Dataset Information

Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease.

ABSTRACT: Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Approximately 35% to 50% of HCT recipients develop aGVHD; however, there are no validated diagnostic and predictive blood biomarkers for aGVHD in clinical use. Here, we show that plasma samples from aGVHD patients have a distinct microRNA (miRNA) expression profile. We found that 6 miRNAs (miR-423, miR-199a-3p, miR-93*, miR-377, miR-155, and miR-30a) were significantly upregulated in the plasma of aGVHD patients (n = 116) when compared with non-GVHD patients (n = 52) in training and validation phases. We have developed a model including 4 miRNAs (miR-423, miR-199a-3p, miR-93*, and miR-377) that can predict the probability of aGVHD with an area under the curve of 0.80. Moreover, these elevated miRNAs were detected before the onset of aGVHD (median = 16 days before diagnosis). In addition, the levels of these miRNAs were positively associated with aGVHD severity, and high expression of the miRNA panel was associated with poor overall survival. Furthermore, the miRNA signature for aGVHD was not detected in the plasma of lung transplant or nontransplant sepsis patients. Our results have identified a specific plasma miRNA signature that may serve as an independent biomarker for the prediction, diagnosis, and prognosis of aGVHD.

SUBMITTER: Xiao B

PROVIDER: S-EPMC3821726 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease.

Xiao Bin B Wang Yu Y Li Wei W Baker Megan M Guo Jian J Corbet Kelly K Tsalik Ephraim L EL Li Qi-Jing QJ Palmer Scott M SM Woods Christopher W CW Li Zhiguo Z Chao Nelson J NJ He You-Wen YW

Blood 20130916 19

Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Approximately 35% to 50% of HCT recipients develop aGVHD; however, there are no validated diagnostic and predictive blood biomarkers for aGVHD in clinical use. Here, we show that plasma samples from aGVHD patients have a distinct microRNA (miRNA) expression profile. We found that 6 miRNAs (miR-423, miR-199a-3p, miR-93*, miR-377, miR-155, and miR-30a) ...[more]

PMID: 24041574

Similar Datasets

Project description:Allogeneic hematopoietic stem cell transplantation is a curative treatment for numerous hematological malignancies. However, acute graft-versus-host disease (aGvHD) is a major complication affecting 40-70% of all transplant patients, whereby the earliest and most frequent presentation is in the skin. MicroRNAs play a role in varied biological process and have been reported as potential biomarkers for aGvHD. More recently, microRNAs have received added attention as circulatory biomarkers that can be detected in biofluids. In this study, we performed global microRNA expression profiling using a discovery cohort of diagnostic cutaneous aGvHD biopsies (n?=?5, stages 1-3) and healthy volunteers (n?=?4), in order to identify a signature list of microRNAs that could be used as diagnostic biomarkers for cutaneous aGvHD. Candidate microRNAs (n?=?8) were then further investigated in a validation cohort of post-HSCT skin biopsies (n?=?17), pre-HSCT skin biopsies (n?=?6) and normal controls (n?=?6) for their association with aGvHD. Expression of let-7c (p?=?0.014), miR-503-5p (p?=?0.003), miR-365a-3p (p?=?0.02), miR-34a-5p (p?<?0.001) and miR-34a-3p (p?=?0.006) were significantly differentially expressed between groups and significantly associated with survival outcome in post-HSCT patients (miR-503-5p ROC AUC?=?0.83 p?=?0.021, Log Rank p?=?0.003; miR-34a-3p ROC AUC?=?0.93, p?=?0.003, Log Rank p?=?0.004). There was no association with relapse. A statistical interaction between miR-34a-3p and miR-503-5p (p?=?0.016) was diagnostic for aGvHD. Expression levels of the miR-34a-5p protein target p53 were assessed in the epidermis of the skin, and an inverse correlation was identified (r2?=?0.44, p?=?0.039). Expression of the validated candidate microRNAs was also assessed at day 28 post-HSCT in the sera of transplant recipients, in order to investigate their potential as circulatory microRNA biomarkers. Expression of miR-503-5p (p?=?0.001), miR-34a-5p (p?=?0.005), and miR-34a-3p (p?=?0.004) was significantly elevated in the sera of patients who developed aGvHD versus no-aGvHD (n?=?30) and miR-503-5p was associated with overall survival (OS) (ROC AUC?=?0.80, p?=?0.04, Log Rank p?=?0.041). In conclusion, this investigation reports that microRNA expression levels in clinical skin biopsies, obtained at the time of cutaneous aGvHD onset, show potential as diagnostic biomarkers for aGvHD and as predictive biomarkers for OS. In addition, the same microRNAs can be detected in the circulation and show predictive association with post-HSCT outcomes.

Project description:MicroRNAs (miRNA) have emerged as central regulators of diverse biological processes and contribute to driving pathology in several diseases. Acute graft-versus-host disease (aGvHD) represents a major complication after allogeneic hematopoietic stem cell transplantation, caused by alloreactive donor T cells attacking host tissues leading to inflammation and tissue destruction. Changes in miRNA expression patterns occur during aGvHD, and we hypothesized that we could identify miRNA signatures in target tissues of aGvHD that may potentially help understand the underlying molecular pathology of the disease. We utilized a rat model of aGvHD with transplantation of fully MHC-mismatched T cell depleted bone marrow, followed by infusion of donor T cells. The expression pattern of 423 rat miRNAs was investigated in skin, gut, and lung tissues and intestinal T cells with the NanoString hybridization platform, in combination with validation by quantitative PCR. MHC-matched transplanted rats were included as controls. In the skin, upregulation of miR-34b and downregulation of miR-326 was observed, while in the intestines, we detected downregulation of miR-743b and a trend toward downregulation of miR-345-5p. Thus, tissue-specific expression patterns of miRNAs were observed. Neither miR-326 nor miR-743b has previously been associated with aGvHD. Moreover, we identified upregulation of miR-146a and miR-155 in skin tissue of rats suffering from aGvHD. Analysis of intestinal T cells indicated 23 miRNAs differentially regulated between aGvHD and controls. Two of these miRNAs were differentially expressed either in skin (miR-326) or in intestinal (miR-345-5p) tissue. Comparison of intestinal and peripheral blood T cells indicated common dysregulated expression of miR-99a, miR-223, miR-326, and miR-345-5p. Analysis of predicted gene targets for these miRNAs indicated potential targeting of an inflammatory network both in skin and in the intestines that may further regulate inflammatory cytokine production. In conclusion, comprehensive miRNA profiling in rats suffering from aGvHD demonstrate tissue-specific differences in the expression patterns of miRNA that may not be detected by profiling of peripheral blood T cells alone. These tissue-specific miRNAs may contribute to distinct pathologic mechanisms and could represent potential targets for therapy.

Dataset Information

Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease.

Publications

Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets