Similar Datasets
Project description:Acute myeloid leukemia (AML) is a devastating cancer affecting the hematopoietic system. Previous research has relied on RNA sequencing and microarray techniques to study the downstream effects of genomic alterations. While these studies have proven efficacious, they fail to capture the changes that occur at the proteomic level. To interrogate the effect of protein expression alterations in AML, we performed a quantitative mass spectrometry in parallel with RNAseq analysis using AML mouse models. These combined results identified 34 proteins whose expression was upregulated in AML tumors, but strikingly, were unaltered at the transcriptional level. Here we focus on mitochondrial electron transfer proteins ETFA and ETFB. Silencing of ETFA and ETFB led to increased mitochondrial activity, mitochondrial stress, and apoptosis in AML cells, but had little to no effect on normal human CD34+ cells. These studies identify a set of proteins that have not previously been associated with leukemia and may ultimately serve as potential targets for therapeutic manipulation to hinder AML progression and help contribute to our understanding of the disease.
| S-EPMC9061297 | biostudies-literature
Project description:Multi-omics reveals mitochondrial metabolism proteins susceptible for drug discovery in AML
| PRJNA795977 | ENA
Project description:Acute myeloid leukemia (AML) is a devastating cancer affecting the hematopoietic system. Although this disease represents only 35% of diagnosed leukemias, it accounts for nearly 50% of leukemia-related deaths, making it the leading cause of leukemia-related mortality. Although many AML initiating mutations have been identified, the downstream effects leading to disease progression are still largely unknown. Previous research has relied on RNA sequencing and microarray techniques to study the downstream effects, providing data at the transcriptional level. While these studies have proven efficacious, they fail to capture the changes that occur at the proteomic level. To interrogate the effect of protein expression alterations in AML, we performed a quantitative mass spectrometry analysis using mouse models to compare three tumor types to untransformed tumor-initiating population. In parallel, we performed RNA sequencing for the same populations. With these combined results, we identified 34 proteins whose expression was upregulated in AML tumors, but strikingly, were unaltered at the transcriptional level. These proteins are shown to be associated with mitochondrial function as well as RNA processing. These studies identify a set of proteins not previously associated with leukemia, and may ultimately serve as potential targets for therapeutic manipulation.
2022-05-20 | PXD025628 | Pride
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.
2025-04-01 | GSE279397 | GEO
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
Project description:Abstract Background: Acute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. The mitochondrial fusion protein optic atrophy (OPA)1 is upregulated in AML patients with adverse mutations and correlates with poor prognosis. Method: This study investigated targeting OPA1 with TMQ0153, a tetrahydrobenzimidazole derivative, to disrupt mitochondrial metabolism and dynamics as a novel therapeutic approach to overcome treatment resistance. Effects of TMQ0153 treatment on OPA1 and mitofusin (MFN)2 protein levels, mitochondrial morphology, and function in AML cells. In this study, reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis were examined. Additionally, metabolic profiling was conducted to analyze the changes in metabolic pathways. Results: TMQ0153 treatment significantly reduced OPA1 and mitofusin (MFN)2 protein levels and disrupted the mitochondrial morphology and function in AML cells. This increases ROS production and inhibits OXPHOS, MMP depolarization, and caspase-dependent apoptosis. Metabolic reprogramming was observed, shifting from mitochondrial respiration to glycolysis and impaired respiratory chain activity. Profiling revealed reduced overall metabolism, alongside changes in the glutathione (GSH)/oxidized glutathione (GSSG) and NAD⁺/NADH redox ratios. TMQ0153 treatment reduces tumor volume and weight in MV4-11 xenografts in vivo. Combination therapies with TMQ0153 and other AML drugs significantly reduced the leukemic burden and prolonged survival in NOD scid gamma (NSG) mice xenografted with U937-luc and MOLM-14-luc cells. Conclusion: TMQ0153 targets mitochondrial dynamics by inhibiting OPA1, inducing metabolic reprogramming, and triggering apoptosis in AML cells. It enhances the efficacy of existing AML therapies, providing a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML
2025-04-13 | GSE292091 | GEO
Project description:Relapse remains a determinant of treatment failure and contributes significantly to mortality in acute myeloid leukemia (AML) patients. Despite efforts to understand AML progression and relapse mechanisms, findings on acquired gene mutations in relapse vary, suggesting inherent genetic heterogeneity and emphasizing the role of epigenetic modifications. Herein, we characterized genetic and epigenetic changes in AML progression using multi-omics approaches to elucidate the underlying mechanisms of relapse. Differential interaction analysis showed significant 3D chromatin landscape reorganization between relapse and diagnosis samples. Comparing global open chromatin profiles revealed that relapse samples had significantly fewer accessible chromatin regions than diagnosis samples. In addition, we discovered that relapse-related upregulation was achieved either by forming new active enhancer contacts or by losing interactions with poised enhancers/potential silencers. Altogether, our study highlights the impact of genetic and epigenetic changes on AML progression, underlining the importance of multi-omics approaches in understanding disease relapse mechanisms and guiding potential therapeutic interventions.
2024-07-31 | GSE267376 | GEO
Project description:Relapse remains a determinant of treatment failure and contributes significantly to mortality in acute myeloid leukemia (AML) patients. Despite efforts to understand AML progression and relapse mechanisms, findings on acquired gene mutations in relapse vary, suggesting inherent genetic heterogeneity and emphasizing the role of epigenetic modifications. Herein, we characterized genetic and epigenetic changes in AML progression using multi-omics approaches to elucidate the underlying mechanisms of relapse. Differential interaction analysis showed significant 3D chromatin landscape reorganization between relapse and diagnosis samples. Comparing global open chromatin profiles revealed that relapse samples had significantly fewer accessible chromatin regions than diagnosis samples. In addition, we discovered that relapse-related upregulation was achieved either by forming new active enhancer contacts or by losing interactions with poised enhancers/potential silencers. Altogether, our study highlights the impact of genetic and epigenetic changes on AML progression, underlining the importance of multi-omics approaches in understanding disease relapse mechanisms and guiding potential therapeutic interventions.
2024-07-31 | GSE267375 | GEO
Project description:To explore how the loss of function of CHD7 leads to drug resistance in acute myeloid leukemia (AML) cells, we investigated the transcriptional programs regulated by CHD7 in OCI-AML2 cells under different drug treatment conditions. This study aims to uncover the role of CHD7 in drug sensitivity and resistance, providing a theoretical basis for developing new therapeutic strategies.
2025-02-21 | PXD061029 |
Project description:Identifying potential drug targets using metabolic modeling requires integrating multiple modeling methods and heterogeneous biological datasets, which can be challenging without efficient tools. We developed Constraint-based Optimization of Metabolic Objectives (COMO), a user-friendly pipeline that integrates multi-omics data processing, context-specific metabolic model development, simulations, drug databases and disease data to aid drug discovery. COMO can be installed as a Docker Image or with Conda and includes intuitive instructions within a Jupyter Lab environment. It provides a comprehensive solution for the integration of bulk and single-cell RNA-seq, microarrays and proteomics outputs to develop context-specific metabolic models. Using public databases, open-source solutions for model construction and a streamlined approach for predicting repurposable drugs, COMO enables researchers to investigate low-cost alternatives and novel disease treatments. As a case study, we used the pipeline to construct metabolic models of B cells, which simulate and analyze them to predict metabolic drug targets for rheumatoid arthritis and systemic lupus erythematosus, respectively. COMO can be used to construct models for any cell or tissue type and identify drugs for any human disease where metabolic inhibition is relevant. The pipeline has the potential to improve the health of the global community cost-effectively by providing high-confidence targets to pursue in preclinical and clinical studies. The source code of the COMO pipeline is available at https://github.com/HelikarLab/COMO. The Docker image can be pulled at https://github.com/HelikarLab/COMO/pkgs/container/como.
| S-EPMC10627799 | biostudies-literature