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Genome-wide CRISPR/Cas9 guide library knockout screening in Nalm6 ALL cells under CART19 selective pressure

ABSTRACT: Genome-wide CRISPR/Cas9 guide library knockout screening in Nalm6 ALL cells under CART19 selective pressure

PROVIDER: PRJNA541517 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9024411.fastq.gz	Fastqsanger.gz
	SRR9024412.fastq.gz	Fastqsanger.gz
	SRR9024413.fastq.gz	Fastqsanger.gz
	SRR9024414.fastq.gz	Fastqsanger.gz
	SRR9024415.fastq.gz	Fastqsanger.gz

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Genome-wide CRISPR/Cas9 guide library knockout screening in Nalm6 ALL cells under CART19 selective pressure

Project description:Cellular immunotherapy using T cells engineered to express chimeric antigen receptors targeting CD19 (CART19) leads to long-term remission in patients with B-cell malignancies1-5. Unfortunately, a significant fraction of patients demonstrate primary resistance to CART19 or experience relapse after achieving remission. Beyond loss of target antigen, the molecular pathways governing CART19 failure are unknown. Here we demonstrate that death receptors, cell surface signaling molecules that induce target cell apoptosis, are key mediators of leukemic resistance and CART19 failure. Using a functional CRISPR/Cas9-based genome-wide knockout screen6 in B-cell acute lymphoblastic leukemia (ALL), we identified the death receptor signaling pathway as a central regulator of sensitivity to CART19-induced cell death. In the absence of the pro-apoptotic death receptor signaling molecules BID or FADD, ALL cells were resistant to CART19 cytotoxicity, resulting in rapid disease progression in mice. We found that this initial resistance to cytotoxicity led to persistence of tumor cells, which drove the development of T cell dysfunction that further compromised anti-tumor immunity and permitted tumor outgrowth. We validated these findings using clinical samples collected from patients with ALL treated with CD19-targeted CAR T cells and found that expression of pro-apoptotic death receptor pathway genes in pre-treatment tumor samples correlated with CAR T cell expansion and persistence, as well as patient response and overall survival. Our findings indicate that tumor-intrinsic death receptor signaling directly contributes to CAR T cell failure.

2020-02-17 | GSE130819 | GEO

ATAC profiling of CART19 cells exposed to WT and BIDko Nalm6 cells

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Transcriptional profiling of CART19 cells exposed to WT and BIDko Nalm6 cells

Project description:Transcriptional profiling of CART19 cells exposed to WT and BIDko Nalm6 cells

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ATAC profiling of CART19 cells exposed to WT and BIDko Nalm6 cells

Project description:ATAC profiling of CART19 cells exposed to WT and BIDko Nalm6 cells

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mRNA profiling on GM-CSF knockout CART19 compared to wildtype CART19 and Ctrl gRNA CART19 produced from normal donors

Project description:RNA sequencing was performed on three biological replicates of CART19 (GM-CSF wildtype), GM-CSF knockout CART19, and Ctrl gRNA CART19 produced from normal donors.

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Project description:RNA sequencing was performed on three biological replicates of untransduced (UTD) T cells, CART19 (TNFR2 wildtype) and TNFR2 knockout CART19 produced from normal donors.

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Project description:RNA sequencing was performed on three biological replicates of DMSO treated CART19 (control) and TP0903 treated CART19 produced from normal donors.

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