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

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

PROVIDER: PRJNA1101988 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28737259_1.fastq.gz	Fastqsanger.gz
	SRR28737259_2.fastq.gz	Fastqsanger.gz
	SRR28737260.fastq.gz	Fastqsanger.gz
	SRR28737260_1.fastq.gz	Fastqsanger.gz
	SRR28737260_2.fastq.gz	Fastqsanger.gz

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

Project description:Inotuzumab Ozogamicin (InO) is an antibody-drug conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide inter-patient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered the loss of DNTT as a top driver of InO resistance. Our results directly show the effects of DNTT expression on H2AX phosphorylation, DNA damage response signaling, cell cycle arrest and mitochondrial apoptotic priming, ultimately conferring leukemia resistance to InO. Screening 196 primary human B-ALL samples for InO sensitivity confirmed the impact of DNTT expression on InO response. Additionally, low DNTT expression was found in the residual leukemia blasts post InO treatment in patients enrolled in the COG trial AALL1621. Collectively, we demonstrate that loss of DNTT diminishes B-ALL sensitivity to InO in vitro and promotes leukemia cell survival during InO treatment in vivo.

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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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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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Genome-wide CRISPR screen identifies IRF1 and TFAP4 as transcriptional regulators of Galectin-9 in T cell acute lymphoblastic leukemia [CRISPR]

Project description:Galectin-9 is overexpressed in a variety of cancers and associated with worse clinical outcome in some cancers. However, the regulators driving Galectin-9 expression are unknown. Here, we defined the transcriptional regulators and epigenetic circuitry of Galectin-9 in pediatric T cell acute lymphoblastic leukemia (T-ALL), as an example of a disease with strong Galectin-9 expression, in which higher expression was associated with lower overall survival. By performing a genome-wide CRISPR screen, we identified the transcription factors IRF1 and TFAP4 as key regulators for Galectin-9 expression by binding its regulatory elements. While IRF1 was observed exclusively on the promoter, TFAP4 binding was detected at an enhancer solely in T-ALL cells associated with higher Galectin-9 levels. Together, our results show that IRF1 is responsible and indispensable for Galectin-9 expression and TFAP4 further fine-tunes its expression. Our approach, a flow-based genome-wide CRISPR screen complemented by transcription factor binding and enhancer mapping, creates innovative opportunities for understanding and manipulating epigenetic transcriptional regulation in cancer.

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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

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

2024-09-04 | GSE267342 | GEO

CRISPR screen of venetoclax response-associated genes identifies transcription factor ZNF740 as a key functional regulator.

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 1400 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 ventoclax, 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.

| S-EPMC11350041 | biostudies-literature

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