Project description:FFPE brain biopsy specimens of 64 patients with primary central nervous system lymphoma and 9 patients with secondary central nervous system lymphoma were analyzed in the study. We used the NanoSting nCounter human v3 miRNA assay for characterizing miRNA expression and carried out a detailed differential expression and clustering analysis of samples and miRNAs to look for expression changes associated to primary or secondary origin, cell of origin, mutation status or survival.
Project description:To characterize the genetic alterations in lymphomas in immune-privileged sites (IP-DLBCLs), we performed whole-genome sequencing (WGS) of 22 primary central nervous system lymphomas (PCNSLs), 8 primary testicular lymphomas (PTLs) and 6 secondary CNS lymphomas.
Project description:The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well documented during tumor initiation. However, little is known about miR-17-19b function in established cancers. Here we investigate the role of miR-17-19b in c-MYC-driven lymphomas by integrating SILAC-based quantitative proteomics, transcriptomics and 3’ UTR analysis upon miR-17-19b overexpression. We identify over one hundred novel miR-17-19b targets, of which 40% are co-regulated by c-MYC. Down-regulation of a new miR-17/20 target Chek2 increases the recruitment of HuR to c-MYC transcripts, resulting in the inhibition of c-MYC translation and thus interfering with in vivo tumor growth. Hence, in established lymphomas, miR-17-19b fine-tunes c-MYC activity through a tight control of its function and expression, ultimately ensuring cancer cell homeostasis. Our data highlight the plasticity of miRNA function, reflecting changes in the mRNA landscape and 3’ UTR shortening at different stages of tumorigenesis.
Project description:The oncogenic microRNA 17-92 cluster is involved in the lymphomagenesis of nodal and systemic B cell lymphomas, but has not been studied so far in primary cutaneous B cell lymphomas. We performed the quantitative analysis of miR-17-92 cluster and its paralogs miR-106a-363 and miR-106b-25 in 22 primary cutaneous diffuse large B-cell lymphomas-leg type (PCLBCL-LT) and 22 primary cutaneous follicle center lymphomas (PCFCL). Mir-20a and miR-106a were overexpressed in PCLBCL-LT compared to PCFCL. Multivariate Cox analysis showed that higher miR-20a and miR-20b were associated with poorer disease-free survival and poorer overall survival, independently of histological type. Gene expression profiling showed underexpression of 8 candidate target genes of miR-20a, miR-20b and miR-106a in PCLBCL-LT compared to PCFCL. Among the candidate target genes, PTEN, NCOA3 and CAPRIN2 were confirmed to be underexpressed in PCLBCL-LT using quantitative RT-PCR of laser-microdissected tumor cells. In multivariate Cox analysis, lower PTEN mRNA expression level was associated with poorer disease-free survival, independently of the histological type. Altogether, this molecular and bioinformatics study of patients’ skin biopsy samples showed that the oncogenic miR-17-92 cluster is involved in cutaneous B cell lymphoma progression, and that the down-regulation of its target gene PTEN is associated with poorer disease-free survival.
Project description:microRNAs (miRNAs) have been implicated in oligodendrogenesis and demyelinating diseases; however, identification of individual miRNAs responsible has remained elusive. Through targeted mutagenesis, we find that miR-219 is required for proper oligodendrocyte differentiation and myelination in vivo. Deletion of miR-338 together with miR-219 further exacerbates hypomyelination phenotypes. Temporally specific ablation reveals a critical role for miR-219 in oligodendrocyte remyelination after demyelination, while overexpression of miR-219 promotes precocious oligodendrocyte maturation and myelin regeneration. Accordingly, administration of miR-219 mimics to lysolecithin-induced demyelinating lesions in the murine spinal cord and brain enhances myelin restoration. Through integrating analyses of transcriptome profiling and biotin-affinity miRNA pull-down, we identify a set of stage-specific targets of miR-219, including Etv5 and Lingo1, as oligodendrocyte differentiation inhibitors. Inhibiting Etv5 and Lingo1 leads to a partial rescue of differentiation defects observed in miR-219-mutant OLs in vitro. Together, our findings identify context-specific miRNA-regulated checkpoints that control CNS myelinogenesis and myelin repair.
Project description:This SuperSeries is composed of the following subset Series: GSE30763: Integration of BRCA1-mediated miRNA and mRNA signatures reveal miR-146a, miR-99b and miR-205 regulation of the TRAF2 and NFkB pathways (miRNA dataset) GSE30821: Integration of BRCA1-mediated miRNA and mRNA signatures reveal miR-146a, miR-99b and miR-205 regulation of the TRAF2 and NFkB pathways (mRNA dataset) Refer to individual Series
Project description:Purpose: To evaluate whether the single nucleotide polimorphsim rs41291957, located in the pri-miR-143/145, influences the primary RNA secondary structure. Methods: In vitro transcription and folding for the pri-miR-143/145 carrying the WT allele (G) or the mutated one (A) was carried out. The RNAs were then subjected to RNAseI treatement for 30 minutes and RNA seq performed on the digested nucleic acids. Results: Using an optimized data analysis workflow for small RNAs, we mapped the sequence reads on the human pri-miR-143/145 carrying the G- or A-allele. We observed an increase of small reads (<60bps) for the A-allele and a different profile of read enrichement between the digested G- and A-allele RNA, indicating the difference in secondary structure.
Project description:Mice lacking the p27Kip1 Cdk inhibitor (Cdkn1b) exhibit increased susceptibility to lymphomas from the Maloney murine leukemia virus (M-MuLV), and exhibit a high frequency of viral integrations at Xpcl1 (Kis2), a locus on the X-chromosome. Xpcl1 encodes miR-106a~363, a cluster of microRNAs that are expressed in response to adjacent retroviral integrations. We report the first large-scale profile of microRNA expression in MuLV-induced lymphomas, in combination with microarray gene expression analysis. The source material was T-cell lymphomas induced by M-MuLV in p27Kip1 knockout mice and normal thymus. Surprisingly, the overall levels of miRNA expression were equivalent in lymphomas and normal thymus. Nonetheless, the expression of specific microRNAs was altered in tumors. The miR-106a~363 miRNA were over-expressed in lymphomas, particularly those with viral integrations at the Xpcl1 locus. In contrast, p27Kip1 deletion itself was associated with a different pattern of microRNA expression. Gene expression was dramatically altered in lymphomas, yet paralleled data from T-cell lymphomas induced by other mechanisms. Genes with altered expression in association with the p27Kip1 null genotype were of similar functional classes to those associated with Xpcl1 integration, but with the opposite pattern of expression. Thus, the effect of p27Kip1 deletion may be to oppose an anti-oncogenic effect of Xpcl1 rather than enhancing its oncogenic functions. A subset of miR-106a~363 target genes was consistently reduced in lymphomas with Xpcl1 integrations, particularly genes with cell cycle and immune functions. We identify four predicted target genes of miR-106a~363 miRNA, including N-Myc (Mycn), and the TGF-beta receptor (Tgfbr2) using 3'UTR reporter assays. Still, bioinformatic miRNA target predictions were poor predictors of altered gene expression in lymphomas with Xpcl1 integration. Confirmation of miR- 106a~363 gene targeting relevant to the tumor phenotype requires in vivo validation, because only a subset of predicted targets are consistently reduced in tumors that overexpress miR- 106a~363.
Project description:Gene expression profiling (GEP) of ARL patient samples was done to determine whether gene expression signatures derived from HIV- lymphomas retained their ability to molecularly classify HIV+ lymphomas. The GEP-based predictors robustly classified ARL tumors, distinguishing molecular Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), as well as activated B-cell-like (ABC) and germinal center B-cell-like (GCB) molecular subtypes of DLBCL. Gene expression profiles were used to identify coordinately regulated gene sets and pathways that differ between HIV+ and HIV- lymphomas of corresponding molecular subtype.