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Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib
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Resumo(s)
Despite the success of imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), approximately 30\% of patients are resistant to therapy, mostly due to unknown causes. To profile the expression signatures of drug transporters throughout IM therapy and correlate them with resistance, we quantified mRNA expression levels of the SLC22A12, ABCB1, ABCC1, ABCG2 and MVP genes in consecutive samples from peripheral blood or bone marrow of CML patients who were either responsive or resistant to IM. Additionally we identified and quantified BCR-ABL1 transcript variants and analyzed 1236T>C ABCB1 and 480G>C SLC22A1 polymorphisms. A relationship between the type of BCR-ABL1 transcript or ABCB1 or SLC22A1 genotype and response to treatment was not discovered. However, the studied genes had higher expression levels in follow-up compared to the diagnostic samples, demonstrating a possible induction in expression. IM-sensitive patients presented significantly higher values of SLC22A1 expression, suggesting higher drug influx. Most importantly, while responding patients demonstrated stable expression signatures in consecutive samples, there was considerable variation in IM-resistant patients, indicating that single point sampling expression signatures are not reliable in predicting clinical outcomes or prognostic features in these patients. Studies that assessed consecutive samples from CML patients in order to evaluate the variation in expression levels of transporter genes are limited yet our study emphasizes the importance of such approaches.
Descrição
Palavras-chave
MOLECULAR RESPONSES BCR-ABL1 ABCG2 KINASE DOMAIN MUTATIONS drug resistance MVP FUSION GENE TRANSCRIPTS STANDARD-DOSE IMATINIB EUROPEAN LEUKEMIANET tyrosine kinase inhibitors drug transporters SLC22A1 chronic myeloid leukemia LOW OCT-1 ACTIVITY SUBOPTIMAL RESPONSE P-GLYCOPROTEIN MULTIDRUG-RESISTANCE ABCC1 imatinib ABCB1 BINDING-CASSETTE TRANSPORTERS ABCB1 ABCC1 ABCG2 BCR-ABL1 Chronic myeloid leukemia Drug resistance rug transporters Imatinib MVP SLC22A1 Tyrosine kinase inhibitors