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ABSTRACT: Evaluation of mutations upon aquired Venetoclax or S63845 resistance

PROVIDER: PRJNA716141 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14040769_1.fastq.gz	Fastqsanger.gz
	SRR14040769_2.fastq.gz	Fastqsanger.gz
	SRR14040770_1.fastq.gz	Fastqsanger.gz
	SRR14040770_2.fastq.gz	Fastqsanger.gz
	SRR14040771_1.fastq.gz	Fastqsanger.gz

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S63845 resistance mechnism

Project description:S63845 resistance mechnism

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Dynamic molecular monitoring reveals that SWI/SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma [ATAC-Seq]

Project description:Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and non-responders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI/SNF chromatin remodeling complex were present in all patients with primary resistance and 2/3 patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored providing concurrent information on treatment response and tumour evolution. Functional modeling demonstrated that compromise of the SWI/SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a paradigm for real-time assessment of innovative targeted therapies.

2018-11-21 | GSE122510 | GEO

Assessing DNA methylation differences upon aquired Venetoclax resistance

Project description:Assessing DNA methylation differences upon aquired Venetoclax resistance

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Assessing DNA methylation differences upon aquired Venetoclax resistance

Project description:We analyzed DNA methylation alterations upon acquired Venetoclax resistance using 8 different cell line pairs

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Project description:Venetoclax Resistance

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Dynamic molecular monitoring reveals that SWI/SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma [RNA-Seq]

2018-11-21 | GSE122509 | 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

Determinants of venetoclax resistance

Project description:Determinants of venetoclax resistance

| PRJNA558092 | ENA

Determinants of venetoclax resistance

Project description:Determinants of venetoclax resistance

| PRJNA558091 | ENA