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Expression of Serum microRNAs is Altered During Acute Graft-versus-Host Disease
Rachel E Crossland1, Jean Norden1, Mateja Kralj Juric2
1Haematological Sciences, Medical School, Newcastle University , Newcastle upon Tyne , UK.
Abstract:
Acute graft-versus-host disease (aGvHD) is the most frequent and serious complication following hematopoietic stem cell transplantation (HSCT), with a high mortality rate. A clearer understanding of the molecular pathogenesis may allow for improved therapeutic options or guide personalized prophylactic protocols. Circulating microRNAs are expressed in body fluids and have recently been associated with the etiology of aGvHD, but global expression profiling in a HSCT setting is lacking. This study profiled expression of n = 799 mature microRNAs in patient serum, using the NanoString platform, to identify microRNAs that showed altered expression at aGvHD diagnosis. Selected microRNAs (n = 10) were replicated in independent cohorts of serum samples taken at aGvHD diagnosis (n = 42) and prior to disease onset (day 14 post-HSCT, n = 47) to assess their prognostic potential. Sera from patients without aGvHD were used as controls. Differential microRNAs were investigated in silico for predicted networks and mRNA targets. Expression analysis identified 61 microRNAs that were differentially expressed at aGvHD diagnosis. miR-146a (p = 0.03), miR-30b-5p (p = 0.007), miR-374-5p (p = 0.02), miR-181a (p = 0.03), miR-20a (p = 0.03), and miR-15a (p = 0.03) were significantly verified in an independent cohort (n = 42). miR-146a (p = 0.01), miR-20a (p = 0.03), miR-18 (p = 0.03), miR-19a (p = 0.03), miR-19b (p = 0.01), and miR-451 (p = 0.01) were differentially expressed 14 days post-HSCT in patients who later developed aGvHD (n = 47). High miR-19b expression was associated with improved overall survival (OS) (p = 0.008), whereas high miR-20a and miR-30b-5p were associated with lower rates of non-relapse mortality (p = 0.05 and p = 0.008) and improved OS (p = 0.016 and p = 0.021). Pathway analysis associated the candidate microRNAs with hematological and inflammatory disease. Circulating biofluid microRNAs show altered expression at aGvHD onset and have the capacity to act as prognostic and diagnostic biomarkers. Their differential expression in serum suggests a role for circulatory microRNAs in aGvHD pathology, which warrants further investigation.
Insights
This study identified specific microRNAs in patient serum that change during acute graft-versus-host disease (aGvHD) after stem cell transplants. These microRNAs could serve as biomarkers for diagnosis and prognosis, improving patient outcomes.
Area of Science:
- Hematology
- Immunology
- Molecular Biology
Background:
- Acute graft-versus-host disease (aGvHD) is a major complication of hematopoietic stem cell transplantation (HSCT), leading to high mortality.
- Understanding aGvHD's molecular basis is crucial for developing better therapies and personalized prevention strategies.
- Circulating microRNAs in body fluids are implicated in aGvHD, but comprehensive profiling in HSCT patients is lacking.
Purpose of the Study:
- To profile global microRNA expression in serum from HSCT patients to identify biomarkers for aGvHD.
- To assess the diagnostic and prognostic potential of differentially expressed microRNAs.
- To investigate the role of these microRNAs in aGvHD pathogenesis through in silico analysis.
Main Methods:
- Serum samples from 799 mature microRNAs were analyzed using the NanoString platform.
- Expression profiling was performed at aGvHD diagnosis and at day 14 post-HSCT.
- Independent cohorts were used for validation, and in silico tools predicted microRNA networks and mRNA targets.
Main Results:
- 61 microRNAs showed differential expression at aGvHD diagnosis.
- Six microRNAs (miR-146a, miR-30b-5p, miR-374-5p, miR-181a, miR-20a, miR-15a) were validated in an independent cohort.
- Several microRNAs (miR-146a, miR-20a, miR-18, miR-19a, miR-19b, miR-451) were differentially expressed pre-symptomatically (day 14 post-HSCT).
- High miR-19b, miR-20a, and miR-30b-5p expression correlated with improved overall survival and reduced non-relapse mortality.
Conclusions:
- Circulating microRNAs exhibit altered expression patterns during aGvHD onset.
- These microRNAs demonstrate potential as diagnostic and prognostic biomarkers for aGvHD.
- The findings suggest a role for circulating microRNAs in aGvHD pathology, meriting further investigation.