Exosomes released by imatinibresistant K562 cells contain specific membrane markers, IFITM3, CD146 and CD36 and increase the survival of imatinibsensitive cells in the presence of imatinib.
Int J Oncol
; 58(2): 238-250, 2021 02.
Article
em En
| MEDLINE
| ID: mdl-33491750
ABSTRACT
Chronic myeloid leukemia (CML) is a malignant hematopoietic disorder distinguished by the presence of a BCRABL1 fused oncogene with constitutive kinase activity. Targeted CML therapy by specific tyrosine kinase inhibitors (TKIs) leads to a marked improvement in the survival of the patients and their quality of life. However, the development of resistance to TKIs remains a critical issue for a subset of patients. The most common cause of resistance are numerous point mutations in the BCRABL1 gene, followed by less common mutations and multiple mutation-independent mechanisms. Recently, exosomes, which are extracellular vesicles excreted from normal and tumor cells, have been associated with drug resistance and cancer progression. The aim of the present study was to characterize the exosomes released by imatinibresistant K562 (K562IR) cells. The K562IRderived exosomes were internalized by imatinibsensitive K562 cells, which thereby increased their survival in the presence of 2 µM imatinib. The exosomal cargo was subsequently analyzed to identify resistanceassociated markers using a deep labelfree quantification proteomic analysis. There were >3,000 exosomal proteins identified of which, 35 were found to be differentially expressed. From this, a total of 3, namely the membrane proteins, interferoninduced transmembrane protein 3, CD146 and CD36, were markedly upregulated in the exosomes derived from the K562IR cells, and exhibited surface localization. The upregulation of these proteins was verified in the K562IR exosomes, and also in the K562IR cells. Using flow cytometric analysis, it was possible to further demonstrate the potential of CD146 as a cell surface marker associated with imatinib resistance in K562 cells. Taken together, these results suggested that exosomes and their respective candidate surface proteins could be potential diagnostic markers of TKI drug resistance in CML therapy.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mielogênica Crônica BCR-ABL Positiva
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Proteínas de Fusão bcr-abl
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Inibidores de Proteínas Quinases
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Exossomos
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Mesilato de Imatinib
Tipo de estudo:
Diagnostic_studies
Aspecto:
Patient_preference
Limite:
Humans
Idioma:
En
Revista:
Int J Oncol
Ano de publicação:
2021
Tipo de documento:
Article