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Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax

ABSTRACT: Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax

PROVIDER: PRJNA685356 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13255527_1.fastq.gz	Fastqsanger.gz
	SRR13255527_2.fastq.gz	Fastqsanger.gz
	SRR13255528_1.fastq.gz	Fastqsanger.gz
	SRR13255528_2.fastq.gz	Fastqsanger.gz
	SRR13255529_1.fastq.gz	Fastqsanger.gz

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Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [ATAC-Seq]

Project description:The prognosis for B cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however lack of sufficient responses in pre-clinical models and possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in patient derived xenograft model leads to downregulation of particular p53-related genes. Interestingly, addition of auranofin, a thioredoxin system inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently on the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of NOXA-encoding gene (PMAIP1) by chromatin remodeling and increased transcriptional accessibility. Altogether, these results present novel, promising drug combination that could be exploited for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations.

2022-01-19 | GSE163228 | GEO

Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [RNA-Seq]

2022-01-19 | GSE163227 | GEO

Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [RNA-Seq]

Project description:Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [RNA-Seq]

| PRJNA685404 | ENA

Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [ATAC-Seq]

Project description:Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [ATAC-Seq]

| PRJNA685405 | ENA

Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax

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

2022-01-19 | GSE163229 | GEO

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.

2019-05-03 | GSE125403 | GEO

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

Targeting mitochondrial structure sensitizes AML to Venetoclax

Project description:Targeting mitochondrial structure sensitizes AML to Venetoclax

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Targeting SUMOylation sensitizes Acute myeloid leukemia to Venetoclax treatment

Project description:Targeting SUMOylation sensitizes Acute myeloid leukemia to Venetoclax treatment

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