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The BCL-2 Inhibitor Venetoclax in Combination with Azacitidine Disrupts Energy Metabolism and Targets Leukemia Stem Cells in Acute Myeloid Leukemia Patients

ABSTRACT: The BCL-2 Inhibitor Venetoclax in Combination with Azacitidine Disrupts Energy Metabolism and Targets Leukemia Stem Cells in Acute Myeloid Leukemia Patients

PROVIDER: PRJNA479415 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7466800.fastq.gz	Fastqsanger.gz
	SRR7466801.fastq.gz	Fastqsanger.gz
	SRR7466802.fastq.gz	Fastqsanger.gz
	SRR7466803.fastq.gz	Fastqsanger.gz
	SRR7466804.fastq.gz	Fastqsanger.gz

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Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia

Project description:Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Leukemia stem cells (LSCs) drive the initiation and perpetuation of AML, are quantifiably associated with worse clinical outcomes, and often persist after conventional chemotherapy resulting in relapse1-5. In this report, we show that treatment of older patients with AML with the B cell lymphoma 2 (BCL-2) inhibitor venetoclax in combination with azacitidine results in deep and durable remissions and is superior to conventional treatments. We hypothesized that these promising clinical results were due to targeting LSCs. Analysis of LSCs from patients undergoing treatment with venetoclax + azacitidine showed disruption of the tricarboxylic acid (TCA) cycle manifested by decreased α-ketoglutarate and increased succinate levels, suggesting inhibition of electron transport chain complex II. In vitro modeling confirmed inhibition of complex II via reduced glutathionylation of succinate dehydrogenase. These metabolic perturbations suppress oxidative phosphorylation (OXPHOS), which efficiently and selectively targets LSCs. Our findings show for the first time that a therapeutic intervention can eradicate LSCs in patients with AML by disrupting the metabolic machinery driving energy metabolism, resulting in promising clinical activity in a patient population with historically poor outcomes.

2019-01-30 | GSE116481 | GEO

The BCL-2 Inhibitor Venetoclax in Combination with Azacitidine Disrupts Energy Metabolism and Targets Leukemia Stem Cells in Acute Myeloid Leukemia Patients

Project description:The manuscript summarizes clinical and laboratory-based evaluation of 33 AML patients treated with a novel drug combination, venetoclax and azacytidine. Our findings indicate that this regimen is exceptionally promising for the treatment of de novo AML patients. The improvement in outcomes in comparison to conventional therapy is quite remarkable. The manuscript explores the mechanistic basis for the clinical outcomes, testing the hypothesis that venetoclax and azacytidine effectively target leukemia stem cells (LSCs) in vivo. Our findings indicate the regimen is highly active towards the LSC population. Specifically, we describe a mechanism that suppresses the activity of electron transport complex II, resulting in inhibition of oxidative phosphorylation.

2018-09-01 | GSE116567 | GEO

Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia

Project description:Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia

| PRJNA478784 | ENA

IMPRINTS-CETSA Venetoclax in Kasumi-1 cells, 6h incubation

Project description:IMPRINTS-CETSA data acquisition of Kasumi-1 cells treated with Vehicle (DMSO), Venetoclax, Decitabine, Azacitidine and Azacitidine+Venetoclax using TMT 16 plex.

2024-10-23 | PXD056189 | Pride

IMPRINTS-CETSA Venetoclax in Kasumi-1 cells, 1h incubation

Project description:IMPRINTS-CETSA data acquisition of Kasumi-1 cells treated with Vehicle (DMSO), Venetoclax, Decitabine, Azacitidine and Azacitidine+Venetoclax using TMT 16 plex.

2024-10-23 | PXD056183 | Pride

Transcriptional changes in human natural killer cells derived from umbilical cord blood in response to the BCL-2 inhibitor Venetoclax

Project description:Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment, but its efficacy is still limited, necessitating the development of new strategies. Here, we report an unexpected discovery that venetoclax, the first FDA-approved BCL-2 inhibitor, acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against acute myeloid leukemia (AML). Venetoclax directly activates human NK cells, boosting their cytotoxicity against AML both in vitro and in vivo, independent of BCL-2 inhibition. Venetoclax enhances NK cell binding avidity and lytic granule polarization during immunological synapse (IS) formation.Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, facilitating IS formation and effector function in human NK cells.Our findings establish venetoclax as a multifaceted immunometabolic modulator that enhances NK cell function, providing new insights for augmenting NK cell-mediated cytotoxicity in cancer immunotherapy.

2023-07-31 | GSE237922 | GEO

Single-cell transcriptome analysis of human natural killer cells derived from umbilical cord blood in response to the BCL-2 inhibitor venetoclax

Project description:Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment, but its efficacy is still limited, necessitating the development of new strategies. Here, we report an unexpected discovery that venetoclax, the first FDA-approved BCL-2 inhibitor, acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against acute myeloid leukemia (AML). Venetoclax directly activates human NK cells, boosting their cytotoxicity against AML both in vitro and in vivo, independent of BCL-2 inhibition. Notably, we identify a distinct CD161low CD218b+ NK cell subpopulation exhibiting the most pronounced proportional increase and transcriptomic changes upon venetoclax treatment.Venetoclax enhances NK cell binding avidity and lytic granule polarization during immunological synapse (IS) formation.Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, facilitating IS formation and effector function in human NK cells.Our findings establish venetoclax as a multifaceted immunometabolic modulator that enhances NK cell function, providing new insights for augmenting NK cell-mediated cytotoxicity in cancer immunotherapy.

2023-07-31 | GSE237923 | GEO

Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia.

| S-EPMC7001730 | biostudies-literature

CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) of paired diagnosis and relapse specimens from acute myeloid leukemia (AML) patients treated with venetoclax plus azacitidine

Project description:To understand relapse mechanisms related to AML patients treated with venetoclax plus azacitidine therapy, we performed CITE-seq on paired diagnosis and relapse specimens from an AML patient treated with the therapy.

2020-01-24 | GSE143363 | GEO

Effect of pharmacological BCL-2 inhibition with venetoclax on T cell homeostasis

Project description:Venetoclax, a BCL-2 specific inhibitor, has been show to confer transcriptional changes in T cell populations. In order to elucidate how these changes may be occuring, we sought to investigate whether there are epigenetic alterations that may offer a potential explanation. To begin to answer this question, we conducted ATAC-sequencing on Treg cells isolated from FOXP3-IRES-GFP mice treated for 14 days with 50mg/kg of venetoclax and assessed for global accessibility changes.

2023-09-01 | GSE224080 | GEO

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