Project description:To determine the mechanisms of the initial extramedullary translocation of myeloma cells from bone marrow into peripheral blood. We found that the clonal cPCs were more frequently detected by flowcytometry in extramedullary plasmacytoma patients and worsened their prognosis. It is technically much easier to collect single cPCs using FACS than it is to perform EMP biopsy. Combining imaging extramedullary plasmacytoma diagnosis and cPCs detection may be a promising strategy for prognostic stratification. Using single-cell transcriptome analysis, we found that CXCL12, a key molecule for the CXCR4-dependent cell retention mechanism in bone marrow, was abnormally up-regulated in cPCs and might initially enable cPCs evasion and translocation into blood.
Project description:To identify differentially expressed genes in mouse IL6 and Myc double TG plasmacytoma, total RNAs from mouse plasmacytoma generated from IL6 + Myc TG mice were applied to NIAID mouse gene expression arrays. The transcriptome in IL6+ Myc TG mouse PCT was compared to transcriptome in IL6 TG mouse PCT
Project description:To identify differentially expressed genes in mouse IL6 and Myc double TG plasmacytoma, total RNAs from mouse plasmacytoma generated from IL6 + Myc TG mice were applied to NIAID mouse gene expression arrays. The transcriptome in IL6+ Myc TG mouse PCT was compared to transcriptome in IL6 TG mouse PCT Eleven set of IL6+Myc TG PCTs and ten set of IL6 TG PCTs were used. Total RNAs from each mouse labelled with Cy3, and reference RNAs labeled with Cy5 were hybridzed to spotted oligomicroarray.
Project description:Despite the development of novel therapeutic agents, multiple myeloma (MM) remains incurable, owing mainly to inevitable relapse in almost all patients. Some relapses occur as extramedullary disease (EMD), which is rare but is the most aggressive event in MM patients. Extramedullary myeloma (EMM) has extraordinary heterogeneous biological and clinical features. Previous studies have shown that expression levels of LncRNAs and mRNAs in different stages of MM are different. This study analyzes the expression levels of LncRNAs and mRNAs in primary plasma cells (PCs) from MM and EMM patients.
Project description:Extramedullary relapse (EM) of multiple myeloma (MM) is defined as infiltration of plasma cells (PC) outside of the bone marrow. EM is an aggressive form of the disease with a dismal outcome. We present cytogenetic findings of a 52-year-old female patient who was diagnosed with MM in 2008 and progression of MM to EM and plasmocellular leukemia retrospective analysis of TP53 mutation status showed presence of 2 known missense mutations in exon 6 (c.632C>T) and exon 7 (c.700T>C). EM relapse of this patient was connected to a change of the entire genome profile. We suppose that the extramedullary lesion originated by an expansion of one clone of tumor plasma cells from the bone marrow, which was confirmed by identical genomic profile of both tested samples. Thus, change of ploidy status should be considered as potential hallmark of adverse course of the disease.
Project description:Retrospective investigation of genetic background of rapid progression of multiple myeloma into extramedullary relapse. Array-CGH showed chromothripsis in chromosome 18, hyperdiploidy, structural copy-number alterations. Utilization of novel NGS leukemia-related gene custom panel revealed patholological mutation in NRAS (c.181C>A; p.Gln61Lys) or variants of unknown significance in TP53, CUX1 and POU4F1.
Project description:The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. We found that miR-1204 was significantly increased in both plasma and aorta of elder patients with AAD, and was positively correlated with age. Cell senescence induced the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induced vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop.
Project description:Background: Extramedullary disease (EM) in multiple myeloma (MM) is defined by escape of malignant plasma cells out of the bone marrow. The mechanisms of extramedullary spread are not well understood. MicroRNAs (miRNA) were proven to be involved in the pathogenesis of MM; nevertheless, there is a lack of knowledge about their role in EM. Methods: Using NGS analysis, we identified ten differentially expressed miRNA in plasma cells of MM versus EM patients. We performed qPCR in validation phase, using TaqMan Advanced MiRNA Assays. Results: In this study, we identified 10 miRNAs differentially expressed between MM and EM patiens.
Project description:Macrophage migration inhibitory factor (MIF) has been shown to promote disease progression in many malignancies, including multiple myeloma (MM). We previously reported that MIF regulates MM bone marrow homing and knockdown of MIF favors the extramedullary myeloma formation in mice. Here, based on MIF immunostaining of myeloma cells in paired intramedullary and extramedullary biopsies from 17 patients, we found lower MIF intensity in extramedullary MM (EMM) versus intramedullary MM (IMM). Flow cytometry and histology analysis in ARD cell line-derived xenograft models showed a portion of inoculated human MM cells lost their MIF expression (MIFLow) in vivo. Of note, IMM had dominantly MIFHigh cells, while EMM showed a significantly increased ratio of MIFLow cells. We harvested the extramedullary human MM cells from a mouse and generated single-cell transcriptomic data. The developmental trajectories of MM cells from the MIFHigh to MIFLow state were indicated. The MIFHigh cells featured higher proliferation. The MIFLow ones were more quiescent and harbored abundant ribosomal protein genes. Our findings identified in vivo differential regulation of MIF expression in MM and suggested a potential pathogenic role of MIF in the extramedullary spread of disease.
Project description:A patient derived orthotopic xenograft (PDOX) was generated from a patient with an 53 aggressive extramedullary multiple myeloma (EMM) to study in-depth genetic and epigenetic events and drug responses related to extramedullary disease. Whole DNA methylome of the EMM PDOX was also evaluated and compared with a published dataset of 101 newly-diagnosed and chemotherapy-naïve MM patients and normal plasma cells (NPC) (Agirre et al., 2015) A rather balanced proportion of hyper/hypomethylated sites different to previously reported widespread hypomethylation in MM was observed.