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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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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

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Improved Prediction of Venetoclax and Azacitidine Efficacy in Acute Myeloid Leukemia through Machine Learning

Project description:Despite the transformative impact of venetoclax-azacitidine in treating acute myeloid leukemia (AML), reliable markers for accurately predicting patient responses remain urgently needed. To address this challenge, we employed a multidisciplinary approach that combined transcriptomic profiling, ex vivo drug sensitivity testing, functional assays, and clinical data to identify robust predictors of venetoclax-azacitidine response. We pinpointed a set of core genes linked to both ex vivo and in vivo drug responsiveness, validated through CRISPR-Cas9 screens in the setting of both venetoclax and azacitidine therapies. In particular, silencing BCL2L1 and PINK1 preferentially enhanced response to the venetoclax-azacitidine treatment. Building on these insights, we further developed and validated an 8-gene random forest model (RF8) that demonstrated high specificity and sensitivity in four independent cohorts comprising 498 patients. This model was capable of distilling downstream effects of genetic alterations to assist in predicting treatment response and outperformed existing genetic mutation-based signatures. Furthermore, the RF8 score demonstrated a nearly monotonic relationship with venetoclax-azacitidine response probabilities and patient outcomes, enabling precise stratification of patients. These findings illustrated the feasibility of translating integrated transcriptomic and drug-response profiling data into more refined risk stratification approaches, offering a new avenue for optimizing clinical decision-making in AML.

2025-02-18 | GSE289785 | 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.

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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

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

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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

Improved Prediction of Venetoclax and Azacitidine Efficacy in Acute Myeloid Leukemia through Machine Learning

Project description:Improved Prediction of Venetoclax and Azacitidine Efficacy in Acute Myeloid Leukemia through Machine Learning

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Immune recovery in tumor microenvironment of TP53-mutated AML following venetoclax combination therapy

Project description:The BCL-2 inhibitor venetoclax combined with the hypomethylating agent azacitidine or with low-dose cytarabine significantly improves response rates and overall survival (OS) for newly diagnosed unfit and relapsed / refractory (R/R) acute myeloid leukemia (AML) patients. We retrospectively analyzed our experience with venetoclax combination therapy in 41 unfit AML patients (23 untreated, 18 R/R). Overall response rates were 78.3% for untreated patients and 61.1% for R/R patients. TP53 alterations were observed in 13 patients (31.7%) and were identified as an independent predictor of poor outcome (p=0.0008). We further conducted single-cell RNA sequencing in bone marrow, sampled before and after venetoclax and azacitidine treatment, of three TP53-mutated AML patients who achieved complete remission (CR) or CR with incomplete hematologic recovery. After treatment, numbers of cells expressing anti-apoptotic genes such as BCL2 and MCL1 decreased. CD4 T cells, cytotoxic CD8 T cells, and NK cells significantly increased both in number and in levels of gene expression associated with cytotoxicity post-treatment, confirming immune recovery in the tumor microenvironment. Residual AML cells expressed CD47 and CLEC12A (CLL1). These results indicate that venetoclax combination therapy of AML is promising in real-world clinical practice and suggest a role for ancillary treatment targeting antigens expressed on residual AML cells as a therapeutic strategy in TP53-mutated AML.

2025-08-30 | GSE306339 | GEO

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