Circulating microRNAs as minimal residual disease biomarkers in childhood acute lymphoblastic leukemia
Andrea Rzepiel1, Nóra Kutszegi1,2, András Gézsi3,4
12nd Department of Paediatrics, Semmelweis University, Budapest, Hungary.
Background:
Treatment stratification based on bone marrow minimal residual disease (MRD) at set time points has resulted in considerably improved survival in pediatric acute lymphoblastic leukemia (ALL). Treatment response is assessed using bone marrow samples. MicroRNAs (miRs) easily traffic among fluid spaces and are more stable than most other RNA classes. We examined the role of circulating miRs as putative less invasive MRD biomarkers.
Methods:
In an exploratory experiment, expression of 46 preselected miRs was studied in platelet-free blood plasma samples of 15 de novo, 5 relapsed ALL patients and 10 controls by Custom TaqMan Array Advanced MicroRNA Card. Based on their high expression in ALL compared to controls, and on the reduction observed along the induction therapy, four miRs were selected for further analyses: miR-128-3p, -181a-5p, -181b-5p and 222-3p. Their expression was measured by qPCR at 4 time points in 27 de novo ALL patients treated in the ALL IC-BFM 2009 study.
Results:
The expression of all 4 miRs significantly decreased over the first week of therapy (miR-128-3p: log2 fold change - 2.86; adjusted p 3.6 × 10-7; miR-181b-5p: log2 fold change - 1.75; adjusted p 1.48 × 10-2; miR-181a-5p: log2 fold change -1.33; adjusted p 3.12 × 10-2; miR-222-3p: log2 fold change - 1.25; adjusted p 1.66 × 10-2). However, no significant further reduction in miR expression was found after the 8th day of therapy. Measured drop in expression of 2 miRs at day 8 strongly correlated with day 15 bone marrow flow cytometry MRD results (miR-128-3p: Pearson's r = 0.88, adjusted p = 2.71 × 10-4; miR-222-3p: r = 0.81, adjusted p = 2.99 × 10-3).
Conclusion:
In conclusion, these circulating miRs might act as biomarkers of residual leukemia. MiR-128-3p and miR-222-3p in blood predict day 15 flow cytometry MRD results 7 days earlier. Although, their sensitivity falls behind that of bone marrow flow cytometry MRD at day 15.
Insights
Circulating microRNAs (miRs) show promise as less invasive biomarkers for minimal residual disease (MRD) in pediatric acute lymphoblastic leukemia (ALL). Specific miRs in blood can predict MRD status earlier than traditional bone marrow tests.
Area of Science:
- Oncology
- Molecular Biology
- Biomarker Discovery
Background:
- Minimal residual disease (MRD) monitoring is crucial for improving survival in pediatric acute lymphoblastic leukemia (ALL).
- Current MRD assessment relies on invasive bone marrow sampling.
- MicroRNAs (miRs) are stable molecules found in circulation, making them potential non-invasive biomarkers.
Purpose of the Study:
- To investigate the potential of circulating microRNAs (miRs) as less invasive biomarkers for MRD in pediatric ALL.
- To identify specific miRs whose expression levels correlate with treatment response.
Main Methods:
- Exploratory analysis of 46 preselected miRs in plasma from ALL patients and controls using Custom TaqMan Array.
- Selection of four candidate miRs (miR-128-3p, -181a-5p, -181b-5p, -222-3p) based on expression patterns.
- Quantitative PCR (qPCR) measurement of selected miR expression at four time points in ALL patients.
Main Results:
- All four selected miRs showed significant decreased expression within the first week of therapy.
- No further significant reduction in miR expression was observed after day 8.
- Decreased expression of miR-128-3p and miR-222-3p at day 8 strongly correlated with day 15 bone marrow MRD results.
Conclusions:
- Circulating miRs, particularly miR-128-3p and miR-222-3p, may serve as early biomarkers for residual leukemia.
- These miRs can predict day 15 MRD status 7 days earlier than bone marrow analysis.
- While promising, the sensitivity of these circulating miRs is currently lower than bone marrow flow cytometry MRD assessment.
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