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Defective Drosha Processing Contributes to Downregulation of MiR-15/-16 in Chronic Lymphocytic Leukemia.

ABSTRACT: MIR15A and MIR16-1, located in chromosomal band 13q14, are tumor suppressor miRNAs often deleted and downregulated in chronic lymphocytic leukemia (CLL). This downregulation is not only due to loss of 13q, as it occurs also in 13q+/+ CLL patients. We found that a subgroup of CLL patients has a dysregulation of miR-15 /-16 processing intermediates due to defective processing by Drosha. These patients have reduced levels of miR-15a, miR-16 and miR-15b (another member of the miR-15 family), but not of most other miRNAs. Thus, we show that modulation of miRNA maturation leads to specific downregulation of a family of tumor suppressor miRNAs in leukemic cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE30927 | GEO | 2011/12/31

SECONDARY ACCESSION(S): PRJNA146275

REPOSITORIES: GEO

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Similar Datasets

Defective Drosha Processing Contributes to Downregulation of MiR-15/-16 in Chronic Lymphocytic Leukemia.

Project description:MIR15A and MIR16-1, located in chromosomal band 13q14, are tumor suppressor miRNAs often deleted and downregulated in chronic lymphocytic leukemia (CLL). This downregulation is not only due to loss of 13q, as it occurs also in 13q+/+ CLL patients. We found that a subgroup of CLL patients has a dysregulation of miR-15 /-16 processing intermediates due to defective processing by Drosha. These patients have reduced levels of miR-15a, miR-16 and miR-15b (another member of the miR-15 family), but not of most other miRNAs. Thus, we show that modulation of miRNA maturation leads to specific downregulation of a family of tumor suppressor miRNAs in leukemic cells. 11 normal processing CLL sample; 12 processing defective CLL patients

2011-12-31 | E-GEOD-30927 | biostudies-arrayexpress

Transcription profiling of human 13q14-\- cell line expressing doxycylin-inducible miR-15a/16-1 and empty vector (EV)

Project description:Reexpression of microRNAs miR-15a/16-1 in a cell line deficient for these miRs (homozygous deletion of chromosomal region 13q14) results in the downregulation of certain mRNAs. Experiment Overall Design: A doxycyclin-inducible expression vector containing miR-15a/16-1 was transfected into CLL-I83E95 cells that are deficient for those miRs. miR-expression was induced by addition of doxycyclin to the medium, and cell were harvested 48 hours later. Labeled cRNA was hybridized to microarrays and gene expression data were compared to CLL-I83U95 stably transfected with an empty vector.

2009-12-05 | E-GEOD-18866 | biostudies-arrayexpress

217CLL

Project description:In this study we compared the miRNA expression profile of 217 CLL cases versus various normal B cell subpopulations in the attempt of finding the normal cell subset most similar to CLL cells and gain information on possible miRNA deregulations. Our analyses indicated that CLL cells exhibited a miRNA expression pattern close to memory and marginal zone-like B cells. Conversely, tonsil GC and CD19+ peripheral blood B cells appeared only distantly related to CLL. Memory and marginal zone B cells were used as reference to identify differentially expressed miRNAs in CLL, which included miR-193b, miR-33b*, miR-365, miR-181b and miR-196a/b among the down-regulated and miR-23a/b, miR-26a, miR-130a, miR-532 (5p and 3p) among the up-regulated miRNAs. We also investigated differences of miRNA expression related to the IGHV somatic mutation status and to deletions at 13q, 11q and 17p or trisomy 12. Little differences were detected between unmutated (UM) versus mutated (M) CLLs, although miR-29c, miR-29c* and miR-146b were strongly down-modulated in the UM-CLL subgroup. Each of the cytogenetic classes of CLL was characterized by uniquely abnormally expressed miRNAs. Deletion at 13q displayed a reduced expression of miR-16, more evident if the deletion was biallelic. Deletion of 17p was characterized by the strong reduction of miR-34a expression and up-regulation of miR-96. Deletion at 11q was characterized by the up-regulation of miR-338-3p and miR-769-5p. Trisomy 12 was characterized by a strong down-regulation of miR-483-5p.

2014-03-01 | E-MTAB-1454 | biostudies-arrayexpress

Expression data of lentivirus sponge MicroRNA16 (miR16) downregulated RPMI 8226 and MMS1 multiple myeloma (MM) cell lines compared with control lentivirus sponge

Project description:Multiple myeloma is characterized by frequent chromosomal alterations. Deletion of chr 13, especially band 13q14, is commonly observed in early stages of MM, suggesting the presence of tumor suppressor genes (TSG) within this region. We sought to functionally validate the role of the microRNAs-15a/16 cluster, centered at the deleted region, as TSGs and delineate their downstream target genes in MM. Using âspongeâ lentiviral vectors to competitive stably inhibit mature microRNAs in vitro and in vivo, we have documented enhanced proliferative and invasive capacity of cells with stably inhibition of miR-16. Expression profiling analysis of miR-16-deficient cells identified a large number of downstream target genes. This loss-of-function system, which mimics the 13q chromosomal deletion, provides a valuable tool to investigate their function in MM pathogenesis and their potential use as therapeutic targets. We used microarrays to detail the global programme of gene expression underlying miR16 downregulation, simulating the 13q- cytogenetic changes related to MM in order to identified distinct classes of up-regulated genes during this process. MM cell lines were stably tranduced and sorted with miR16 lentiviruses expressing miR downregulating sponges or control sponges, and analyzed for GEP to asses possible miR16 target genes. Cells were lysed and the RNA extraction and hybridization was peformed on Affymetrix microarrays. We sought to obtain homogeneous populations of cells and therefore collected all at the same timepoint.

2010-10-20 | E-GEOD-24522 | biostudies-arrayexpress

Expression data of lentivirus sponge MicroRNA16 (miR16) downregulated RPMI 8226 and MMS1 multiple myeloma (MM) cell lines compared with control lentivirus sponge

2010-10-20 | GSE24522 | GEO

Expression data from doxycylin-inducible miR-15a/16-1 and empty vector (EV) expression in a 13q14-\- cell line

2009-12-01 | GSE18866 | GEO

Genomic approach in B-cell Chronic Lymphocytic Leukemia: molecularly distinct subgroups of patients with 13q14 deletion

Project description:B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a highly variable clinical course that reflects its heterogeneous genomic pattern. To better define molecular subtypes of the disease, we performed SNP and gene expression profiling microarray analyses in a panel of early stage (Binet A) patients. A clustering analysis of genomic profiles identified four significant groups mainly driven by del(13)(q14) and trisomy 12. Notably, patients with del(13)(q14) were grouped in two separate clusters based on the presence of a biallelic loss and the extension of the deletion. The shorter monoallelic deleted 13q14 region was found to be 635 kb in length, not encompassing the mir-15a/16-1 locus. Interestingly, the mir-15a and mir-16 expression was found to be significantly down-regulated only in patients with biallelic loss. Furthermore, a multiclass supervised analysis identified a different transcriptional signatures in the two genomic subgroups with del(13)(q14). Finally, an integrative approach identified 93 transcripts, mainly mapped to chromosome 12 and 13q12-q14.3, whose expression was significantly correlated with the DNA copy number. Overall, our data further support the notion that transcription deregulation in B-CLL could be mostly due to a gene dosage effect and underscore the presence of two distinct molecular types of 13q14 deleted patients with potential clinical relevance.

2010-09-01 | GSE16746 | GEO

Comparative genomic hybridization of human chronic lymphocytic leukemia CLL patients and subtypes of del13q14

Project description:Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous illness with a variable clinical course. Loss of chromosomal material on chromosome 13 at cytoband 13q14 is the most frequent genetic abnormality in CLL, but the molecular aberrations underlying del13q14 in CLL remain incompletely characterized. We analyzed 171 CLL cases for LOH and sub-chromosomal copy loss on chromosome 13 in DNA from FACS-sorted CD19+ cells and paired buccal cells using the Affymetrix XbaI 50K SNP-array platform. The resulting high-resolution genomic maps, together with array-based measurements of expression levels of RNA in CLL cases with and without del13q14 and Q-PCR-based expression analysis of selected genes support the following conclusions: i) del13q14 is heterogeneous and composed of multiple subtypes with deletion of Rb or the miR15a/16 loci serving as anatomic landmarks, respectively ii) del13q14 type Ia deletions are relatively uniform in length and extend from breakpoints close to the miR15a/16 cluster to a newly identified telomeric breakpoint cluster at ~50.2-50.5 Mb physical position iii) LATS2 RNA levels are ~2.6-2.8-fold lower in cases with del13q14 type I that do not delete Rb as opposed to all other CLL cases and iv) ~15% of CLL cases display marked reductions in miR15a/16 expression often but not invariably associated with bi-allelic miR15a/16 loss. This data should aid future investigations into biological differences imparted on CLL by different del13q14 subtypes including investigations into LATS2 as one of the genes found deregulated as part of del13q14. Experiment Overall Design: The goal of this analysis is to detect probesets that are differentially expressed between CLL patients with wild type chromosome 13 and 13q-deleted samples. There are a total of 20 arrays.

2008-06-16 | E-GEOD-9250 | biostudies-arrayexpress

MicroRNA profiling of peripheral blood mononuclear cells from CLL patients to identify a signature for specific chromasomal abnormalities (OSU-CCC microRNA array)

Project description:We studied the value of the microRNAs as a signature for CLL patients with specific chromosomal abnormalities. We identified 32 microRNAs able to discriminate the 11q deletion, 17p deletion, trisomy 12, and 13q deletion and normal karyotype cytogenetic subgroups. The expression values of 9 among the 32 microRNAs (miR-151-3p, miR-34a, miR-29c, miR-29b, miR-155, miR-148a, miR-146a, miR-146b5p and miR-640) were correlated with genes expression data from the same samples to assess their biological impact on CLL. In this study we also found that IGHV unmutated, high expression of ZAP-70 protein and low expression of the miR-223, miR-29c, miR-29b, and miR-181 family were strongly associated with disease progression in CLL cases harboring 17p deletion; whereas in those harboring trisomy 12 only high expression of the miR-181a, among the analyzed parameters, suggested more aggressive disease. Thus, the use of the microRNA-based classifications may yield clinically useful bio-markers of tumor behavior in CLL.

2009-10-01 | E-TABM-762 | biostudies-arrayexpress

MicroRNA profiling of peripheral blood mononuclear cells from CLL patients to identify a signature for specific chromasomal abnormalities

2009-10-01 | E-TABM-763 | biostudies-arrayexpress

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