MPO and TRH within leukemia stem cells increased chemosensitivity in acute myeloid leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1004316 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The "7+3" regimen is widely recognized as the established standard induction therapy for newly diagnosed acute myeloid leukemia (AML), exhibiting a complete remission (CR) rate of 70%. By employing single-cell RNA sequencing (scRNA-seq), we meticulously examined the cellular states of bone marrow mononuclear cells from AML patients at the time of diagnosis and identified leukemia stem cells (LSCs) among these cells. The genetic profiles of the LSCs were subsequently compared between the CR and non-CR groups and further validated using independent cohorts. The non-CR AML patients exhibited a significant increase in the proportion of immature cells during hematopoiesis within the AML cell populations. Moreover, we found that expressions of MPO (log2 fold-change = 0.89; adjusted p <0.0001) and TRH (log2 fold-change = 0.65; adjusted p <0.0001) within LSCs were significantly higher in the CR than non-CR groups, which were further validated by independent cohorts. Furthermore, patients with higher expression of TRH and MPO demonstrated substantially improved relapse-free survival (p = 0.009 for TRH; p = 0.002 for MPO) and overall survival (p < 0.001 for TRH; p = 0.002 for MPO). The dysregulation of the OXPHOS pathway, along with altered interferon alpha and gamma responses, disrupted cholesterol homeostasis, and aberrant MYC activity, may contribute as underlying mechanisms for the observed association between MPO or TRH and chemotherapy response.
2024-12-25 | GSE240618 | GEO
Project description:In an effort to develop a genomics-based approach to the prediction of drug response, we have developed an algorithm for classification of cell line chemosensitivity based on gene expression profiles alone. Using oligonucleotide microarrays, the expression levels of 6,817 genes were measured in a panel of 60 human cancer cell lines (the NCI-60) for which the chemosensitivity profiles of thousands of chemical compounds have been determined. We sought to determine whether the gene expression signatures of untreated cells were sufficient for the prediction of chemosensitivity. Gene expression-based classifiers of sensitivity or resistance for 232 compounds were generated and then evaluated on independent sets of data. The classifiers were designed to be independent of the cells' tissue of origin. The accuracy of chemosensitivity prediction was considerably better than would be expected by chance. Eighty-eight of 232 expression-based classifiers performed accurately (with P < 0.05) on an independent test set, whereas only 12 of the 232 would be expected to do so by chance. These results suggest that at least for a subset of compounds genomic approaches to chemosensitivity prediction are feasible. golub-00299 Assay Type: Gene Expression Provider: Affymetrix Array Designs: Hu6800 Organism: Homo sapiens (ncbitax) Tissue Sites: Kidney, Brain, Blood, Lung, Skin, Colon, Breast, Prostate, Ovary Material Types: cell, synthetic_RNA, whole_organism, total_RNA Disease States: Carcinoma, Glioblastoma, Lymphoma, Adenocarcinoma, Melanoma, Amelanotic Melanoma, Large Cell Carcinoma, Precursor Lymphoblastic Leukemia, Carcinosarcoma, Myeloid Leukemia, Plasma Cell Myeloma, Bronchogenic Carcinoma, Chronic Myelogenous Leukemia, Squamous Cell Carcinoma
2015-05-16 | E-GEOD-68936 | biostudies-arrayexpress
Project description:Myeloperoxidase (MPO) is an enzyme, which functions in host defence by catalysing the formation of reactive oxygen intermediates. Synthesized majorly by myeloid progenitor cell types and neutrophils MPO is released into vascular lumen during inflammation, where it may adhere and internalize the endothelial cells coating vascular walls. Here we describe the moonlighting properties of MPO and its regulation of gene transcription in endothelial cells upon nuclear internalization. We show that MPO independently of its enzymatic activity possess chromatin binding properties in vitro and in cyto. Upon nuclear translocation, MPO changes chromatin condensation. Locally at sites of binding, MPO drives de-condensation of chromatin and at the regions flanking MPO binding sites drives an increased chromatin condensation. MPO-guided changes in chromatin condensation lead to activation of endothelial-to-mesenchymal transition in ECs and enhanced migratory potential. Moreover, MPO directly binds to the double-stranded RNA binding protein and transcription factor ILF3 and facilitates translocation of its isoform NF90 into the nucleus. This results in positive regulation of expression of VEGFA, as well lowered stability of CXCL1 and CXCL8 transcripts due to loss of cytoplasmic ILF3.
2023-05-03 | GSE202860 | GEO
Project description:Myeloperoxidase (MPO) is an enzyme, which functions in host defence by catalysing the formation of reactive oxygen intermediates. Synthesized majorly by myeloid progenitor cell types and neutrophils MPO is released into vascular lumen during inflammation, where it may adhere and internalize the endothelial cells coating vascular walls. Here we describe the moonlighting properties of MPO and its regulation of gene transcription in endothelial cells upon nuclear internalization. We show that MPO independently of its enzymatic activity possess chromatin binding properties in vitro and in cyto. Upon nuclear translocation, MPO changes chromatin condensation. Locally at sites of binding, MPO drives de-condensation of chromatin and at the regions flanking MPO binding sites drives an increased chromatin condensation. MPO-guided changes in chromatin condensation lead to activation of endothelial-to-mesenchymal transition in ECs and enhanced migratory potential. Moreover, MPO directly binds to the double-stranded RNA binding protein and transcription factor ILF3 and facilitates translocation of its isoform NF90 into the nucleus. This results in positive regulation of expression of VEGFA, as well lowered stability of CXCL1 and CXCL8 transcripts due to loss of cytoplasmic ILF3.
2023-05-03 | GSE202013 | GEO
Project description:The etiopathogenesis underlying myeloperoxidase anti-neutrophil cytoplasmic antibody associated glomerulonephritis (MPO-AAGN) remains incompletely understood. Furthermore, there are only limited treatment options and treatment resistance of MPO-AAGN is still a common problem. To identify new targeted treatment options, intrarenal single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from MPO-AAGN patients and control health kidney tissues to define the transcriptomic landscape at single-cell resolution. Intrarenal scRNAseq was also applied to a pre-clinical mouse model of MPO-AAGN to show that this model of disease can be used to trial new targeted treatments. NF-κB pathway activation was confirmed in a variety of kidney cells in MPO-AAGN patients. Kidney infiltrating immune cells of MPO-AAGN patients were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling and NOD-like receptor signaling. These findings were similar in our pre-clinical mouse model of MPO-AAGN. Furthermore, there was an overexpression of inflammasome related genes (AIM2, IFI16) in MPO-AAGN patients. A dynamic gene expression in glomerular resident cells was observed in MPO-AAGN, including increased expression of several genes, including CD9 and SPARC, which were closely related to parietal epithelial hyperplasia and crescent formation and lesion progression. Importantly, overexpression of HSP90AA1 in non-focal mesangial cells and endothelial cells was found and the expression of several chemokines (CCL20, CXCL3, CXCL8, CXCL1, CCL2) were upregulated in non-focal proximal tubule cells. Moreover, MPO-AAGN patients with treatment resistance had higher proportions of kidney infiltrating classical monocytes and CD8+ T cells. Elevated expression of SPARC and LAMA4 in mesangial cells, IL33 in endothelial cells, and CFL1 in several cell clusters (proximal tubule cells, loop of Helen, macrophages) were observed in MPO-AAGN patients with treatment resistance when compared with patients who achieved remission after induction therapy. These results offer new insight into the pathogenesis of the progression and treatment resistance MPO-AAGN. We have identified new therapeutic targets for MPO-AAGN that can be tested in a pre-clinical model of disease.
2024-01-01 | GSE229857 | GEO
Project description:Myeloperoxidase (MPO) is an enzyme, which functions in host defence by catalysing the formation of reactive oxygen intermediates. Synthesized majorly by myeloid progenitor cell types and neutrophils MPO is released into vascular lumen during inflammation, where it may adhere and internalize the endothelial cells coating vascular walls. Here we describe the moonlighting properties of MPO and its regulation of gene transcription in endothelial cells upon nuclear internalization. We show that MPO independently of its enzymatic activity possess chromatin binding properties in vitro and in cyto. Upon nuclear translocation, MPO changes chromatin condensation. Locally at sites of binding, MPO drives de-condensation of chromatin and at the regions flanking MPO binding sites drives an increased chromatin condensation. MPO-guided changes in chromatin condensation lead to activation of endothelial-to-mesenchymal transition in ECs and enhanced migratory potential. Moreover, MPO directly binds to the double-stranded RNA binding protein and transcription factor ILF3 and facilitates translocation of its isoform NF90 into the nucleus. This results in positive regulation of expression of VEGFA, as well lowered stability of CXCL1 and CXCL8 transcripts due to loss of cytoplasmic ILF3.
2023-05-03 | GSE202014 | GEO
Project description:Mutations on NOTCH1 gene are the most commonly found mutations in T-cell acute lymphoblastic leukemia (T-ALL) and they are reported to be favorable indicators for T-ALL patients' prognosis. However, the effects of activating NOTCH1 mutations on T-ALL's chemosensitivity have not been studied. We reported that NOTCH1 inhibition by gamma-secretase inhibitors or shRNA knockdown in MOLT-3 cells could reduce the T-ALL cells' sensitivity to chemotherapeutic drugs. However, this effect was absent in Jurkat and CUTLL1 cells. We further demonstrated that NOTCH1 inhibition could activate the PI3K-AKT pathway in a cell specific pattern similar as their effects on chemosensitivity. RNA-seq revealed that Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 2 (PREX2) is a target gene of NOTCH1 and may mediate the effects of activating NOTCH1 mutations on chemosensitivity. Consistently, we proved that overexpression of PREX2 could mimic the effects of NOTCH1 inhibition on chemosensitivity. Our study has highlighted the effects of activating NOTCH1 mutations on T-ALL's chemosensitivity by altering PREX2-AKT pathway, which may explain the favorable effects of NOTCH1 mutations on T-ALL patients' prognosis, as well as provided potential targets to sensitize T-ALL cells to chemotherapy.
2021-07-07 | GSE179425 | GEO
Project description:Human monocytes treated with LPS and MPO-ANCA or control IgG
2017-08-23 | GSE89153 | GEO
Project description:In an effort to develop a genomics-based approach to the prediction of drug response, we have developed an algorithm for classification of cell line chemosensitivity based on gene expression profiles alone. Using oligonucleotide microarrays, the expression levels of 6,817 genes were measured in a panel of 60 human cancer cell lines (the NCI-60) for which the chemosensitivity profiles of thousands of chemical compounds have been determined. We sought to determine whether the gene expression signatures of untreated cells were sufficient for the prediction of chemosensitivity. Gene expression-based classifiers of sensitivity or resistance for 232 compounds were generated and then evaluated on independent sets of data. The classifiers were designed to be independent of the cells' tissue of origin. The accuracy of chemosensitivity prediction was considerably better than would be expected by chance. Eighty-eight of 232 expression-based classifiers performed accurately (with P < 0.05) on an independent test set, whereas only 12 of the 232 would be expected to do so by chance. These results suggest that at least for a subset of compounds genomic approaches to chemosensitivity prediction are feasible.
2015-05-16 | GSE68936 | GEO
Project description:Sensitivity to platinum-based combination chemotherapy is associated with a favorable prognosis in the patients of non-small cell lung cancer (NSCLC). Here, our results obtained from analyses of the Gene Expression Omnibus database of NSCLC patients showed that cartilage acidic protein 1 (CRTAC1) plays a role in the response to platinum-based chemotherapy. Overexpression of CRTAC1 increased sensitivity to cisplatin in vitro, whereas knockdown of CRTAC1 decreased chemosensitivity of NSCLC cells. In vivo mouse experiments showed that CRTAC1 overexpression increased the antitumor effects of cisplatin. CRTAC1 overexpression promoted NFAT transcriptional activation by increasing intracellular Ca2+ levels, thereby inducing its regulated STUB1 mRNA transcription and protein expression, accelerating Akt1 protein degradation, and in turn enhancing cisplatin-induced apoptosis. Taken together, the present results indicate that CRTAC1 overexpression increases the chemosensitivity of NSCLC to cisplatin treatment by inducing Ca2+-dependent Akt1 degradation and apoptosis, suggesting the potential of CRTAC1 as a biomarker for predicting cisplatin chemosensitivity. Our results further reveal that modulating the expression of CRTAC1 could be a new strategy for increasing the efficacy of cisplatin in chemotherapy of NSCLC patients.
2023-08-29 | PXD041782 | Pride