Circulating miRNA panel for prediction of acute graft-versus-host disease in lymphoma patients undergoing matched unrelated hematopoietic stem cell transplantation

Abstract

Acute graft-versus-host disease (aGVHD) results in significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Noninvasive diagnostic and prognostic tests for aGVHD are currently lacking, but would be beneficial in predicting aGVHD and improving the safety of allo-HSCT. Circulating microRNAs exhibit marked stability and may serve as biomarkers in several clinical settings. Here, we evaluated the use of circulating microRNAs as predictive biomarkers of aGVHD in lymphoma patients after allo-HSCT from matched unrelated donors (MUDs). After receiving informed consent, we prospectively collected plasma samples from 24 lymphoma patients before and after unmanipulated MUD allo-HSCT; microRNAs were then isolated. Fourteen patients developed aGVHD symptoms at a median of 48 days (range: 32-90) post-transplantation. Two patients developed intestinal GVHD, eight cutaneous GVHD, and four multiorgan GVHD. The microRNA expression profile was examined using quantitative real-time polymerase chain reaction (qRT-PCR). MicroRNAs 194 and 518f were significantly upregulated in aGVHD samples compared with samples taken from non-aGVHD patients. Remarkably, these upregulated microRNAs could be detected before the onset of aGVHD. Pathway prediction analysis indicated that these microRNAs may regulate critical pathways involved in aGVHD pathogenesis. Considering the noninvasive characteristics of plasma sampling and the feasibility of detecting miRNAs after allo-HSCT using real-time polymerase chain reaction, our results indicate that circulating microRNAs have the potential to enable an earlier aGVHD diagnosis and might assist in individualizing therapeutic strategies after MUD allo-HSCT. Nevertheless, standardization of blood sampling and analysis protocols is mandatory for the introduction of miRNA profiling into routine clinical use.

Expression of Serum microRNAs is Altered During Acute Graft-versus-Host Disease

“…Although previous groups have performed microRNA profiling post-HSCT, these studies have focused on specific subgroups of patients or a refined signature of microRNAs limited by the qRT-PCR technology used (13, 17). This study was based on NanoString technology, which incorporates over 700 validated microRNA targets allowing for the most comprehensive assessment of circulating microRNA expression in a HSCT setting to date.…”

“…Preliminary studies have assessed expression of specific circulating microRNAs in the serum or plasma of patients post-HSCT to identify potential biomarkers for aGvHD incidence, severity, or outcome (13–17), and some investigations have included profiling of an extended microRNA repertoire (13, 17). However, these studies have focused on a subset of microRNAs that can be detected by high-throughput qRT-PCR-based arrays (13, 17) or within specific subsets of patients such as lymphoma patients receiving matched unrelated donor (MUD) allo-HSCT (17).…”

“…However, these studies have focused on a subset of microRNAs that can be detected by high-throughput qRT-PCR-based arrays (13, 17) or within specific subsets of patients such as lymphoma patients receiving matched unrelated donor (MUD) allo-HSCT (17). …”

B-Cell-Based and Soluble Biomarkers in Body Liquids for Predicting Acute/Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

“…In a separate study, Gimondi et al focused on lymphoma patients receiving MUD allo-transplants to profile the plasma using qRT-PCR for global miRNA expression (94). Assessing samples collected 28 days post-HSCT, 113 miRNAs were detected in all samples and of these, 27 could collectively discriminate between aGvHD versus no aGvHD and miRNA-194 and miRNA-518f were significantly upregulated in the patients who later developed the disease (94).…”

“…Assessing samples collected 28 days post-HSCT, 113 miRNAs were detected in all samples and of these, 27 could collectively discriminate between aGvHD versus no aGvHD and miRNA-194 and miRNA-518f were significantly upregulated in the patients who later developed the disease (94). The authors did not detect differential expression of miRNAs identified by Xiao et al (92), and there was no validation cohort included in the investigation.…”