Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting STAT3-Mediated Lipid Metabolism Reprogramming Overcomes Chemoresistance in Acute Myeloid Leukemia

ABSTRACT: Chemotherapy resistance and intolerance pose significant challenges in the effective treatment of leukemia. Among the distinctive features associated with chemoresistance, metabolic reprogramming emerges as a key factor. In this study, we unveil a novel mechanism contributing to chemoresistance in leukemia, specifically highlighting the pivotal role of altered lipid homeostasis.We found that multiple lipid metabolism processes are aberrantly activated in Ara-C resistant AML cells, with upregulation of JAK-STAT3 signaling pathways and multiple enzymes in the process of fatty acid metabolism. A potent, and highly selective STAT3 inhibitor, W1307, was designed, and exhibited significant anti-tumor activities in vitro and in vivo. Genetic and pharmacological inhibition of STAT3 leads to inhibition of lipid synthesis and catabolism, resulting lipids metabolic disorder. Mechanistically, STAT3 binds to consensus DNA response elements in the promoters of the lipid metabolism associated genes (SREBP1, CPT2) and regulates their expression. Furthermore, inhibition of STAT3 enhances the anti-tumor effect of Ara-C and sensitizes resistant AML cell line to Ara-C through disrupting lipid homeostasis and triggering lipotoxicity. Collectively, our work illuminates the pivotal role of lipid metabolism adaptation driven by STAT3 in chemoresistance. The identification of W1307 as a promising candidate compound underscores its potential as a therapeutic intervention in leukemia treatment and overcoming chemoresistance.

ORGANISM(S): Homo

PROVIDER: GSE327495 | GEO | 2026/04/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Targeting STAT3-Mediated Lipid Metabolism Reprogramming Overcomes Chemoresistance in Acute Myeloid Leukemia

Project description:Targeting STAT3-Mediated Lipid Metabolism Reprogramming Overcomes Chemoresistance in Acute Myeloid Leukemia

| PRJNA1451102 | ENA

Mechanisms of Chemotherapy Failure in Refractory/Relapsed Acute Myeloid Leukemia: The Role of Cytarabine Resistance and Mitochondrial Metabolism

Project description:Acute myeloid leukemia (AML) originates from malignant, immature myeloid progenitor cells that differentiate into dysfunctional myeloblasts. While cytarabine (Ara-C) and daunorubicin (DNR)-based chemotherapy regimens are the standard treatments, approximately 10-40% of AML patients under the age of 60 and 40-60% over 60 do not respond, leading to refractory or relapsed (R/R) AML. Targeted chemotherapy for FLT3-ITD mutated R/R AML cells improves response rates and survival outcomes in FLT3-ITD mutated R/R AML patients. However, patients with wild-type FLT3 R/R AML remain therapeutically challenged, with persistent difficulty in finding effective treatments. Better insights on the fundamental understanding of treatment failure in wild-type FLT3 AML cells are needed to enhance therapeutic outcomes. However, precise mechanisms behind the treatment failure remain unclear. This study investigates the mechanisms underlying the failure of Ara-C and DNR-based chemotherapy in wild-type FLT3 R/R AML. Using RHI-1 cells, a wild-type FLT3 AML cell line with Ara-C resistance, we demonstrated that Ara-C resistance-mediated DNR tolerance did not result from reducing the concentration of DNR in RHI-1 cells, but rather from interrupting the cytotoxic mechanisms of DNR through the Ara-C resistance of RHI-1. The down-regulated deoxycytidine kinase (DCK) in RHI-1 cells interrupted mechanisms of Ara-C cytotoxic action. Also, the down-regulation of DCK enhanced mitochondrial metabolic pathways, DNA repair process, and ROS detoxification. Through these pathways, RHI-1 cells exhibit tolerance under DNR treatment. Among these enhanced processes, targeting mitochondrial metabolism, particularly OXPHOS complex I proteins, improved the efficacy of both Ara-C and DNR. Our findings shed light on a potential mechanism underlying the treatment failure and the role of mitochondrial metabolism in wild-type FLT3 R/R AML cells.

2025-05-07 | PXD054797 | Pride

Inhibitor of apoptosis protein antagonist BV6 – potential for new combinatorial treatment strategies in acute myeloid leukemia

Project description:Apoptosis is deregulated in most, if not all, cancers, including hematological malignancies. In this study, we wanted to test whether primary acute myeloid leukemia (AML) samples are sensitive for inhibitor of apoptosis (IAP) protein antagonist treatment in vitro, and which AML subgroup might profit most from such a novel therapeutic strategy. We treated diagnostic samples of 67 adult AML patients with either cytarabine (ara-C) or IAP antagonist BV6 and correlated sensitivity with clinical, cytogenetic and molecular markers, and expression levels of selected genes involved in apoptosis. Primary AML samples showed differential sensitivity to treatment with either ara-C (40% sensitive, 17% intermediate, 43% resistant) or BV6 (51% sensitive, 21% intermediate, 28% resistant). Notably, 69% of ara-C resistant samples showed a good to fair response to IAP inhibition. Furthermore, combination treatment of ara-C with BV6 showed additive effects in most samples. Differences in sensitivity to IAP antagonist treatment correlated with significantly elevated expression levels of TNF and lower levels of XIAP in BV6 sensitive samples, as well as with NPM1 mutations. Gene expression profiling pointed to apoptosis-related pathways, which were specifically induced by IAP inhibition in sensitive samples. Thus, our results suggest IAP inhibition as a potential novel therapeutic option in AML.

2014-12-31 | GSE46819 | GEO

Cellular and Molecular Characteristics of Drug Resistance in AML cells Unveiled by Multi-Omics Analysis

Project description:Acute myeloid leukemia (AML) exhibits a spectrum of responses to chemotherapy, with drug resistance being a significant clinical challenge. This study employs a multi-omics approach, particularly multiplexed single-cell RNA sequencing (scRNA-seq), to characterize the molecular mechanisms underlying drug resistance in AML cells. We identified significant cellular heterogeneity and a dynamic transcriptomic trajectory in AML cells with specific drug treatment, and discovered a reprogramming towards a more stem-like state. Interestingly, Ara-C-resistant KG-1a cells predominantly originated from G2/M subpopulations, indicating a cell cycle-specific resistance mechanism. Our analysis also revealed that epigenetic changes of DNA methylation and chromatin architechture, and altered transcription factor activities were implicated in rapid Ara-C resistance, whereas exomic mutations did not significantly contribute to it. We suggest both intrinsic and acquired resistance mechanisms act together and build a resultant force that aids AML cells in evading therapeutic interventions. The multidimensional changes observed post-treatment showed a complex interplay in the development of drug resistance. This study provides a cellular and molecular portrait of drug response and resistance in AML, offering potential therapeutic targets and a foundation for future research aimed at overcoming chemoresistance.

2025-05-20 | GSE279118 | GEO

Cellular and Molecular Characteristics of Drug Resistance in AML cells Unveiled by Multi-Omics Analysis

2025-04-01 | GSE279397 | GEO

Genome wide CRISPR screen in AML chemotherapy resistance.

Project description:Chemoresistance is the leading cause of acute myeloid leukemia (AML)-related deaths, and elucidation of the mechanisms of AML chemoresistance is necessary to effectively target this process. Here, we performed genome wide CRISPR-Cas9 screening to identify key molecules regulating AML chemoresistance.

2023-06-30 | GSE235688 | GEO

Proteomics of mouse bone marrow MLL-AF9 leukemia cells treated with Lep or Allo-aca in combination with Arac

Project description:Leptin is enriched in bone marrow adipose tissue, but its impact on therapeutic response in acute myeloid leukemia (AML) remains incompletely elucidated. Here, we report that in MLL-AF9 mouse model, exogenous leptin significantly compromised the cytotoxicity of Ara-C, whereas a high-affinity leptin receptor antagonist, Allo-aca, restored chemosensitivity without altering basal leukemia growth, accompanied by marked alterations in mitochondria-associated proteins.

2025-07-28 | PXD066693 |

RETRACTED BY AUTHORS

Project description:Title: Gene Expression in Ara-C Resistance in AML A microarray study of altered gene expression in acute myeloid leukemia cell lines Keywords: cell type comparison Keywords: Expression profiling by array

2005-09-01 | GSE2788 | GEO

DNMT3A mutation coordinates epigenetic and translational regulation through orchestrating BCAA metabolism in acute myeloid leukemia

Project description:Acute myeloid leukemia (AML) harboring DNMT3A mutation exhibits epigenetic dysregulation, chemoresistance and poor outcome, but the underlining mechanism remains elusive. Here, inspired by the unexpected finding that DNMT3A-mutated AML patients exhibit a unique translatome landscape, we connected this epigenetic mutation to translational dysregulation through reprogrammed branched-chain amino acid (BCAA) metabolism. Particularly, DNMT3A mutation induces DNA hypomethylation-dependent activation of BCAT1, a rate-limiting aminotransferase gene for BCAA metabolism. Thereafter, the accumulation of intracellular BCAA more profoundly alters translation of a select subset of transcripts with higher BCAA codon ratios. Accordingly, deficiency in BCAA availability reduces the translation of target genes and attenuated the proliferative advantages of DNMT3A-mutated AML cells. More importantly, the pharmacological inhibition of BCAT1 with Gabapentin normalized BCAA levels, reversed target genes translation and repressed leukemia cell growth specifically in DNMT3A-mutated AML cells. Collectively, these findings uncovered a novel epigenetics-metabolism axis, in which DNMT3A mutation boosts BCAA metabolism thereby not only forming a positive feedback loop to enhance DNA hypomethylation through alpha ketoglutarate (α-KG)-dependent ten-eleven translocation (TET) activation, but also affecting gene translation in a BCAA codon-biased manner. Moreover, the efficacy of Gabapentin in suppressing AML cell proliferation highlights the clinical relevance of targeting BCAA metabolism to improve outcomes of DNMT3A-mutated AML.

2026-05-31 | GSE296332 | GEO

DNMT3A mutation coordinates epigenetic and translational regulation through orchestrating BCAA metabolism in acute myeloid leukemia (WGBS)

2026-05-31 | GSE296563 | GEO