Multiple myeloma (MM) is malignant tumor with abnormal proliferation of bone marrow plasma cells. The existing clinical tools used to determine treatment response and tumor relapse are limited in sensitivity. We investigated the CD138+ microparticles (MPs) of MM patients to find out whether MPs could provide a novel means to monitor the malignant cells in MM patients. Our study showed that the levels of MPs were significantly elevated in MM patients. The MP counts in peripheral blood from new diagnosed MM patients were significantly higher than patients in CR and HD. Consist with the total MPs, the number of the PC‐derived MPs (CD138+) increased in BM from MM patients compared with CR and HD. The ratio of the PC‐derived MPs (CD138+) in BM increased in MM patients compared with CR and HD. The correlation test revealed that the CD138+ MPs in BM and PB were all positively correlated with the plasmacyte ratio in bone marrow (BMPC) and the β2‐MG. New diagnosed MM patients and controls were compared, and ROC curves were used to identify cutoff points with optimal sensitivity and specificity concerning the ratios and counts of CD138+ MPs in BM and PB. The AUC of the CD138+ MP counts in BM was 0.767, and in PB was 0.680. The AUC of the CD138+ MP ratios in BM was 0.714, and in PB was 0.666. According to this, the counts of CD138+ MPs in BM showed to be a powerful marker of diagnosis. We demonstrated that CD138+ MPs from the plasma provide support for a potential monitoring biomarker of MM.

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Summary High expression of the inhibitory receptor programmed cell death ligand 1 (PD‐L1) on tumor cells and tumor stromal cells have been found to play a key role in tumor immune evasion in several human malignancies. However, the expression of PD‐L1 on bone marrow mesenchymal stem cells (BMSCs) and whether the programmed cell death 1 (PD‐1)/PD‐L1 signal pathway is involved in the BMSCs versus T cell immune response in multiple myeloma (MM) remains poorly defined. In this study, we explored the expression of PD‐L1 on BMSCs from newly diagnosed MM (NDMM) patients and the role of PD‐1/PD‐L1 pathway in BMSC‐mediated regulation of CD8+ T cells. The data showed that the expression of PD‐L1 on BMSCs in NDMM patients was significantly increased compared to that in normal controls (NC) (18·81 ± 1·61 versus 2·78± 0·70%; P < 0·001). Furthermore, the PD‐1 expression on CD8+ T cells with NDMM patients was significantly higher than that in normal controls (43·22 ± 2·98 versus 20·71 ± 1·08%; P < 0·001). However, there was no significant difference in PD‐1 expression of CD4+ T cells and natural killer (NK) cells between the NDMM and NC groups. Additionally, the co‐culture assays revealed that BMSCs significantly suppressed CD8+ T cell function. However, the PD‐L1 inhibitor effectively reversed BMSC‐mediated suppression in CD8+ T cells. We also found that the combination of PD‐L1 inhibitor and pomalidomide can further enhance the killing effect of CD8+ T cells on MM cells. In summary, our findings demonstrated that BMSCs in patients with MM may induce apoptosis of CD8+ T cells through the PD‐1/PD‐L1 axis and inhibit the release of perforin and granzyme B from CD8+ T cells to promote the immune escape of MM.

PIM2 proto-oncogene, serine/threonine kinase (PIM2) is a serine/threonine protein kinase that is upregulated in different types of cancer and serves essential roles in the regulation of signal transduction cascades, which promote cell survival and cell proliferation. The present study demonstrated that PIM2 was highly expressed in CD34 + cells derived from the bone marrow of patients with myelodysplastic syndromes (MDS)/acute myeloid leukemia. The mRNA expression level of PIM2 was quantified in MDS cell lines and mRNA expression was significantly decreased compared with that in KG-1 cells. In vitro , downregulation of PIM2 by short interfering RNA (siRNA) inhibited cell proliferation and delayed G 0 /G 1 cell cycle progression in the MDS cell line SKM-1. Western blotting revealed that cyclin dependent kinase 2 was markedly downregulated and cyclin dependent kinase inhibitor 1A was markedly upregulated following transfection with PIM2 siRNA. Cell Counting Kit-8 analysis demonstrated that cell proliferation of si-PIM2-transfected cells was significantly decreased compared with control cells. Reverse-transcription quantitative polymerase chain reaction and western blotting revealed that PIM2 expression was negatively correlated with isocitrate dehydrogenase [NADP(+)]1 cytosolic (IDH1) and positively correlated with hypoxia inducible factor 1 subunit α (HIF1A) in CD34 + MDS cells. Collectively, these results suggested that the expression of PIM2 induced increased expression of HIF1A by decreasing the expression of IDH1, resulting in increased CD34 + cell proliferation. Therefore, PIM2 may be a potential biomarker for the diagnosis of MDS and AML or a target for novel therapeutic agents.

RNA modification plays important roles in many biological processes such as gene expression control. Genetic variants that affect RNA modification may have functional roles in aortic dissection. The aim of this study was to identify RNA modifications related to spontaneous coronary artery dissection (SCAD). We examined the association of RNA modification-associated single-nucleotide polymorphisms (RNAm-SNPs) with SCAD in summary data from a genome-wide association study (GWAS) of European descent (270 SCAD cases and 5,263 controls). Furthermore, we performed expression quantitative loci (eQTL) and protein quantitative loci (pQTL) analyses for the RNAm-SNPs using publicly available data. Functional enrichment and protein–protein interaction analyses were performed for the identified proteins. We found 11,464 unique RNAm-SNPs in the SCAD GWAS dataset, and 519 were nominally associated with SCAD. Nine RNAm-SNPs were associated with SCAD at p &lt; 0.001, and among them, seven were N6-methyladenosine (m6A) methylation-related SNPs, one (rs113664950 in HLA-DQB1) was m7G-associated SNP, and one [rs580060 in the 3′-UTR of Mitochondrial Ribosomal Protein S21 (MRPS21)] was A-to-I modification SNP. The genome-wide significant SNP rs3818978 (SCAD association p = 5.74 × 10–10) in the 5′-UTR of MRPS21 was related to m6A modification. These nine SNPs all showed eQTL effects, and six of them were associated with circulating protein or metabolite levels. The related protein-coding genes were enriched in specific Gene Ontology (GO) terms such as extracellular space, extracellular region, defense response, lymphocyte migration, receptor binding and cytokine receptor binding, and so on. The present study found the associations between RNAm-SNPs and SCAD. The findings suggested that RNA modification may play functional roles in SCAD.