Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells
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ABSTRACT:
PROVIDER: PRJNA656302 | ENA |
REPOSITORIES: ENA
Dataset's files
| 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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Project description:Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells
| PRJNA649749 | ENA
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.
2020-08-31 | GSE155431 | GEO
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
Project description:Relapse remains a leading cause of death in acute myeloid leukemia (AML), in part because host immune surveillance declines over time. Gamma delta (gamma-delta) T cells contribute to immune surveillance and have been linked to better outcomes in AML. Here we show that gamma-deltaT cells from patients with relapsed AML display reduced effector programs compared with those from patients in complete remission. In a targeted screen of approved AML drugs, the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax emerged as a potent enhancer of gamma-deltaT-cell cytotoxicity against primary AML blasts from both newly diagnosed and relapsed patients. Short ex vivo venetoclax exposure activated gamma-deltaT cells, increased proliferation, and lowered markers of exhaustion, thereby sustaining antileukemia activity over time. Venetoclax also increased mitochondrial respiration (oxidative phosphorylation) and respiratory reserve and shifted metabolism toward fatty acid oxidation. In AML xenograft models, adoptive transfer of venetoclax-pretreated gamma-deltaT cells, including chimeric antigen receptor (CAR)–engineered gamma-deltaT cells, produced superior tumor clearance compared with untreated cells. These findings indicate that venetoclax rejuvenates gamma-deltaT-cell function through metabolic remodeling and supports combining venetoclax with gamma-deltaT-cell–based immunotherapy for relapsed AML.
2025-11-26 | GSE306856 | GEO
Project description:Venetoclax Enhances gamma-deltaT cell Antileukemia Activity via Fatty Acid Oxidation in Relapsed Acute Myeloid Leukemia.
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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
Project description:EVI1-rearranged acute myeloid leukemia (AML) with inv(3)(q21q26) or t(3;3)(q21q26) represents a distinct and aggressive subtype characterized by poor prognosis and limited treatment options. However, the optimal strategy to overcome resistance to conventional therapy remains elusive. Building upon observations correlating EVI1 overexpression with reduced sensitivity to venetoclax, a BH3-mimetic inhibitor, we investigated the mechanisms of resistance to venetoclax in combination with hypomethylating agents in inv(3)/t(3;3) AML cells. Utilizing novel murine models recapitulating inv(3) AML with concomitant SF3B1 mutations, we conducted comprehensive phenotypic and transcriptomic analyses in the presence or absence of venetoclax-containing therapy. Despite initial therapeutic responses, manifested as partially prolonged survival and myeloid differentiation, resistant leukemic cells demonstrated enhanced dependency on BRD4 and MYB pathways with a dormant phenotype. Notably, inhibition of either BRD4 or MYB significantly augmented the efficacy of venetoclax and hypomethylating agents in both murine and patient-derived AML models harboring inv(3) and SF3B1 mutations. These findings elucidate the transcriptional dynamics underlying venetoclax resistance and propose alternative therapeutic strategies targeting BRD4 and MYB as promising avenues for improving outcomes in patients with EVI1-rearranged AML. Our work highlights the necessity for innovative combination therapies to address the multifaceted mechanisms of resistance in this high-risk leukemia subtype.
2025-12-02 | GSE292744 | GEO
Project description:Targeting SUMOylation sensitizes Acute myeloid leukemia to Venetoclax treatment
| PRJNA1113589 | ENA
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
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