Abstract
BackgroundApproximately 5–20% of chronic myeloid leukemia (CML) patients demonstrate primary resistance or intolerance to imatinib. None of the existing predictive scores gives a good prognosis of TKI efficacy. Gene polymorphisms, expression and microRNAs are known to be involved in the pathogenesis of TKI resistance in CML. The aim of our study is to find new molecular markers of TKI therapy efficacy in CML patients.MethodsNewly diagnosed patients with Ph+ CML in chronic phase were included in this study. Optimal and non-optimal responses to TKI were estimated according to ELN 2013 recommendation. We performed genotyping of selected polymorphisms in 62 blood samples of CML patients, expression profiling of 33 RNA samples extracted from blood and miRNA profiling of 800 miRNA in 12 blood samples of CML patients.ResultsThe frequencies of genotypes at the studied loci did not differ between groups of patients with an optimal and non-optimal response to TKI therapy. Analysis of the expression of 34,681 genes revealed 26 differently expressed genes (p < 0.05) in groups of patients with different TKI responses, but differences were very small and were not confirmed by qPCR. Finally, we did not find difference in miRNA expression between the groups.ConclusionsUsing modern high-throughput methods such as whole-exome sequencing, transcriptome and miRNA analysis, we could not find reliable molecular markers for early prediction of TKI efficiency in Ph+ CML patients.
Highlights
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of [9;22] translocation and BCR/ABL fusion gene with high tyrosine kinase activity which activates MAPK pathway, cell proliferation, blocks apoptosis and leads to genome instability resulting in further development of the disease
Patients Newly diagnosed patients with Ph+ chronic myeloid leukemia (CML) in chronic phase were included in this study
Prognostic role of the polymorphisms in cancerassociated genes Seven variants were found to associate with the tyrosine kinase inhibitor (TKI) efficacy in a small group of CML patients: rs115 79366, rs1990236 (DNAH9), rs176037 (MAGEC1), rs10653661 (TOX3), rs3803264 (THSD1), rs3099950 (MORN2), and rs9471966 (PTCRA)
Summary
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of [9;22] translocation and BCR/ABL fusion gene with high tyrosine kinase activity which activates MAPK pathway, cell proliferation, blocks apoptosis and leads to genome instability resulting in further development of the disease. BCR/ABL tyrosine kinase inhibitor (TKI) is the standard therapy in CML-Ph+ patients since its FDA approval in 2001. Despite high efficacy of imatinib the problem of primary resistance persists. Based on the recent report about 21% of CML patients are switched to another TKI because of resistance or intolerance [2]. 5–20% of chronic myeloid leukemia (CML) patients demonstrate primary resistance or intolerance to imatinib. The aim of our study is to find new molecular markers of TKI therapy efficacy in CML patients
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