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

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

PROVIDER: PRJNA1111109 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29012912_1.fastq.gz	Fastqsanger.gz
	SRR29012912_2.fastq.gz	Fastqsanger.gz
	SRR29012913_1.fastq.gz	Fastqsanger.gz
	SRR29012913_2.fastq.gz	Fastqsanger.gz
	SRR29012914_1.fastq.gz	Fastqsanger.gz

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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.

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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 [RNA-Seq]

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

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Histone Variant H2A.J is a Key Epigenetic Regulator in Human Trophoblast Development [CUT&RUN]

Project description:Histone Variant H2A.J is a Key Epigenetic Regulator in Human Trophoblast Development [CUT&RUN]

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Paired single-cell RNA-seq pre- and post-venetoclax therapy of 8 AML patients

Project description:Acute myeloid leukemia (AML) remains a cancer with dismal prognosis, particularly in high-risk disease patients and those ineligible for allogeneic stem cell transplantation. BCL-2 inhibitor venetoclax, in combination with hypomethylating agents, has emerged as an effective therapy and forms the backbone of multiple combination therapies in clinical trials. However, venetoclax-based therapy is rarely curative. While multiple venetoclax resistance mechanisms have been discovered, most of these have been identified using cell line models that only partially reflect the heterogeneous composition of human AML. Using paired single-cell data from 8 AML patients with pre- and post-venetoclax therapy samples, we aimed to characterize mechanisms driving venetoclax resistance in a clinically relevant setting.

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A Genome-Wide CRISPR Screen Identifies BRD4 as a Regulator of Cardiomyocyte Differentiation [CUT&RUN]

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Targeting mitochondrial structure sensitizes AML to Venetoclax

Project description:The BCL-2 family plays important roles in acute myeloid leukemia (AML) and Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML cells to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.

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