Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia

Wang, L; Romero, Martha; Ratajczak, Philippe; Lebœuf, Christophe; Belhadj, Stéphanie; Latour, Régis Peffault de; Wl, Zhao; Socié, Gèrard; Janin, Anne

doi:10.1038/bmt.2012.237

Cited by 25 publications

(35 citation statements)

References 25 publications

(24 reference statements)

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“…Previous studies indicate that microRNAs (miRs) play critical roles in the pathogenesis of aGVHD, including but not limited to miR-155, miR-146a, miR-181a, miR34a, and miR-100 (refs. 7-10). These miRs were found differentially expressed in effectors cells associated with aGVHD such as T cells subsets and antigen presenting cells (APCs) and modulate aGVHD by affecting mostly T cell function (7-10).…”

Section: Introductionmentioning

confidence: 99%

“…7-10). These miRs were found differentially expressed in effectors cells associated with aGVHD such as T cells subsets and antigen presenting cells (APCs) and modulate aGVHD by affecting mostly T cell function (7-10). Emerging data indicate that miRs can also be found in different body fluids such as serum, plasma, saliva and urine (11-14).…”

Section: Introductionmentioning

confidence: 99%

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Serum miR-29a Is Upregulated in Acute Graft-versus-Host Disease and Activates Dendritic Cells through TLR Binding

Ranganathan

Ngankeu

Zitzer

et al. 2017

The Journal of Immunology

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Acute Graft-Versus-Host Disease (aGVHD) continues to be a frequent and devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT); posing as a significant barrier against the widespread use of HSCTs as a curative modality. Recent studies suggested serum/plasma microRNAs (miR) may predict aGVHD onset. However, little is known about the functional role of circulating miRs in aGVHD. Here, we show in two independent cohorts that miR-29a expression is significantly upregulated in the serum of allo-HSCT patients at aGVHD onset compared to those who did not. Serum miR-29a is also elevated as early as two weeks before time of diagnosis of aGVHD compared to time-matched controls. We demonstrate novel functional significance of serum miR-29a by showing that miR-29a binds and activates dendritic cells via Toll like receptors (TLRs) 7 and 8, resulting in the activation of the NF-κB pathway and secretion of pro-inflammatory cytokines TNF-α and IL-6. Treatment with locked nucleic acid (LNA) anti miR-29a significantly improved survival in a mouse model of aGVHD while retaining graft-versus-leukemia (GVL) effects, unveiling a novel therapeutic target in aGVHD treatment or prevention.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Serum miR-29a Is Upregulated in Acute Graft-versus-Host Disease and Activates Dendritic Cells through TLR Binding

Ranganathan

Ngankeu

Zitzer

et al. 2017

The Journal of Immunology

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“…In the case of Fanconi anemia (FA), an inherited disorder characterized by developmental defects, genomic instability and progressive bone marrow failure (110), miR-34a expression in patient gut biopsies after HSCT was significantly higher in aGvHD grades II–IV compared to grade 0–I or with non-transplanted FA patient gut biopsies (111). …”

Section: Mirna and Mrna Expression Profiling In Hsctmentioning

confidence: 99%

Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes

Gam

Shah²,

Crossland

et al. 2017

Front. Immunol.

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The outcome of hematopoietic stem cell transplantation (HSCT) is controlled by genetic factors among which the leukocyte antigen human leukocyte antigen (HLA) matching is most important. In addition, minor histocompatibility antigens and non-HLA gene polymorphisms in genes controlling immune responses are known to contribute to the risks associated with HSCT. Besides single-nucleotide polymorphisms (SNPs) in protein coding genes, SNPs in regulatory elements such as microRNAs (miRNAs) contribute to these genetic risks. However, genetic risks require for their realization the expression of the respective gene or miRNA. Thus, gene and miRNA expression studies may help to identify genes and SNPs that indeed affect the outcome of HSCT. In this review, we summarize gene expression profiling studies that were performed in recent years in both patients and animal models to identify genes regulated during HSCT. We discuss SNP–mRNA–miRNA regulatory networks and their contribution to the risks associated with HSCT in specific examples, including forkheadbox protein 3 and regulatory T cells, the role of the miR-155 and miR-146a regulatory network for graft-versus-host disease, and the function of MICA and its receptor NKG2D for the outcome of HSCT. These examples demonstrate how SNPs affect expression or function of proteins that modulate the alloimmune response and influence the outcome of HSCT. Specific miRNAs targeting these genes and directly affecting expression of mRNAs are identified. It might be valuable in the future to determine SNPs and to analyze miRNA and mRNA expression in parallel in cohorts of HSCT patients to further elucidate genetic risks of HSCT.

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“…A clinical trial to further establish the significance of miR-155 in aGVHD is currently ongoing (ClinicalTrials.gov Identifier: NCT01521039). In addition, a group of miRs (miR-423, miR-199-3p, miR-93*, and miR-377) [6], miR-100 [7], miR-34a [8], and miR-146a [9] has also been identified to play an important role in the process of aGVHD after allo-HSCT. Atarod et al identified eight miRs (miR-146a, miR-155, miR-515, miR-346, miR-143, miR-373, miR-310, and miR-29) which could target different molecules in the GVHD signaling pathway [10].…”

Section: Introductionmentioning

confidence: 97%

Plasma microRNA-586 is a new biomarker for acute graft-versus-host disease

Wang

Zhao

et al. 2015

Ann Hematol

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Acute graft-versus-host disease (aGVHD) is one of the major causes of morbidity and mortality in patients receiving allogeneic hematopoietic cell transplantation (allo-HSCT). MicroRNAs (miRs) were found to have the potential to be the new biomarkers of aGVHD. In this study, we collected samples from 98 patients who underwent allo-HSCT; 63 patients developed aGVHD, and 35 patients did not. Plasma samples were collected at three time points (before aGVHD, at the onset of aGVHD, and after aGVHD) from 52 patients, and the miR-586 expression level was detected by quantitative real-time PCR. We found that the plasma miR-586 level was decreased at the onset of grade I-II aGVHD (P = 0.074). In contrast, when infections were detected, plasma miR-586 level was increased. Moreover, we detected the miR-586 expression level in patients who had infections but did not have aGVHD, and we found that miR-586 was upregulated (P = 0.005). We also compared the plasma miR-586 level at day 7 after transplantation between aGVHD patients and control patients. In the aGVHD group, there was a considerably higher miR-586 expression in comparison with the non-aGVHD group (P < 0.05). A more significant difference between the two groups was found when the patients with infections were excluded (P = 0.004). Furthermore, receive operating characteristic (ROC) analysis indicated that a higher expression level of miR-586 at day 7 could predict impending aGVHD. The optimal cutoff value of miR-586 to predict aGVHD was 2200 copies/μL with a sensitivity of 87.5 % and specificity of 55.0 %, and the area under the curve (AUC) was 0.739 (95 % CI 0.598-0.880, P = 0.004). Our study suggests that miR-586 might participate in the occurrence of aGVHD and could be a putative target for novel aGVHD therapy. The plasma level of miR-586 at day 7 after allo-HSCT would be a potential biomarker for predicting the occurrence of aGVHD.

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Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia

Cited by 25 publications

References 25 publications

Serum miR-29a Is Upregulated in Acute Graft-versus-Host Disease and Activates Dendritic Cells through TLR Binding

Serum miR-29a Is Upregulated in Acute Graft-versus-Host Disease and Activates Dendritic Cells through TLR Binding

Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes

Plasma microRNA-586 is a new biomarker for acute graft-versus-host disease

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