Exome, transcriptome and miRNA analysis don’t reveal any molecular markers of TKI efficacy in primary CML patients

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.Electronic supplementary materialThe online version of this article (10.1186/s12920-019-0481-z) contains supplementary material, which is available to authorized users.

Expression differences of miR-142-5p between treatment-naïve chronic myeloid leukemia patients responding and non-responding to imatinib therapy suggest a link to oncogenic ABL2, SRI, cKIT and MCL1 signaling pathways critical for development of therapy resistance

“…Jurkovicova et al found a total of 70 differentially expressed miRNAs between treatment-naïve non-responders and responders, José-Enériz et al identified 19 miRNAs and Mosakhani et al detected only one miRNA, miR-181c-5p, to be significantly down-regulated in non-responders compared to responders [9][10][11]. Furthermore, Lavrov et al did not find any miRNA, whose expression pattern could discriminate between non-responds and responds to TKI therapy at time of diagnosis [12]. This inconsistency of study results might be based on factors such as differences in study design including diverse sample origin (peripheral blood or bone marrow), differences in patient cohorts, e.g.…”

“…As drug resistance still remains a challenge in CML treatment, predictive biomarkers would help to optimize patients’ therapy. MiRNAs are frequently discussed as potential candidates for these biomarkers [ 12 , 71 , 72 ]. So far, three out of the four studies analyzing miRNA expression pattern of treatment-naïve CML patients at time of diagnosis suggested selected miRNAs as potential predictive markers for TKI resistance [ 9 – 12 ].…”

“…Furthermore, Lavrov et al . did not find any miRNA, whose expression pattern could discriminate between non-responds and responds to TKI therapy at time of diagnosis [ 12 ]. This inconsistency of study results might be based on factors such as differences in study design including diverse sample origin (peripheral blood or bone marrow), differences in patient cohorts, e.g.…”

“…As these resistances are a major challenge in CML treatment, predictive markers are desirable to improve the selection of appropriate therapy regimes and thereby patient outcome. MiRNAs as potent regulators of gene expression are discussed as biomarkers for diagnosis, progression and drug response in various tumor types [ 9 – 12 ]. Previous studies analyzing miRNA expression patterns of treatment-naïve CML patients at diagnosis aiming to predict TKI resistances included only 8–12 patients and led to contradictory results.…”

“…Previous studies analyzing miRNA expression patterns of treatment-naïve CML patients at diagnosis aiming to predict TKI resistances included only 8–12 patients and led to contradictory results. While Lavrov et al did not find any significant differences in miRNA expression pattern between non-responding and responding patients to TKI therapy, the other three studies suggested selected miRNAs as potential predictive biomarkers for TKI response [ 9 – 12 ]. However, even these suggested miRNAs were inconsistent between the studies.…”