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

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

PROVIDER: PRJNA656302 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12424812.fastq.gz	Fastqsanger.gz
	SRR12424813.fastq.gz	Fastqsanger.gz
	SRR12424814.fastq.gz	Fastqsanger.gz
	SRR12424815.fastq.gz	Fastqsanger.gz
	SRR12424816.fastq.gz	Fastqsanger.gz

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

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

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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

Expression data from free fatty acid polarized bone marrow Gr1- myeloid cells

Project description:Free fatty acids accumulate in tumor microenvironment which facilitate the polarization of bone marrow derived myeloid cells into tumor associated macrophages. However, the underlying mechanism is still unclear. Here we use microarray to detail the impact of variant free fatty acids on the maturation of bone marrow derived myeloid cells.

2018-08-04 | GSE118080 | GEO

Targeting SUMOylation sensitizes Acute myeloid leukemia to Venetoclax treatment

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

| PRJNA1113589 | ENA

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

Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells.

Project description:We previously demonstrated that leukemia stem cells (LSCs) in de novo acute myeloid leukemia (AML) patients are selectively reliant on amino acid metabolism and that treatment with the combination of venetoclax and azacitidine (ven/aza) inhibits amino acid metabolism, leading to cell death. In contrast, ven/aza fails to eradicate LSCs in relapsed/refractory (R/R) patients, suggesting altered metabolic properties. Detailed metabolomic analysis revealed elevated nicotinamide metabolism in relapsed LSCs, which activates both amino acid metabolism and fatty acid oxidation to drive OXPHOS, thereby providing a means for LSCs to circumvent the cytotoxic effects of ven/aza therapy. Genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide metabolism, demonstrated selective eradication of R/R LSCs while sparing normal hematopoietic stem/progenitor cells. Altogether, these findings demonstrate that elevated nicotinamide metabolism is both the mechanistic basis for ven/aza resistance and a metabolic vulnerability of R/R LSCs.

| S-EPMC7655603 | biostudies-literature

Targeting SUMOylation sensitizes Acute myeloid leukemia to Venetoclax treatment

Project description:Acute myeloid leukemia (AML) is a hematopoietic cancer characterized by the proliferation and accumulation of aberrant immature myeloid progenitor blasts in bone marrow and peripheral blood. Venetoclax (VEN), a selective B-cell lymphoma 2 (BCL-2) inhibitor, has received FDA approval for AML treatment in combination with hypomethylating agents (HMA). However, treatment failure and therapy resistance present an urgent need for new therapies to overcome VEN resistance and enhance VEN efficacy. We propose inhibition of SUMOylation as a novel therapy with the potential to address this need. SUMOylation regulates protein function by covalently attaching Small Ubiquitin-like MOdifier (SUMO) proteins to target proteins via an enzymatic cascade. Our study aims to evaluate the effects of SUMOylation inhibition on anti-AML activity of VEN and dissert the underlying mechanism.

2024-05-27 | GSE267885 | GEO

A novel covalent inhibitor of CDK7 synergizes with Venetoclax in acute myeloid leukemia

Project description:To assess the synergistic effects of CDK7 inhibitor with Venetoclax, we performed RNA sequencing and gene set enrichment analysis using Venetoclax sensitive and resistant model systems. RNA-sequencing from paired Venetoclax-sensitive and Venetoclax-resistant cells treated with CDK7 inhibitor showed downregulation of genes involved in proliferation and apoptosis. CDK7 inhibitor induces apoptosis in AML cells and combined treatment with Venetoclax led to synergistic effects in overcoming resistance.

2023-07-24 | GSE231745 | GEO

High-fat diet activated fatty acid oxidation mediates intestinal stemness and tumorigenicity

Project description:High-fat diet activated fatty acid oxidation mediates intestinal stemness and tumorigenicity

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