MiR-126 identifies a quiescent and chemo-resistant human B-ALL cell subset that correlates with minimal residual disease [scRNAseq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE236136 | GEO | 2023/08/30
REPOSITORIES: GEO
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Project description:Complete elimination of B-cell acute lymphoblastic leukemia (B-ALL) by a risk-adapted primary treatment approach remains a clinical key objective, which fails in up to a third of patients. Recent evidence has implicated subpopulations of B-ALL cells with stem-like features in disease persistence. We hypothesized that microRNA-126, a core regulator of hematopoietic and leukemic stem cells, may resolve intra-tumor heterogeneity in B-ALL and uncover therapy-resistant subpopulations. We exploited patient-derived xenograft (PDX) models with B-ALL cells transduced with a miR-126 reporter allowing the prospective isolation of miR-126(high) cells for their functional and transcriptional characterization. Discrete miR-126(high) populations, often characterized by MIR126 locus de-methylation, were identified in 8/9 PDX models and showed increased repopulation potential, in vivo chemotherapy resistance and hallmarks of quiescence, inflammation and stress-response pathway activation. Cells with a miR-126(high) transcriptional profile were identified as distinct disease subpopulations by single cell RNA sequencing in diagnosis samples from adult and pediatric B-ALL. Expression of miR-126 and locus methylation were tested in several pediatric and adult B-ALL cohorts, which received standardized treatment. High microRNA-126 levels and locus de-methylation at diagnosis associate with sub-optimal response to induction chemotherapy (MRD > 0.05% at day +33 or MRD+ at day +78).
2023-08-30 | GSE236141 | GEO
Project description:Complete elimination of B-cell acute lymphoblastic leukemia (B-ALL) by a risk-adapted primary treatment approach remains a clinical key objective, which fails in up to a third of patients. Recent evidence has implicated subpopulations of B-ALL cells with stem-like features in disease persistence. We hypothesized that microRNA-126, a core regulator of hematopoietic and leukemic stem cells, may resolve intra-tumor heterogeneity in B-ALL and uncover therapy-resistant subpopulations. We exploited patient-derived xenograft (PDX) models with B-ALL cells transduced with a miR-126 reporter allowing the prospective isolation of miR-126(high) cells for their functional and transcriptional characterization. Discrete miR-126(high) populations, often characterized by MIR126 locus de-methylation, were identified in 8/9 PDX models and showed increased repopulation potential, in vivo chemotherapy resistance and hallmarks of quiescence, inflammation and stress-response pathway activation. Cells with a miR-126(high) transcriptional profile were identified as distinct disease subpopulations by single cell RNA sequencing in diagnosis samples from adult and pediatric B-ALL. Expression of miR-126 and locus methylation were tested in several pediatric and adult B-ALL cohorts, which received standardized treatment. High microRNA-126 levels and locus de-methylation at diagnosis associate with sub-optimal response to induction chemotherapy (MRD > 0.05% at day +33 or MRD+ at day +78).
2023-08-30 | GSE236138 | GEO
Project description:In order to test the effects of metastasis suppressive miR-126/126* on primary tumor microenvironment, we designed a real-time PCR-based mouse cytokine/chemokine array containing 95 cytokines/chemokines and their receptors. Considering the possibility that production of cytokines/chemokines may be dependent on the interactions among different cell types within the tumor mass, we inoculated GFP-labeled 4T1 cells with a control vector or 4T1 cells with pri-miR-126 overexpression into the fat pad of BALB/c mice. 10 days later, we harvested the primary tumors, isolated GFP-positive cancer cells, and analyzed the expression levels of different cytokines/chemokines and their receptors in the cancer cells at the mRNA level using the cytokine array.
2012-12-13 | GSE42885 | GEO
Project description:To investigate the pathological effect of miR-126 on the progression of acute myeloid leukemia (AML) induced by AML1-ETO9a (AE9a), we conducted a series of mouse bone marrow transplantation (BMT) assays with the following groups: AE9a (primary donor cells were wild-type mouse bone marrow progenitor (i.e., lineage negative; Lin-) cells retrovirally transduced with MSCV-PIG-AE9a), AE9a+miR-126 (primary donor cells were wild-type mouse bone marrow progenitor (i.e., Lin-) cells retrovirally transduced with MSCV-PIG-AE9a-miR-126), and miR-126KO+AE9a (primary donor cells were miR-126 knockout mouse bone marrow progenitor (i.e., Lin-) cells retrovirally transduced with MSCV-PIG-AE9a), along with a control group (primary donor cells were wild-type mouse bone marrow progenitor (i.e., Lin-) cells retrovirally transduced with MSCV-PIG empty vector). The control group was only used in the primary and secondary BMT assays, whereas the three leukemic groups including AE9a, AE9a+miR-126 and miR-126KO+AE9a were used in four passages (i.e., primary, secondary, tertiary and quaternary) of BMT assays. Then, gene expression profiling was conducted with bone marrow samples collected from different groups to decipher the molecular mechanisms underlying miR-126 effects on leukemia initiation and progression and maintenance and self-renewal of leukemia stem/initiating cells.
2015-09-07 | GSE65939 | GEO
Project description:"The analysis was designed to search for putative seed sequences for miR-126 in the 3’UTR of up-regulated genes. ECs were co-transfected with anti-miR-126 and a plasmid vector bearing the GFP-coding sequence and three complementary sites for miR-126 downstream. As a consequence of the presence of miR-126 binding sites the GFP expression was under the control of miR-126. Fluorescente cells were the cells transfected with anti-miR-126 oligo. MiR-126 target enrichment analysis was performed on the basis of the Miranda database, as provided by Diana miRGen. Significance was estimated on the basis of hyper geometric distribution p-values comparing the occurrence of miR targets in the signature with respect to the universe, defined as the genes expressed in HUVEC. Frequency of log 2 ratio between the subset of mir-126 targets and the genes which are not targets of miR-126 were plotted, highlighting enrichment of the target of miR in differentially regulated genes. "
2013-10-18 | GSE32089 | GEO
Project description:In order to test the effects of metastasis suppressive miR-126/126* on primary tumor microenvironment, we designed a real-time PCR-based mouse cytokine/chemokine array containing 95 cytokines/chemokines and their receptors. Considering the possibility that production of cytokines/chemokines may be dependent on the interactions among different cell types within the tumor mass, we inoculated GFP-labeled 4T1 cells with a control vector or 4T1 cells with pri-miR-126 overexpression into the fat pad of BALB/c mice. 10 days later, we harvested the primary tumors, isolated GFP-positive cancer cells, and analyzed the expression levels of different cytokines/chemokines and their receptors in the cancer cells at the mRNA level using the cytokine array. qPCR gene expression profiling. Equal amount total RNA from each cell line was pooled prior to gene expression analysis.
2012-12-13 | E-GEOD-42885 | biostudies-arrayexpress
Project description:Based on microRNA expression profiling studies, here we focus on miR-126&126* as the most downmodulated microRNAs in a panel of melanoma cell lines at different stages of progression compared with normal human melanocytes. At present no data exist on miR-126&126* possible role in melanoma. Our results show miR-126/miR-126* downregulation associated with tumor progression and the antineoplastic role deriving from their restored expression in metastatic melanomas in vitro as well as in vivo.
2013-05-21 | E-MEXP-3629 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduced AML rate and extended survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibited AML cell survival, reduced leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. Combination of miRisten with chemotherapy further enhanced the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a new therapeutic approach for inv(16) AML.
2021-09-15 | GSE184015 | GEO
Project description:The goal of this study is to investigate the cell type-specific targets of miR-126-3p in human lung microvascular endothelial cells (HLMVEC). Following the transfections of HLMVEC with non-targeting negative controls, miR-126 mimics, or miR-126 antisense inhibitors, we calculated the copy number concentration of miR-126 in each sample and performed genome-wide RNA sequencing. Plotting the gene expression data for each transfection condition (Scramble, 126-OE and 126-KD) against their respective miR-126 concentrations, we performed a linear regression analysis to discover genes that were the most sensitive to changes in miR-126 levels. We identified 1258 genes that were upregulated and 1436 genes that were downregulated by miR-126-3p. Further comparison between the downregulated genes in HLMVEC and targets predicted by online databases including TargetScan and miRDB revealed 6 genes as potential direct targets of miR-126-3p. Our study is the first to report targets of miR-126-3p in HLMVEC and demonstrate the effect of miR-126 level alteration on the HLMVEC global transcriptome. These results add to the diverse functions of miR-126-3p in different endothelial cell types and provide basis for the development of cell type-specific treatment for lung diseases.
2022-11-27 | GSE141129 | GEO
Project description:"The analysis was designed to search for putative seed sequences for miR-126 in the 3M-bM-^@M-^YUTR of up-regulated genes. ECs were co-transfected with anti-miR-126 and a plasmid vector bearing the GFP-coding sequence and three complementary sites for miR-126 downstream. As a consequence of the presence of miR-126 binding sites the GFP expression was under the control of miR-126. Fluorescente cells were the cells transfected with anti-miR-126 oligo. MiR-126 target enrichment analysis was performed on the basis of the Miranda database, as provided by Diana miRGen. Significance was estimated on the basis of hyper geometric distribution p-values comparing the occurrence of miR targets in the signature with respect to the universe, defined as the genes expressed in HUVEC. Frequency of log 2 ratio between the subset of mir-126 targets and the genes which are not targets of miR-126 were plotted, highlighting enrichment of the target of miR in differentially regulated genes. " 3 x biological replicates of transiently trasfected cells with anti miR-126 oligo (LNA), and controls oligo. 2 biological replicates for GFP are included as technical controls.
2013-10-18 | E-GEOD-32089 | biostudies-arrayexpress