Expression data from miR-142 WT and KO spleen and bone marrow
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE85476 | GEO | 2018/11/01
REPOSITORIES: GEO
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Project description:MiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.
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Project description:Tumor progression is accompanied by an altered myelopoiesis that causes the accumulation of cells inhibiting anti-tumor T lymphocytes. We previously reported that immunosuppressive cells can be generated in vitro from bone marrow cells (BM) after four days GM-CSF and IL-6 treatment. Here, we describe that miR-142-3p down-regulation directs macrophage differentiation and determines the acquisition of their immunosuppressive function in cancer. Enforced miR over-expression impaired monocyte to macrophage transition both in vitro and in vivo. Conversely, forced miR down-regulation promoted the generation of immunosuppressive macrophages even during G-CSF-induced granulocytic differentiation. To identify how miR-142-3p regulates MDSC generation and activity, we analyze the gene expression of BM cultures transfected with either CTRL- or miR 142-3p mimic oligo -transfected before four days GM-CSF and IL-6 treatment. Keywords: Expression profiling by array
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Project description:To gain insight into how miR-142 deficit drives a BC-like transformation, we performed RNA-seq on bone marrow (BM) Lin-Sca-1+c-Kit+ cells (LSKs) harvested from normal miR-142+/+ (wt) and miR-142−/− (miR-142 KO) mice, as well as from leukemic miR-142+/+ BCR-ABL (CP CML) and miR-142−/− BCR-ABL (BC CML) mice, two weeks after BCR-ABL induction. We then performed gene expression profiling analysis using data obtained from RNA-seq of 24 samples of LSK cells from 4 mouse strains (KO vs WT, KO CML vs CML).
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Project description:Tumor progression is accompanied by an altered myelopoiesis that causes the accumulation of cells inhibiting anti-tumor T lymphocytes. We previously reported that immunosuppressive cells can be generated in vitro from bone marrow cells (BM) after four days GM-CSF and IL-6 treatment. Here, we describe that miR-142-3p down-regulation directs macrophage differentiation and determines the acquisition of their immunosuppressive function in cancer. Enforced miR over-expression impaired monocyte to macrophage transition both in vitro and in vivo. Conversely, forced miR down-regulation promoted the generation of immunosuppressive macrophages even during G-CSF-induced granulocytic differentiation. To identify how miR-142-3p regulates MDSC generation and activity, we analyze the gene expression of BM cultures transfected with either CTRL- or miR 142-3p mimic oligo -transfected before four days GM-CSF and IL-6 treatment. Keywords: Expression profiling by array BM cells were transfected either CTRL- or miR 142-3p mimic oligo before GM-CSF and IL-6 treatment to generate in vitro MDSCs during enforced miR over-expression. A triplicate of each sample was considered.Total RNA from obtained in vitro BM-differentiated MDSCs was isolated by Trizol reagent, and cRNA samples were hybridized to the Affymetrix GeneChip MOE430 2.0.
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Project description:T cells are critical for modulating immune responses. miRNAs are small, noncoding RNAs and play a significant role in T cell responses. miR-142 is a hematopoietic specific miRNA. To explore the potential role of miR-142 in regulating T cell responses, we generated mutant mice bearing a targeted deletion of the miR-142 gene. We used microarrays to detail the global programme of gene expression underlying the profile changes between miR-142 KO and WT T cell and identified distinct classes of up-regulated genes during this process.
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Project description:DCs are critical for regulating immune responses. miRNAs are small, noncoding RNAs and play a significant role in regulating immune responses. miR-142 is a hematopoietic specific miRNA. To explore the role of miR-142 in regulating DCs’ immune responses, we generated mutant mice bearing a targeted deletion of the miR-142 gene. We used microarrays to detail the global program of gene expression underlying the profile changes between miR-142 KO and WT DCs and identified distinct classes of up-regulated or down-regulated genes in steady state or LPS stimulation during this process.
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Project description:T cells are critical for modulating immune responses. miRNAs are small, noncoding RNAs and play a significant role in T cell responses. miR-142 is a hematopoietic specific miRNA. To explore the potential role of miR-142 in regulating T cell responses, we generated mutant mice bearing a targeted deletion of the miR-142 gene. We used microarrays to detail the global programme of gene expression underlying the profile changes between miR-142 KO and WT T cell and identified distinct classes of up-regulated genes during this process. miR-142 KO mice and WT littermates (biological triplicates) matched with age and sex were selected. T cells were purified from spleens by negative selection and processed for RNA isolation and hybridization on Affymetrix microarrays.
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Project description:Developing CD4+ T-cells in the thymus mature from CD69+Qa2- cells to CD69-Qa2+ T-cells. This maturation is accombanied by increased expression of CD62L and S1PR1 in Qa2+ cells, which allows mature T-cells to emigrate from the thymus to the periphery. However, miR-142-/- mice are characterized by an altered thymocytes homeostasis, characterized by reduced CD62L protein levels on their cell surface. To characterize the underlying molecular mechanisms, which lead to reduced CD62L expression in miR-142-/- CD4+ thymocytes, we investigated the mRNA levels in immature Qa2- as well as mature Qa2+ thymocytes isolated ex vivo from WT and miR-142 deficient Bl6 mice.
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Project description:Developing CD4+ T-cells in the thymus mature from CD69+Qa2- cells to CD69-Qa2+ T-cells. This maturation is accombanied by increased expression of CD62L and S1PR1 in Qa2+ cells, which allows mature T-cells to emigrate from the thymus to the periphery. However, miR-142-/- mice are characterized by an altered thymocytes homeostasis, characterized by reduced CD62L protein levels on their cell surface. To characterize the underlying molecular mechanisms, which lead to reduced CD62L expression in miR-142-/- CD4+ thymocytes, we investigated the mRNA levels in immature Qa2- as well as mature Qa2+ thymocytes isolated ex vivo from WT and miR-142 deficient Bl6 mice. Thymi were isolated from a pool of 4-5 mice per genotype and cells were isolated by FACS sorting. After sorting, total mRNA was isolated and expression levels were investigated with an Affymetrix microarrage Gene 1.0ST chip.
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