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Effects of miR-125b expression on the transcriptome of B cell precursors

ABSTRACT: Here, we have screened a miRNA expression library in a pre-B cell expression system to identify miRNAs with a potential oncogenic activity in early lymphocytes. We show that miR-125b is sufficient to transform B cell precursors in vitro as defined by growth factor independence, and demonstrate that continuous expression of miR-125b is necessary to keep cells in the transformed cells. Mechanistically, we find that expression of miR-125b protects against apoptosis induced by growth factor withdrawal, and that miR-125 interferes with the differentiation of pre-B to immature B cells. In consequence, transformed cells express the pre-BCR on the cell surface, which appears to provide signals for ongoing proliferation and survival. Using microarray analysis, we identified several previously known and novel putative target genes of miR-125b in B cell precursors. To evaluate their contribution to the miR-125b-mediated phenotype, transformed cells were reconstituted with expression constructs of validated target genes. Surprisingly, we only find that reconstitution of MAP3K11 interferes with the cellular fitness of transformed cells in vitro as well as in vivo. This indicates that MAP3K11 functions as an important tumor suppressor in the context of miR-125b.

ORGANISM(S): Mus musculus

PROVIDER: GSE59994 | GEO | 2015/01/01

SECONDARY ACCESSION(S): PRJNA257245

REPOSITORIES: GEO

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Effects of miR-125b expression on the transcriptome of B cell precursors

Project description:Here, we have screened a miRNA expression library in a pre-B cell expression system to identify miRNAs with a potential oncogenic activity in early lymphocytes. We show that miR-125b is sufficient to transform B cell precursors in vitro as defined by growth factor independence, and demonstrate that continuous expression of miR-125b is necessary to keep cells in the transformed cells. Mechanistically, we find that expression of miR-125b protects against apoptosis induced by growth factor withdrawal, and that miR-125 interferes with the differentiation of pre-B to immature B cells. In consequence, transformed cells express the pre-BCR on the cell surface, which appears to provide signals for ongoing proliferation and survival. Using microarray analysis, we identified several previously known and novel putative target genes of miR-125b in B cell precursors. To evaluate their contribution to the miR-125b-mediated phenotype, transformed cells were reconstituted with expression constructs of validated target genes. Surprisingly, we only find that reconstitution of MAP3K11 interferes with the cellular fitness of transformed cells in vitro as well as in vivo. This indicates that MAP3K11 functions as an important tumor suppressor in the context of miR-125b. Gene expression in cells expressing a control vector or a vector encoding hsa-miR-125b-1 was measured either in the presence or 24 hours after withdrawal of the growth factor IL-7. Two independent experiments were performed, using independently generated cell clones for each repetition.

2015-01-01 | E-GEOD-59994 | biostudies-arrayexpress

Transcriptomic analysis of targets regulated by miR-125b in primary endothelial cells

Project description:Human vein umbilical endothelial cells (HUVEC) were transfected with pre-miR control and pre-miR 125b (Ambion) in order to identify targets (direct and indirect) downregulated by miR-125b in endothelial cells. 317 transcripts were downregulated with a fold change ≥ 1.5, among which 99 are predicted direct targets of mir-125b. Computional approach performed with Ingenuity Pathway Knowledge shows that movement of cell and cell-to-cell signalling are the top two biological functions affected bewteen control and transfected cells. Experiments performed in zebrafish and in HUVEC confirmed that mir-125b mainly affects genes involved in cellular movements and junctions. Total RNA was obtained from cells transfected in HUVEC with pre-miR control and pre-miR 125b. Three independent transfections were performed for each condition.

2011-04-30 | E-GEOD-21458 | biostudies-arrayexpress

Breast cancer MCF-7 Cells and MDA-MB-435 cells: pre-miR-125b Transfected cells vs. pre-control transfected cells

Project description:Transcriptional profiling of breast cancer cells comparing pre-control transfected cells with cells transfected with pre-miR-125b. We searched for miR-125b targets by systematic screening of mRNA profiling of pre-miR-125b transfected MCF-7 cells and MDA-MB-435 cells. Two-condition experiment, pre-miR-125b Transfected vs. pre-control Transfected MCF-7 cells. One replicate per array.

2010-06-25 | E-GEOD-22546 | biostudies-arrayexpress

Breast cancer MCF-7 Cells and MDA-MB-435 cells: pre-miR-125b Transfected cells vs. pre-control transfected cells

2010-06-25 | GSE22546 | GEO

Transcriptomic analysis of targets regulated by miR-125b in primary endothelial cells

2011-04-30 | GSE21458 | GEO

Role of miR-125b in B-cell acute lymphoblastic leukemia (B-ALL)

Project description:B-cell acute lymphoblastic leukemia (B-ALL) is often associated with chromosomal translocations leading to the deregulation of proto-oncogenes. MicroRNAs can also be affected by chromosomal alterations and thus contribute to carcinogenesis. The microRNA miR-125b-1 is over-expressed in B-ALL cases with the t(11;14)(q24;q34) translocation, therefore we sought to determine the role of this microRNA in B-cell fate. We used murine pre-BI cells alongside murine and human leukemic B-cell lines to show that miR-125b expression enhances proliferation by targeting Bright/ARID3a, an activator of immunoglobulin heavy-chain transcription. Accordingly, this target gene was down-regulated in B-ALL patients with the t(11;14)(q24;q34) translocation. Repression of Bright/ARID3A blocked differentiation and conferred a survival advantage to Ba/F3 cells under IL3 starvation. In addition, over-expression of miR-125b protected pre-BI and leukemic B-cell lines from apoptosis through blockade of caspase activation via a mechanism that was independent of p53 and BAK1. In summary, miR-125b can act as an oncogene in B-ALL by targeting ARID3a and mediating its repression, thus leading to a blockage in differentiation, increased proliferation and inhibition of apoptosis. To identify specific targets of mir-125b, we overexpressed miR-125b as well as a control miRNA in 70Z/3 and 18-81 pre-B leukaemia cells. Chemically synthesized miRNA duplexes, called pre-miR-125b and miR-Neg, were purchased from Ambion. The cells were transfected with pre-miRNA at a final concentration of 10 nM using Lipofectamin RNAi MAX (Invitrogen) according to the manufacturer’s instructions. The medium was replaced 8 hours after transfection. RNA samples were harvested at 48 hours post-transfection. 2 independent experiments were carried out for a total of 8 samples labeled with Cy3 dye (one color design).

2012-06-20 | E-GEOD-30647 | biostudies-arrayexpress

Identification of miR-125b-2 target genes

Project description:The goal of this study is to define miR-125b-2 target genes in the hematopoietic system by genetic alteration of miR-125b expression levels. Here we report the identification of miR-125b-2 targets in the hematopoietic system by repressing miR125b in megakaryoblastic leukemia (AMKL) cell lines and overexpressing miR-125b-2 in hematopoietic stem and progenitor cells (CD34+-HSPCs)

2009-12-29 | GSE19680 | GEO

RNA-sequencing analysis of NB4 cells overexpressing miR-125b

Project description:To better understand the mechanisms of blockage of myeloid differentiation and apoptosis and induction of proliferation by miR-125b, we proceeded to identify miR-125b target genes involved in these pathways. We analyzed the total cellular gene expression pattern by RNA-sequencing of the parental NB4 myeloid cell line and that transiently transfected with miR-125b. We generated four cDNA libraries corresponding to duplicates of miR-125b and control cells. Compare the gene expression levels in miR control transfected cells with that in miR-125b transfected NB4 cells.

2012-04-06 | E-GEOD-37061 | biostudies-arrayexpress

RNA-sequencing analysis of 32Dclone3 cells overexpressing miR-125b

Project description:To better understand the mechanisms of blockage of myeloid differentiation and apoptosis and induction of proliferation by miR-125b, we preceded to identify miR-125b target genes involved in these pathways. We analyzed the total cellular gene expression pattern by RNA-sequencing of the parental 32Dclone3 myeloid cell line and that ectopically expressing miR-125b. We generated four cDNA libraries corresponding to duplicates of miR-125b and control cells. Compare the gene expression level in vector transduced 32Dclone3 cells with that in miR-125b transduced 32Dclone3 cells.

2012-04-04 | E-GEOD-37018 | biostudies-arrayexpress

miR-125b-EPO

Project description:MiR-125b possible targets were identified after transfecting a miRNA-mimic (miR-125b) and a scramble miRNA (Negative control) in MCF7 cell line and analyzing gene expression modifications.

2013-12-02 | E-MTAB-1604 | biostudies-arrayexpress

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