Burkitt lymphoma (BL) and lymphoblasotid cell lines (LCL). Our results highlighted 57 BL and 87 LCL genes selectively critical for their growth and survival. LCL hits were enriched for EBV-induced genes, including viral super-enhancer targets and multiple kinases. We uncovered key CD19/CD81 roles in EBV membrane protein-driven PI3K/AKT activation and mechanisms by which EBV evades tumor suppressor responses to its growth program. LMP1-induced cFLIP was critical for LCL defense against TNFa-mediated programmed cell death, while EBV-induced BATF/IRF4 were critical for LCL BIM suppression and MYC induction. EBV super-enhancer targeted IRF2 protected LCLs against BLIMP1 responses. Collectively, our results identify host/pathogen interaction-driven synthetic lethal targets for therapeutic intervention.

2017-05-11 | GSE93681 | GEO

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9orf72 dipeptide repeat protein toxicity

Project description:Hexanucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9FTD/ALS). The nucleotide repeat expansions are translated into dipeptide repeat (DPR) proteins, which are aggregation-prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene knockout screens for suppressors and enhancers of C9orf72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA processing pathways, and in chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9orf72 DPRs in neurons, and improved survival of human induced motor neurons from C9orf72 ALS patients. Together, this work demonstrates the promise of CRISPR-Cas9 screens to define mechanisms of neurodegenerative diseases. This dataset contains the RNA-sequencing data used to support the conclusions from this study.

2018-02-27 | GSE109177 | GEO

Genome-wide CRISPR-Cas9 screens reveal loss of redundancy between PKMYT1 and WEE1 in Glioblastoma stem-like cells

2016-02-15 | GSE70038 | GEO

CRISPR activation and interference screens decode stimulation responses in primary human T cells [CRISPR]

Project description:Regulation of cytokine production in stimulated T cells can be disrupted in autoimmunity, immunodeficiencies, and cancer. Systematic discovery of stimulation-dependent cytokine regulators requires both loss-of-function and gain-of-function studies, which have been challenging in primary human cells. We now report genome-wide CRISPR activation (CRISPRa) and interference (CRISPRi) screens in primary human T cells to identify gene networks controlling interleukin 2 and interferon gamma production. Arrayed CRISPRa confirmed key hits and enabled multiplexed secretome characterization, revealing reshaped cytokine responses. Coupling CRISPRa screening with single-cell RNA-seq enabled deep molecular characterization of screen hits, revealing how perturbations tuned T cell activation and promoted cell states characterized by distinct cytokine expression profiles. Together, these screens reveal genes that reprogram critical immune cell functions, which could inform the design of immunotherapies.

2021-05-13 | GSE174255 | GEO

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