Exosomal miRNA expression profiling in patients with imatinib-resistant chronic myeloid leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1231083 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32556752.fastq.gz | Fastqsanger.gz | |||
| SRR32556753.fastq.gz | Fastqsanger.gz | |||
| SRR32556754.fastq.gz | Fastqsanger.gz | |||
| SRR32556755.fastq.gz | Fastqsanger.gz | |||
| SRR32556756.fastq.gz | Fastqsanger.gz |
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Project description:Chronic myeloid leukemia (CML) is a stem cell-derived malignancy driven by the BCR-ABL oncogene. Imatinib (IM) is a targeted therapy used to treat CML; however, primary resistance and molecular evidence of persistent disease have been observed in some patients. Recent evidence suggests that exosome-derived microRNAs (miRNAs) contribute to drug resistance and may serve as novel biomarkers for cancer diagnosis and drug sensitivity prediction. This study aimed to explore the plasma exosomal miRNA profiles in patients with CML to identify biomarkers associated with IM resistance. Exosomes isolated from the plasma of patients with IM-sensitive and -resistant CML patients were characterized, and exosomal miRNA profiling was conducted using RNA sequencing. Differential expression analysis identified 13 upregulated miRNAs and 21 downregulated miRNAs. Bioinformatics analysis highlighted pathways related to autophagy and PI3K-Akt signaling. Among the upregulated miRNAs, miR-451 and miR-16 were significantly elevated in exosomes from IM-resistant patients compared with those from IM-sensitive patients. Target gene analysis of these miRNAs was performed. Our findings suggest that plasma exosomal miRNAs, particularly miR-451 and miR-16, can serve as potential biomarkers for IM resistance in CML. These results offer new insights into the molecular mechanisms underlying IM resistance and may inform future therapeutic strategies.
2025-03-03 | GSE290959 | GEO
Project description:Imatinib (IM), a tyrosine kinase inhibitor (TKI), has markedly improved the survival and life quality of chronic myeloid leukemia (CML) patients. However, the lack of specific biomarkers for IM resistance remains a serious clinical challenge. Recently, growing evidence has suggested that exosome-harbored proteins were involved in tumor drug resistance and could be novel biomarkers for the diagnosis and drug sensitivity prediction of cancer. Therefore, we aimed to investigate the proteomic profile of plasma exosomes derived from CML patients to identify ideal biomarkers for IM resistance. We extracted exosomes from pooled plasma samples of 9 imatinib-resistant CML patients and 9 imatinib-sensitive CML patients by ultracentrifugation. Then, we identified the expression levels of exosomal proteins by liquid chromatography-tandem mass spectrometry (LC-MS/MS) based label free quantification. Bioinformatics analyses were used to analyze the proteomic data. we found that RPL13 and RPL14 exhibited exceptional upregulation in imatinib-resistant CML patients, which were further confirmed by PRM and WB. Proteomic analysis of plasma exosomes provides new ideas and important information for the study of IM resistance in CML. Especially the exosomal proteins (RPL13 and RPL14), which may have great potential as biomarkers of IM resistance.
2022-02-16 | PXD028779 | Pride
Project description:Inhibition of deregulated protein kinases by small molecule drugs has evolved into a major therapeutic strategy for the treatment of human malignancies. Imatinib mesylate has emerged as the leading compound to treat chronic myeloid leukemia (CML), through its inhibition of Bcr- Abl tyrosine kinases, and other cancers. However, resistance to imatinib develops frequently, particularly in late-stage disease and has necessitated the development of new BCR-ABL inhibitors. The synthesis of a new series of phenylaminopyrimidines, structurally related to imatinib showed large interest since the introduction of the nilotibin. To identify the cellular pathways affected by new synthesized compounds, we applied mass spectrometry together with stable isotope labeling by amino acids in cell culture (SILAC) for the comparative study of protein expression in K562 cells that were untreated or treated with imatinib and imatinib derivates. Further, the global proteome of the K562 cells treated with imatinib were quantitatively compared with the cells treated with the new compounds. This study enriched our knowledge about direct cellular targets of kinase selective drugs. Further the results offered important new knowledge for gaining insights into the structural effects of action of the new compounds. Samples were analyzed on a longer column (30cm) and a longer gradient (180min). Raw data files were processed with Mascot distiller 2.3. The mgf files were searched with Mascot daemon 2.3. The quantification was also done by Mascot Distiller. All data was stored in ms_lims. The manual validation of false peptide ratios was done with Rover (part of ms_lims). Fixed modifications: none. Variable modifications: acetylation of peptide N-terminus, pyroglutamate formation of N-terminal glutamine, methionine oxidation. Enzyme: trypsine with one missed cleavage allowed. Precursor mass tolerance: 10 ppm. Peptide fragment mass tolerance: 0.5 Da Quantitation method: SILAC arginine and lysine +6 Da. Overview of the 17 different analyses: B SK23 vs DMSO C Y22 vs DMSO D SK20 vs DMSO E Y18 vs DMSO I SK20 vs DMSO K Y18 vs DMSO O Y22 vs DMSO R Imatinib vs Water Z Imatinib vs Water J SK20 vs Imatinib M SK23 vs Imatinib N Y22 vs Imatinib P SK23 vs Imatinib Q Y18 vs Imatinib S Y22 vs Imatinib T SK20 vs Imatinib Y Y18 vs Imatinib
2014-06-30 | PXD000216 | Pride
Project description:Knockdown of TCF7 increases the drug sensitivity of chronic myeloid leukemia to imatinib‑based therapy.
2021-01-19 | GSE152220 | GEO
Project description:Chronic myeloid leukemia is a malignant hematopoietic disorder distinguished by a presence of BCR-ABL fused oncogene with constitutive kinase activity. Although targeted therapy by tyrosine kinase inhibitors (TKI) markedly improved patient´s survival and quality of life, development of drug resistance remains a critical issue for a subset of patients. The most common mechanism of TKI resistance in CML patients is a mutation in BCR-ABL gene which makes oncogenic Bcr-Abl protein insensitive to TKI therapy. Mutation independent mechanisms of TKI resistance are less elucidated, but exosomes, extracellular vesicles excreted from normal and tumor cells were recently linked with cancer progression and drug resistance. We used an imatinib-sensitive CML cell line K562 and derived an imatinib-resistant subline K562IR by prolonged cultivation of cells in presence of imatinib. We demonstrated that exosomes isolated from K562IR cells are internalized by K562 cells and increase their survival in presence of 2µM imatinib. To characterize the exosomal cargo and to identify resistance-associated marker proteins, we performed a deep proteomic analysis of exosomes from both cell sublines using label free quantification (LFQ). In total, we identified over 3000 exosomal proteins including 31 proteins differentially abundant in exosomes derived from K562IR cells. Among the differential proteins were three massively upregulated membrane proteins in K562IR exosomes with surface localization: IFITM3, CD146, CD36. We verified the massive upregulation of the three proteins in K562IR exosomes and also in K562IR cells. Using flow cytometry, we further demonstrated potential of CD146 as cell surface marker associated with imatinib resistance in K562 cells.
2024-10-24 | PXD019283 | Pride
Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which is present in almost every patient with chronic myeloid leukemia. In this study, the tyrosine kinase inhibitor Imatinib was used for pharmacological inhibition of BCR-ABL1. Gene expression profiles of CML cell lines were analyzed in response to Imatinib treatment.
2010-10-10 | GSE24493 | GEO
Project description:Integrated Stress Response (ISR) facilitates cellular adaptation to a variable environmental conditions by reprogramming cellular response. Activation of ISR was reported in neurological disorders and solid tumours, but its function in hematological malignancies remains largely unknown. Previously we showed that ISR is activated in chronic myeloid leukemia (CML) CD34+ cells, and its activity correlates with disease progression and imatinib resistance. Here we demonstrate that inhibition of ISR by small molecule ISRIB, but not by PERK inhibitor GSK2656157, restores sensitivity to imatinib and eliminates CML-BP CD34+ resistant cells. We found that In PDX mouse model bearing CD34+ imatinib/dasatinib-resistant CML blasts with PTPN11 gain-of-function mutation, combination of imatinib and ISRIB decreases leukemia engraftment. Furthermore, genes related to SGK3, RAS/RAF/MAPK, JAK2 and IFN pathways were downregulated upon combined treatment. Remarkably, we confirmed that ISRIB and imatinib combination decreases STAT5 phosphorylation and inhibits expression of STAT5-target genes responsible for proliferation, viability and stress response. Thus, our data point to a substantial effect of imatinib and ISRIB combination, that results in transcriptomic deregulation and eradication of imatinib-resistant cells. Our findings suggest such drug combination might improve therapeutic outcome of TKI-resistant leukemia patients exhibiting constitutive STAT5 activation.
2022-11-04 | GSE171853 | GEO
Project description:An approximately 40% of chronic myeloid leukemia (CML) patients who discontinued imatinib (IM) therapy maintained undetectable minimal residual disease (UMRD) for more than one year (STOP-IM). We therefore set out to examine exosomal miRNAs expression in CML patients who could discontinue IM, to seek the possible distinguishable biomarker in STOP-IM CML patients. We compared CML patients who sustained UMRD for more than one year after discontinuation of imatinib (STOP-IM group) with healthy volunteers (controls).
2016-03-31 | GSE75389 | GEO
Project description:Expression profile of 14 Chronic Myeloid Leukemia Philadelphia chromossome negative patients after allo haematopoietc stem cell transplantation and Chronic Myeloid Leukemia treated with imatinib mesylate. We tested 754 microRNAs by reverse transcription quantitative polymerase chain reaction (RT-qPCR) array for each patient.
2021-01-12 | GSE164549 | GEO
Project description:Epigenetic modifiers were important players in the development of hematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyzes the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukemia progression and resistance to therapy targeting on BCR-ABL remain unclear. Here we found SETD2 acted as a tumor suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukemic stem cell enrichment in CML cell lines. Treatment with JIB-04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell’s imatinib sensitivity and enhanced the chemotherapeutic effect.
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