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An In Vivo Genome-Wide CRISPR Screen Identifies the RNA-Binding Protein Staufen2 as a Key Regulator of Myeloid Leukemia

ABSTRACT: An In Vivo Genome-Wide CRISPR Screen Identifies the RNA-Binding Protein Staufen2 as a Key Regulator of Myeloid Leukemia

PROVIDER: PRJNA556899 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9847672_1.fastq.gz	Fastqsanger.gz
	SRR9847672_2.fastq.gz	Fastqsanger.gz
	SRR9847673_1.fastq.gz	Fastqsanger.gz
	SRR9847673_2.fastq.gz	Fastqsanger.gz
	SRR9847674_1.fastq.gz	Fastqsanger.gz

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An In Vivo Genome-Wide CRISPR Screen Identifies the RNA-Binding Protein Staufen2 as a Key Regulator of Myeloid Leukemia

Project description:While Chronic Myelogenous Leukemia (CML) is generally well controlled with Imatinib and other kinase inhibitors, blast crisis CML (bcCML) continues to be resistant to current therapies and remains highly lethal. In this study, we identify the double stranded RNA binding protein Stau2 as a as key new dependency of bcCML. To define the impact of Staufen2 in myeloid leukemia, we developed a germline knockout with targeted loss of its RNA binding domains. Genetic deletion of Staufen2 led to a profound decrease in bcCML growth and propagation, and markedly improved overall survival in mouse models. Further, Staufen2 was also expressed and required for growth of primary bcCML as well as de novo AML patient samples, indicating a conserved utilization across human disease. Finally, an integrated computational analysis of eCLIP, RNA-Seq analysis and the functional genomic CRISPR screen identified Staufen2 as a regulator of a remarkable network of broad acting chromatin modifiers, resulting in changes in global histone methylation patterns.

2020-04-23 | GSE134971 | GEO

An in vivo genome-wide CRISPR screen identifies the RNA-binding protein Staufen2 as a key regulator of myeloid leukemia.

Project description:Aggressive myeloid leukemias such as blast crisis chronic myeloid leukemia and acute myeloid leukemia remain highly lethal. Here we report a genome-wide in vivo CRISPR screen to identify new dependencies in this disease. Among these, RNA-binding proteins (RBPs) in general, and the double-stranded RBP Staufen2 (Stau2) in particular, emerged as critical regulators of myeloid leukemia. In a newly developed knockout mouse, loss of Stau2 led to a profound decrease in leukemia growth and improved survival in mouse models of the disease. Further, Stau2 was required for growth of primary human blast crisis chronic myeloid leukemia and acute myeloid leukemia. Finally, integrated analysis of CRISPR, eCLIP and RNA-sequencing identified Stau2 as a regulator of chromatin-binding factors, driving global alterations in histone methylation. Collectively, these data show that in vivo CRISPR screening is an effective tool for defining new regulators of myeloid leukemia progression and identify the double-stranded RBP Stau2 as a critical dependency of myeloid malignancies.

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CRISPR Screen of Venetoclax Response-Associated Genes Identifies Transcription Factor ZNF740 as a Key Functional Regulator [CUT&Run]

Project description:CRISPR Screen of Venetoclax Response-Associated Genes Identifies Transcription Factor ZNF740 as a Key Functional Regulator [CUT&Run]

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CRISPR Screen of Venetoclax Response-Associated Genes Identifies Transcription Factor ZNF740 as a Key Functional Regulator [RNA-Seq]

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Genome-wide CRISPR Screen Identifies DNTT as a Key Regulator of Inotuzumab Ozogamicin Response in B-cell Acute Lymphoblastic Leukemia

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CRISPR Screen of Venetoclax Response-Associated Genes Identifies Transcription Factor ZNF740 as a Key Functional Regulator [CUT&Run]

Project description:BCL-2 inhibitors such as venetoclax offer therapeutic promise in acute myeloid leukemia (AML) and other cancers, but drug resistance poses a significant challenge. It is crucial to understand the mechanisms that regulate venetoclax response. While correlative studies have identified numerous genes linked to venetoclax sensitivity, their direct impact on the drug response remains unclear. In this study, we targeted around 1,400 genes upregulated in venetoclax-sensitive primary AML samples and carried out a CRISPR knockout screen to evaluate their direct effects on venetoclax response. Our screen identified the transcription factor ZNF740 as a critical regulator, with its expression consistently predicting venetoclax sensitivity across subtypes of the FAB classification. ZNF740 depletion leads to increased resistance to venetoclax, while its overexpression enhances sensitivity to the drug. Mechanistically, our integrative transcriptomic and genomic analysis identifies NOXA as a direct target of ZNF740, which negatively regulates MCL-1 protein stability. Loss of ZNF740 downregulates NOXA and increases the steady state protein levels of MCL-1 in AML cells. Restoring NOXA expression in ZNF740-depleted cells re-sensitizes AML cells to venetoclax treatment. Furthermore, we demonstrated that dual targeting of MCL-1 and BCL-2 effectively treats ZNF740-deficient AML in vivo. Together, our work systematically elucidates the causal relationship between venetoclax response signature genes and establishes ZNF740 as a novel transcription factor regulating venetoclax sensitivity.

2024-09-04 | GSE267343 | GEO

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