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Exome, transcriptome and miRNA analysis don't reveal any molecular markers of TKI efficacy in primary CML patients
Alexander V Lavrov1,2, Ekaterina Yu Chelysheva3, Elmira P Adilgereeva4
1Laboratory of Mutagenesis, Federal State Budgetary Institution, Research Centre for Medical Genetics, Moskvorechie str., 1, Moscow, Russian Federation, 115522. alexandervlavrov@gmail.com.
Background:
Approximately 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.
Methods:
Newly 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.
Results:
The 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.
Conclusions:
Using 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.
Insights
Researchers investigated molecular markers to predict tyrosine kinase inhibitor (TKI) therapy effectiveness in chronic myeloid leukemia (CML) patients. High-throughput analysis of gene polymorphisms, expression, and microRNAs did not yield reliable early predictive markers for TKI efficacy in CML.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Approximately 5-20% of chronic myeloid leukemia (CML) patients exhibit primary resistance or intolerance to imatinib.
- Current predictive scores lack efficacy in forecasting tyrosine kinase inhibitor (TKI) treatment outcomes.
- Gene polymorphisms, expression patterns, and microRNAs are implicated in the development of TKI resistance in CML.
Purpose of the Study:
- To identify novel molecular markers for predicting TKI therapy efficacy in CML patients.
- To investigate the role of gene polymorphisms, gene expression, and microRNAs in TKI response.
- To enhance personalized treatment strategies for CML.
Main Methods:
- Genotyping of selected polymorphisms in 62 CML patient blood samples.
- Gene expression profiling of 33 RNA samples from CML patients.
- MicroRNA (miRNA) profiling of 800 miRNAs in 12 CML patient blood samples.
- Analysis of optimal vs. non-optimal TKI responses based on ELN 2013 recommendations.
Main Results:
- No significant differences in genotype frequencies were observed between patients with optimal and non-optimal TKI responses.
- While 26 genes were differentially expressed (p < 0.05), the differences were minimal and not validated by qPCR.
- No significant differences in miRNA expression were found between patient groups with varying TKI responses.
Conclusions:
- Modern high-throughput techniques, including whole-exome sequencing, transcriptome, and miRNA analysis, failed to identify reliable molecular markers.
- The study could not establish early predictive markers for TKI efficiency in Philadelphia chromosome-positive (Ph+) CML patients.
- Further research may be needed to uncover predictive biomarkers for TKI therapy in CML.
