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Serum and Extracellular Vesicle MicroRNAs miR-423, miR-199, and miR-93* As Biomarkers for Acute Graft-versus-Host Disease

Lookup NU author(s): Dr Rachel CrosslandORCiD, Jean Norden, Dr Kim PearceORCiD, Dr Clare LendremORCiD, Louis Bibby, Professor Matthew CollinORCiD, Professor Anne Dickinson

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2017 Crossland, Norden, Kralj Juric, Pearce, Lendrem, Bibby, Collin, Greinix and Dickinson.Acute graft-versus-host disease (aGvHD) is a major cause of adverse outcome in hematopoietic stem cell transplantation (HSCT), with a high incidence (20-50%). A novel, non-invasive diagnostic test to predict for prevalence and severity would enable improved prophylaxis and reduce morbidity. Circulatory microRNAs (miRNAs) miR-423, miR-199, miR-93*, and miR-377 have previously been associated with aGvHD in post-HSCT patient plasma, but validation is lacking and their expression within extracellular vesicles (EVs) has not been explored. This study replicated elevated serum expression of miR-423 (p < 0.001), miR-199 (p = 0.04), miR-93* (p < 0.001), and miR-377 (p = 0.03) in aGvHD, using a prognostic cohort of day 14 (D14) post-HSCT patient samples (n = 81). Expression also associated with disease severity. Further analysis at aGvHD diagnosis in an independent cohort (n = 65) confirmed high miR-423 (p = 0.02), miR-199 (p = 0.007), and miR-93* (p = 0.004) expression at disease onset. Investigation of expression patterns during early HSCT sequential timepoints (pre-HSCT to D28) identified elevated miRNAs at D7 post-HSCT in all transplant patients. In a novel investigation of miRNA expression in serum EVs (n = 15), miR-423 (p = 0.09), miR-199 (p = 0.008), and miR-93* (p = 0.001) levels were lower at D14 in patients who later developed aGvHD, and this was replicated for miR-423 (p = 0.02) and miR-199 (p = 0.04) (n = 47). Comparing serum to circulating EVs, at D14 patients remaining aGvHD-free had higher expression of miR-423 (p = 0.03), miR-199 (p = 0.009), and miR-93* (p = 0.002) in the EV fraction. Results verify the capacity for circulating miR-423, miR-199, and miR-93* as diagnostic and prognostic aGvHD biomarkers. The novel finding of their differential expression in EVs suggests a potential role in aGvHD etiology.

Publication metadata

Author(s): Crossland RE, Norden J, Juric MK, Pearce KF, Lendrem C, Bibby LA, Collin M, Greinix HT, Dickinson AM

Publication type: Article

Publication status: Published

Journal: Frontiers in Immunology

Year: 2017

Volume: 8

Online publication date: 10/11/2017

Acceptance date: 17/10/2017

Date deposited: 13/12/2017

ISSN (electronic): 1664-3224

Publisher: Frontiers Media S.A.

URL: https://doi.org/10.3389/fimmu.2017.01446

DOI: 10.3389/fimmu.2017.01446

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