Recent studies have demonstrated that exosomal microRNAs (miRNAs) have the potential of facilitating molecular diagnosis. Currently, little is known about the underlying mechanism behind late-onset acute graft-versus-host disease (LA GVHD). Identifying differentially expressed miRNAs in exosomes should be useful for understanding the role of miRNAs in this disease. This study was established to investigate the relevance of miRNAs in exosomes derived from patients developing LA GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). Plasma samples were collected from patients with LA GVHD (n = 5), non-GVHD (n = 5), and controls (n = 8) for exosomal miRNA expression profiling using a TaqMan low-density array; the results were validated by quantitative reverse transcription polymerase chain reaction (RT-PCR). We analyzed exosomal miRNAs differentially expressed among these three groups. MirTarBase was employed to predict potential target genes of the miRNAs specific for LA GVHD. We detected 55 miRNAs that were differentially expressed with a significant change >2.0-fold between LA GVHD and non-GVHD. Of these, we selected the 10 miRNAs (miR-423-5p, miR-19a, miR-142-3p, miR-128, miR-193b, miR-30c, miR-193a, miR-191, miR-125b, and miR-574-3p) with the most significant differential expression. Using quantitative RT-PCR, we further identified that miR-128 was significantly upregulated at the onset of LA GVHD compared with that in normal controls and is a promising diagnostic marker of LA GVHD, with an area under the curve (AUC) value of 0.975. MirTarBase analysis revealed that the predicted target genes of miR-128 are involved in the immune system and inflammation. Increased expression of miR-128 may serve as a novel, noninvasive biomarker for early LA GVHD diagnosis.

To evaluate the mechanism underlying the communication between myeloid malignant and bone marrow (BM) microenvironment cells in disease progression, the current study established BM mesenchymal stromal cells (MSCs) and assessed extracellular vesicle (EV) microRNA (miR) expression in 22 patients with myelodysplastic syndrome (MDS) and 7 patients with acute myeloid leukemia and myelodysplasia-related changes (AML/MRC). Patients with MDS were separated into two categories based on the revised International Prognostic Scoring System (IPSS-R), and EV-miR expression in BM-MSCs was evaluated using a TaqMan low-density array. The selected miRs were evaluated using reverse transcription-quantitative PCR. The current study demonstrated that the expression of BM-MSC-derived EV-miR was heterogenous and based on MDS severity, the expression of EV-miR-101 was lower in high-risk group and patients with AML/MRC compared with the control and low-risk groups. This reversibly correlated with BM blast percentage, with which the cellular miR-101 from BM-MSCs or serum EV-miR-101 expression exhibited no association. Database analyses indicated that miR-101 negatively regulated cell proliferation and epigenetic gene expression. The downregulation of BM-MSC-derived EV-miR-101 may be associated with cell-to-cell communication and may accelerate the malignant process in MDS cells.

Letter to the Editor Predisposed genomic instability in pre-treatment bone marrow evolves to therapy-related myeloid neoplasms in malignant lymphoma Running head: Predisposed genomic instability of tMN after ML

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A 53-year-old man who was regularly reviewed at our hospital for chronic hepatitis C infection was admitted in November 2012 with severe upper abdominal pain. Ultrasonography and computerized tomography showed multiple liver nodules with hepatomegaly. On magnetic resonance imaging, there were multiple T2 high-intensity nodular lesions, which were interpreted as metastatic liver tumours (upper panel). Upper and lower endoscopy was subsequently performed to identify a primary lesion, but none was found. Liver biopsy, however, showed diffuse large B-cell lymphoma (DLBCL) [lower left: haematoxylin-eosin staining (9100); lower right: CD20 immunohistochemical staining (9100)]. 18 F-fluorodeoxyglucose positron emission tomography revealed multiple lesions with a high maximum standardized uptake value (SUV max ; 10-23) in the lungs, liver and bones, and treatment with the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) was commenced. The patient received eight courses of R-CHOP therapy; he achieved complete remission, which has been maintained to date.Primary hepatic DLBCL can be classified into three morphological patterns: solitary liver mass, multiple focal nodules and diffuse infiltrative disease. The first two patterns are the most common. Imaging studies showing a solitary space-occupying lesion or multiple heterogeneous lesions in the liver are usually interpreted as hepatocellular carcinoma or metastatic cancer. Our patient had multiple focal nodules resembling metastatic liver tumours.Our experience demonstrates that when a patient with multiple nodular lesions of the liver is encountered, the possibility of malignant lymphoma should be considered.