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Genome-wide RNAi screen identifies miR-19 targets in Notch-induced acute T-cell leukaemia (T-ALL)

ABSTRACT: MicroRNAs (miRNAs) have emerged as novel cancer genes. In particular, the 17~92 cluster of miRNAs is highly expressed in haematopoietic cancers and promotes lymphomagenesis in vivo1,2. Clinical use of these findings hinges on isolating the oncogenic activity within the 17~92 cluster and defining its relevant target genes. Here we show that miR-19 is sufficient to promote leukaemogenesis in Notch1 induced T-cell lymphoblastic leukaemia (T-ALL) in vivo. Consistent with the pathogenic importance of this interaction, we report a novel translocation targeting the 17~92 miRNA cluster coinciding with a second rearrangement that activates Notch1 in T-ALL. To identify the miR-19 targets responsible for its oncogenic action, we conducted a large-scale short-hairpin RNA (shRNA) screen for genes whose knockdown could phenocopy miR-19. Strikingly, the results of this screen were enriched for miR-19 target genes, and included Bim (Bcl2L11)1,3, AMP-activated kinase (Prkaa1), and the tumour suppressor phosphatases Pten and PP2A (Ppp2r5e). Hence, an unbiased, functional genomics approach reveals a coordinate clamp down on several regulators of PI3K-related survival signals by the leukaemogenic miR-19.

ORGANISM(S): Mus musculus

PROVIDER: GSE20097 | GEO | 2010/01/30

SECONDARY ACCESSION(S): PRJNA124343

REPOSITORIES: GEO

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Genome-wide RNAi screen identifies miR-19 targets in Notch-induced acute T-cell leukaemia (T-ALL)

Project description:MicroRNAs (miRNAs) have emerged as novel cancer genes. In particular, the 17~92 cluster of miRNAs is highly expressed in haematopoietic cancers and promotes lymphomagenesis in vivo1,2. Clinical use of these findings hinges on isolating the oncogenic activity within the 17~92 cluster and defining its relevant target genes. Here we show that miR-19 is sufficient to promote leukaemogenesis in Notch1 induced T-cell lymphoblastic leukaemia (T-ALL) in vivo. Consistent with the pathogenic importance of this interaction, we report a novel translocation targeting the 17~92 miRNA cluster coinciding with a second rearrangement that activates Notch1 in T-ALL. To identify the miR-19 targets responsible for its oncogenic action, we conducted a large-scale short-hairpin RNA (shRNA) screen for genes whose knockdown could phenocopy miR-19. Strikingly, the results of this screen were enriched for miR-19 target genes, and included Bim (Bcl2L11)1,3, AMP-activated kinase (Prkaa1), and the tumour suppressor phosphatases Pten and PP2A (Ppp2r5e). Hence, an unbiased, functional genomics approach reveals a coordinate clamp down on several regulators of PI3K-related survival signals by the leukaemogenic miR-19. Gene expression data revealing differences in gene expression between parental FL5-12 cells transduced with Vector and miR-19 expressing FL5-12 cells

2010-03-03 | E-GEOD-20097 | biostudies-arrayexpress

miR-19 protects heart from myocardium infarction

Project description:The adult heart has been considered as an organ with limited regenerating capability due to mature cardiomyocytes exit the cell cycle and stop proliferating. It has been reported that miR-17-92 cluster plays a key role in cardiomyocyte proliferation. According to the seed sequence, miR-17-92 cluster includes miR-18, miR-19, miR-20 and miR-92 families. Here, we show that intra-cardiac injection of miR-19 mimic into adult mouse hearts protects heart from myocardial infarction injury with reduced apoptosis, enhanced cardiomyocyte proliferation and cardiac regeneration. We performed the RNA-seq profiling in both injection of control mimic and miR-19 mimic post myocardial infarction. The transcriptome analysis indicates that genes related to immune response and cardiac remodeling were repressed by miR-19 in infarcted hearts.

2019-02-26 | GSE126888 | GEO

The transcription factor TAL1 and the miR-17-92 cluster establish a regulatory loop

Project description:A network of gene regulatory factors such as transcription factors and microRNAs establish and maintain the gene expression pattern during hematopoiesis. In this network transcription factors regulate each other and are involved in regulatory loops with microRNAs.The microRNA cluster miR-17-92 is located within the MIR17HG gene and encodes for six mature microRNAs. It is important for hematopoietic differentiation and plays a central role in malignant disease. However, the transcription factors downstream of miR-17-92 are largely elusive and the transcriptional regulation of miR-17-92 is not fully understood. Here we show that miR-17-92 forms a regulatory loop with the transcription factor TAL1. The miR-17-92 cluster inhibits expression of TAL1 and indirectly leads to decreased stability of the TAL1 transcriptional complex. We found that TAL1 and its heterodimerization partner E47 regulate miR-17-92 transcriptionally. Furthermore, miR-17-92 negatively influences erythroid differentiation, a process that depends on gene activation by the TAL1 complex. Our data give example of how transcription factor activity is fine-tuned during normal hematopoiesis. We postulate that disturbance of the regulatory loop between TAL1 and the miR-17-92 cluster could be an important step in cancer development and progression.

2021-09-09 | PXD018052 | Pride

miRNA expression in E18.5 murine total lung tissue

Project description:Knockout of the ubiquitously expressed microRNA-17~92 cluster in mice produces a lethal developmental lung defect. We validated the equally widely expressed pro-apoptotic Bim gene as joint target of miR-17~92 cluster members. To study the contribution of miR-17~92:Bim interaction to miR-17~92 overall function, we set up a system of conditional mutagenesis of the Bim 3’UTR. Blocking miR-17~92:Bim interaction early in development phenocopied the lethal lung phenotype of miR-17~92 ablation. Thus, despite hundreds of overall predicted targets vital miRNA functions can be mediated by a single target gene.

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Genome-wide prediction of genes targeted by titrated levels of miR-17~92

Project description:The miR-17-92 cluster targets mRNAs involved in distinct pathways which either promote or inhibit tumor progression. However, the cellular and molecular mechanisms underlying miR-17~92 cluster mediated pro- or anti- tumorigenic effects has not been studied. In this study, we found that inhibition of colon cancer progression is dictated by quantitatively controlling expression of the miR-17~92 cluster. To identify molecular mechanisms giving rise to the different growth/metastasis patterns, we profiled gene expression in miR-Ctrl, miR-17~92Med and miR-17~92Hi cells using Affymetrix Murine GeneST Arrays.

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Ago2 PAR-CLIP analysis of Abelson kinase transformed murine B cell progenitors

Project description:Knockout of the ubiquitously expressed microRNA-17~92 cluster in mice produces a lethal developmental defect and blocked B lymphopoiesis. We validated the equally widely expressed Bcl2l11 gene as joint target of miR-17~92 cluster members. Bcl2l11 encodes the pro-apoptotic protein BIM, central to life-death decisions in most mammalian cells. To study the contribution of miR-17~92:Bim interaction to miR-17~92 overall function, we set up a system of conditional mutagenesis of the Bim 3’UTR in mice. Ago2 Photoactivatable-Ribonucleoside Cross-linking and Immunoprecipitation (AGO2 PAR-CLIP) allowed us to assess whether the seed match mutations introduced into the Bim 3’UTR in vivo indeed precluded interaction with the miRNAs of the 17~92 cluster. This analysis was done in Abelson Virus transformed B cell progenitors which we generated from wild type and Bim3’UTRmut/mut E14.5 fetal livers, knowing that these cells express both BIM and miR-17~92, can be expanded to large numbers and incorporate 4-thiouridine sufficiently well. Focusing on 21 nt windows around the 9 putative miR-17~92 seed matches in the Bim 3’UTR and excluding reads lacking T-to-C transitions, we we verified that the introduced mutationsare functional, and we discovered differential seed match coverage in the wild type, with one miR-19 seed match co-dominating with two miR-92 seed matches, while in the mutant 3’UTR miR-17~92 binding was completely abolished. These results demonstrate functionality and efficiency of our genetically engineered mouse model for in vivo conditional seed-match inactivation. These results demonstrate functionality and efficiency of our genetically engineered mouse model for in vivo conditional seed-match inactivation.

2019-11-13 | GSE124605 | GEO

mRNA expression data from primary untreated neuroblastoma tumour samples

2010-12-01 | GSE21713 | GEO

Overexpression of the miR-17-92 cluster in colorectal adenoma organoids induces a carcinoma-like genotype

Project description:Gain of chromosome arm 13q is one of the most prevalent DNA copy number alterations associated with colorectal adenoma-to-carcinoma progression. The oncogenic miR-17-92 cluster, located at 13q, was found to be overexpressed in colorectal cancer and in adenomas harboring 13q gain. However, to what extent overexpression of this group of microRNAs actually drives progression to cancer remains to be resolved. Therefore, we aimed to clarify the role of miR-17-92 cluster in the progression from colorectal adenoma to carcinoma. In human colorectal adenoma organoids without 13q gain, the miR-17-92 cluster was overexpressed and downstream effects on mRNA expression investigated, along with functional effects in vitro and in vivo. Comparison of mRNA sequencing results of organoids overexpressing miR-17-92 and cultures transduced with control vector, revealed a miR-17-92 expression signature. This signature appeared to be enriched in an independent series of colorectal cancers and adenomas tissues with 13q gain, confirming that miR-17-92 expression is associated with malignant progression. However, an increase in proliferation rate was not observed in miR-17-92 overexpressing adenoma organoids in vitro. In addition, subcutaneous injection of these organoids in immunodeficient mice was insufficient to cause tumor outgrowth. Transfecting miR-17-92 cluster in human colon adenoma organoids induces an expression signature that proved to be enriched in both adenomas with 13q gain and in colorectal cancers, supporting its role as a driver of 13q gain. However, overexpression of miR-17-92 alone is not sufficient to transform colorectal adenoma cells into a malignant phenotype.

| EGAS00001005949 | EGA

mRNA expression data from primary untreated neuroblastoma tumour samples

Project description:The miR-17-92 microRNA cluster is often activated in cancer cells, but the identity of its targets remains largely elusive. Here we examined the effects of activation of the entire miR-17-92 cluster on global protein expression in neuroblastoma cells. In this dataset we deposit global mRNA expression data obtained form primary neuroblastoma tumour cells. This data was used to demonstrate negative correlation between TGFB target gene expression and expression of the miR-17-92 cluster. Expression of different TGFB target genes was correlated to miR-17-92 expression using Spearman's Rank statistics in 40 tumours. A correlation heatmap was calculated to visualize the inverse relation between miR-17-92 expression and TGFB target gene expression.

2010-12-01 | E-GEOD-21713 | biostudies-arrayexpress

Genome-wide prediction of genes targeted by titrated levels of miR-17~92

2014-06-01 | E-GEOD-55631 | biostudies-arrayexpress