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

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

PROVIDER: PRJNA478784 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7459012.fastq.gz	Fastqsanger.gz
	SRR7459013.fastq.gz	Fastqsanger.gz
	SRR7459014.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

| PRJNA479415 | ENA

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

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

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

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

Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

Project description:The combination of venetoclax with azacitidine (ven/aza) has recently emerged as a promising regimen for acute myeloid leukemia (AML), with approximately 70% of newly diagnosed patients achieving complete remission (CR). However, 30% of newly diagnosed and nearly all relapsed patients do not achieve CR with ven/aza. Mechanistically, we previously reported that ven/aza efficacy is based on eradication of AML stem cells through a mechanism involving inhibition of amino acid metabolism, a process which is required in primitive AML cells to drive oxidative phosphorylation. In the present study we demonstrate that resistance to ven/aza occurs as a consequence of up-regulated fatty acid oxidation (FAO), which occurs either as an intrinsic property of RAS pathway mutations, or as a compensatory adaptation in relapsed disease. Utilization of FAO obviates the need for amino acid metabolism into the TCA cycle, thereby rendering ven/aza ineffective. Importantly, we show that pharmacological inhibition of FAO via use of MCL-1 or CPT1 inhibitor drugs restores targeting of ven/aza resistant AML stem cells. Based on these findings we propose that inhibition of FAO is a potential therapeutic strategy to address ven/aza resistance.

2020-08-17 | GSE156008 | GEO

Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

2020-08-31 | GSE155431 | GEO

High Expression Level of ROR1 and ROR1-signaling Associates With Venetoclax Resistance In Chronic Lymphocytic Leukemia

Project description:We examined the CLL cells transcriptome data of six patients who fail to clear their leukemia cells and develop progressive disease on venetoclax therapy. Methods: CLL cells were collected prior to venetoclax therapy (Sample Collection 1 (SC1)) and then more than 1 year later (Sample Collection 2 (SC2)). Negative isolation of CLL cells to ≥95% purity was performed prior to RNA isolation.

2022-06-23 | GSE192685 | GEO

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