Our study suggests an association of imatinib treatment, miRNA downregulation and ABCG2 overexpression, possibly contributing to the mechanisms involved in imatinib distribution and response in CML therapy.
Background Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by constitutive activity of the tyrosine kinase BCR-ABL1. Although the introduction of tyrosine kinase inhibitors (TKIs) has substantially improved patients’ prognosis, drug resistance remains one of the major challenges in CML therapy. MicroRNAs (miRNAs), a class of short non-coding RNAs acting as post-transcriptional regulators, are implicated in CML progression and drug resistance. The aim of the present study was to analyze the miRNA expression profiles of 45 treatment-naïve CML patients in chronic phase (28 peripheral blood and 17 bone marrow samples) with respect to future response to imatinib therapy. Methods TaqMan low density arrays were used to analyze the miRNA expression pattern of the patient samples. For selected microRNAs, reporter gene assays were performed to study their ability to regulate CML associated target genes. Results Significant lower expression levels of miR-142-5p were identified in both, peripheral blood and bone marrow samples of future non-responders suggesting a potential tumor suppressor role of this miRNA. This was supported by reporter gene assays that identified the survival, proliferation and invasion promoting CML related genes ABL2, cKIT, MCL1 and SRI as targets of miR-142-5p and miR-365a-3p, the latter identified as potential biomarker in peripheral blood samples. Conclusion MiR-142-5p and to a certain extend also miR-365a-3p were able to discriminate treatment-naïve CML patients not responding to imatinib in the course of their treatment from patients, who responded to therapy. However, further large-scale studies should clarify if the identified miRNAs have the potential as predictive biomarkers for TKI resistance.
Introduction: Treatment of chronic myeloid leukemia (CML) with the BCR/ABL-inhibitor imatinib led to a tremendous progress of over-all survival. However therapy resistance in a significant proportion of patients remains a severe clinical problem. Aside mutations of the BCR/ABL gene, regulation of cellular transporters or downstream factors may contribute to non-response. We aimed to investigate micro-RNA expression profiles in peripheral leukocytes of 21 newly diagnosed CML patients without BCR/ABL-mutations in order to identify biomarkers to treatment-response of imatinib. Methods: Ten responders (molecular remission) and 11 non-responders were included. Expression of 667 microRNAs was analyzed using a TaqMan Low-Density Array system. Relative fold change of microRNAs between groups was calculated according to the 2^-ΔΔCt method. MicroRNAs with a fold change>2 and a P-value<0.01 were considered significant. MicroRNAs with minor expression (Ct-value>20) were not included. Putative targets of dysregulated microRNAs were considered, if predicted by at least three databases, and further analyzed using the DAVID-bioinformatic database. Results: Four microRNAs were significantly deregulated (miR-7, miR-744*, miR-616, miR-212) between responders and non-responders, when being treatment-naïve, predicted to have 97 potential targets. In depth target analysis showed that transcription regulators (21% of the predicted targets) are highly enriched compared to normal gene expression background of humans. Pathway analysis revealed six genes involved in cancer pathways, whereas four of them are directly involved in the chronic myeloid leukemia pathway (SMAD4, NRAS, RB1, RAF1). In responders seven microRNAs were deregulated before and after therapy, whereas five other microRNAs were deregulated within the group of non-responders. Three deregulated microRNAs were identified in both groups. Most predicted target genes are involved in MAPK signaling and exocytosis, 13% of the targets were predicted to be transcription regulators, and 18% cellular (especially uptake) transporters. Conclusion: We identified distinct microRNA pattern comparing blood samples of responders and non-responders prior to imatinib therapy. Predicted target genes were primarily transcription factors and oncogenes. In contrast, transporters and exocytotic pathways are in addition frequent targets of microRNAs deregulated after imatinib therapy. The suitability as biomarkers for prediction of imatinib-response requires further confirmation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1097. doi:1538-7445.AM2012-1097
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