Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156008 | GEO | 2020/08/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

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.

2020-08-31 | GSE155431 | GEO

Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine

Project description:Purpose: To show that 8-Cl-Ado can target FAO and synergizes with VEN to significantly decrease the oxygen consumption rate (OCR) and in turn OXPHOS in CD34-enriched AML cells. Methods: Using AML cell lines and LSC-enriched blast cells from pre-treatment AML patients, we evaluated the effects of 8-Cl-Ado, VEN and the 8-Cl-Ado/VEN combination on fatty acid metabolism, glycolysis and OXPHOS using liquid scintillation counting, a Seahorse XF Analyzer and gene set enrichment analysis (GSEA). Results: We here report that VEN and 8-Cl-Ado synergistically inhibited in vitro growth of AML cells. Furthermore, immunodeficient mice engrafted with MV4-11-Luc AML cells and treated with the combination of VEN plus 8-Cl-Ado had a significantly longer survival than mice treated with either drugs alone (p≤0.006). Conclusion: Taken together, the results suggest that 8-Cl-Ado enhances the antileukemic activity of VEN and that this combination represents a promising therapeutic regimen for treatment of AML.

2021-04-07 | GSE171552 | GEO

AML patients for in vivo study of venetoclax plus AraC treatment

Project description:Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a “MitoScore” signature that identifies high mitochondrial oxidative phosphorylation (OxPHOS) in vivo and in AML patients. Primary AML cells with cytarabine (AraC) resistance and high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) plus AraC (but not to VEN plus azacytidine, AZA). Single-cell transcriptomics of VEN+AraC-residual cell populations revealed adaptive resistance associated with changes in OxPHOS, electron transport chain complex (ETC) and the TP53 pathway.

2021-11-12 | GSE183329 | GEO

Lin28A/CENPE promoting the proliferation and chemo-resistance of acute myeloid leukemia

Project description:Peripheral blood samples of 3 refractory/relapsed AML patients (R/R-AML, relapsed/refractory AML patients who failed to achieve complete remission/CR after 2 courses of induction chemotherapy), 3 refractory secondary AML patients (S-AML, MDS or MPN derived AML patients did not reach CR after 2 rounds of induction chemotherapy), 4 de novo AML patients (AML, CR after standard “3+7” induction chemotherapy), and 3 healthy controls (HC) were collected. Nanodrop was applied to quantify the total RNA samples. Illumina kits were used to prepare the RNA-seq library.

2021-09-10 | GSE183817 | GEO

Expression profiling of CD8+ T-cells in peripheral blood (PB) of AML patients

Project description:1) Transcriptional profiles of highly purified (≥ 98%) PB CD8+ T-cells from newly diagnosed AML patients (pre-treatment) were compared to age-matched healthy controls and transcriptional profiles of PB AML CD8+ T-cells from patients who achieved complete remission (CR) versus non-responders (NR) longitudinally, at pre-treatment and upon recovery following induction chemotherapy (paired samples). 2) Transcriptional profiles of PB AML CD8+ T-cells from patients who achieved complete remission (CR) versus non-responders (NR) longitudinally, at pre-treatment (PRE) and upon recovery following induction chemotherapy (POST) (paired samples).

2018-12-26 | GSE109179 | GEO

Gene expression profiles of primary samples of acute myeloid leukemia (AML)

Project description:As part of a clinical trial of the MDM2 inhibitor DS-3032b, 41 primary tumor samples were obtained before treatment from 38 patients newly diagnosed with AML, or relapsed or refractory to standard induction chemotherapy Gene expression features of pretreatment samples, along with TP53 mutation status, were found to correlate with clinical response to DS-3032b (manuscript under review).

2018-05-23 | GSE110087 | GEO

Expression data in bone marrow mesenchymal stromal cells derived from acute myeloid leukemia patients

Project description:Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic stem/progenitor cells characterized by excessive proliferation and subsequent accumulation of immature myeloid blasts, leading to impaired hematopoiesis in the bone marrow (BM). The progression of AML is closely linked to the crosstalk between leukemic cells and the BM microenvironment, in particular the mesenchymal stromal cells (MSCs). We compared the mRNA expression profile of BM-MSCs from newly diagnosed AML patients (n=3), relapsed AML patients (n=3) and healthy donor controls (n=3)

2021-11-26 | GSE122917 | GEO

A Gene Expression-Based Risk Stratification Model for Newly Diagnosed Multiple Myeloma

Project description:We recently defined a gene expression-based signature of high-risk multiple myeloma; this predictive signature was developed with and independently validated for newly diagnosed patients treated with high dose therapy and stem cell rescue. Here we use Phase 3 clinical trial data to show that this signature also predicts short survival in relapsed disease treated with single agent bortezomib or high dose dexamethasone. In addition, a survival signature derived with relapsed myeloma samples identified newly diagnosed patients with short survival. Taken together these data suggest that a similar biology underlies poor outcome in both newly diagnosed and relapsed myeloma and provide strong evidence that the high-risk signature is a powerful tool to identify patients who are candidates for new therapeutic regimens. Keywords: Model validation See above (Series_summary)

2011-08-19 | E-GEOD-8991 | biostudies-arrayexpress

Single-cell landscape of innate and acquired drug resistance in acute myeloid leukemia

Project description:Deep single-cell multi-omic profiling of drug resistance in patients with relapsed or refractory (rr) acute myeloid leukemia (AML) is a promising approach to understand and identify the molecular and cellular determinants of drug resistance. Here, we address this challenge by integrating single-cell ex vivo drug profiling (pharmacoscopy) with both bulk and single-cell resolved DNA, RNA, and protein profiling, as well as clinical annotations across samples of a cohort of 21 rrAML patients. Unsupervised data integration revealed ex vivo response to the Bcl-2 inhibitor venetoclax (VEN) to be significantly reduced in patients treated with the combination of a hypomethylating agent (HMA) and VEN compared to patients pre-exposed to HMA only, while also exposing innate Ven resistance in a subset of VEN-naive patients. Systematic molecular integration retrieved known and novel molecular mechanisms underlying VEN resistance and identified alternative therapeutic strategies in VEN resistant samples, including targeting increased proliferation by PLK inhibitor volasertib. Across data modalities, high CD36 expression on AML blasts was associated with VENres, while CD36-targeted antibody treatment ex vivo revealed striking sensitivity in VEN resistant AML. In summary, we showcase how single-cell multi-omic and functional profiling can facilitate the discovery of drug resistance mechanisms and emergent treatment vulnerabilities. Our dataset represents a comprehensive molecular and functional profiling of rrAML at single-cell resolution, providing a valuable resource for future studies.

| MSV000092970 | MassIVE

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data