HDAC2-mediated miRNA profiling in acute myeloid leukemia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE129154 | GEO | 2019/10/28
REPOSITORIES: GEO
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Project description:HDAC2-mediated miRNA profiling in acute myeloid leukemia
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Project description:Alterations of TWIST-1 expression are often seen in solid tumors and contribute to tumorigenesis and cancer progression. However, studies concerning its pathogenic role in leukemia are scarce. Here we show that TWIST-1 is a new candidate gene contributing to leukemogenesis of myeloid leukemia. We used array as one tool to determine gene expression profiles of control and TWIST-1-overexpressing U937 cells.
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Project description:Acute myeloid leukemia is a clinically and genetically heterogenous disease characterized by bone marrow infiltration with immature leukemic blasts that cause bone marrow failure. Patient age, comorbidities and genomic disease characteristics have a profound impact on patient outcome. Here, we present an integrated Multi-Omics analysis of protein and gene expression as well as cytogenetics and mutations to capture the rewiring of intracellular protein networks that is most likely caused by genomic aberrations. Because protein networks are downstream of genomic aberrations, we hypothesized that our Multi-Omics approach may add to the current AML classification by identifying proteomic AML subtypes with specific clinical and molecular features that could identify therapeutic vulnerabilities and aid in the identification of predictive biomarkers.
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Project description:Acute myeloid leukemia is a clinically and genetically heterogenous disease characterized by bone marrow infiltration with immature leukemic blasts that cause bone marrow failure. Patient age, comorbidities and genomic disease characteristics have a profound impact on patient outcome. Here, we present an integrated Multi-Omics analysis of protein and gene expression as well as cytogenetics and mutations to capture the rewiring of intracellular protein networks that is most likely caused by genomic aberrations. Because protein networks are downstream of genomic aberrations, we hypothesized that our Multi-Omics approach may add to the current AML classification by identifying proteomic AML subtypes with specific clinical and molecular features that could identify therapeutic vulnerabilities and aid in the identification of predictive biomarkers.
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Project description:Eukaryotic ribosomal RNA carries diverse posttranscriptional modifications, among which the evolutionarily conserved 2’-O-methylation (2’-O-Me) occurs at more than 100 sites and is essential for ribosome biogenesis. Plasticity of 2´-O-Me in ribosomes and its functional consequences in human disease are not yet known. Here, we present the full rRNA 2’-O-Me landscape (ribomethylome) of human acute myeloid leukemia (AML) through profiling 94 patient samples as well as 21 normal hematopoietic samples of 5 different lineages. While interior modification sites in functional centers are persistently fully 2’-O-methylated in human AMLs, methylation on ribosome exterior sites is unprecedentedly dynamic. Higher 2’-O-methylation on exterior dynamic sites is associated with leukemia stem cell (LSC) signatures. Forced expression of enzymatically active but not of the catalytic defect 2’-O-methyltransferase FBL induces AML stemness and accelerates leukemogenesis in patient-derived xenografts. Mechanistically, ribomethylome dynamics shifted mRNA ribosome translation preferences. High rRNA 2’-O-Me enhances translation of amino acid transporters enriched in optimal codons and subsequently increases intra-cellular amino acid levels. Methylation on a single exterior modification site affects leukemia stem cell activity. The Guanosine 1447 on the small subunit ribosomal RNA is the most variable site in primary AMLs. Gm1447 is increased in leukemia stem cell populations compared to non-leukemogenic blast cells and AML specimens with higher Gm1447 are enriched for leukemia stem cell genes. Comparison of Gm1447high and Gm1447low ribosome structure solved by cryo-electron microscopy demonstrated disassociation of LYAR from Gm1447low ribosomes. Suppression of Gm1447 alone is sufficient to suppress translation of amino acid transporters, resulting in decreased cellular amino acid levels and leukemia stem cell activity. Taken together, our data reveal the dynamic FBL-mediated rRNA 2'-O-Me landscape as a novel epitranscriptomic level of control employed by leukemic stem cells and may enable new strategies to target human AML.
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Project description:Acute myeloid leukemia (AML) is fatal in majority of adults. Identification of new therapeutic targets and their pharmacologic modulators are needed to improve outcomes. Previous studies had shown that immunization of rabbits with normal peripheral WBCs that had been incubated with fluorodinitrobenzene elicited high titer antibodies that bound to a spectrum of human leukemias. We report that proteomic analyses of immunoaffinity-purified lysates of primary AML cells showed enrichment of scaffolding protein IQGAP1. Immunohistochemistry and gene-expression analyses confirmed IQGAP1 mRNA overexpression in various cytogenetic subtypes of primary human AML compared to normal hematopoietic cells. shRNA knockdown of IQGAP1 blocked proliferation and clonogenicity of human leukemia cell-lines. To develop small molecules targeting IQGAP1 we performed in-silico screening of 212,966 compounds, selected 4 hits targeting IQGAP1-GRD domain, and conducted SAR of ‘fittest hit’ to identify UR778Br, a prototypical agent targeting IQGAP1. UR778Br inhibited proliferation, induced apotosis, G2/M arrest, and colony formation by leukemia cell-lines and primary-AML while sparing normal marrow cells. IQGAP1/F-actin showed co-localization and UR778Br induced filopodia formation in U937 cells. UR778Br exhibited favorable ADME/T profiles and drug-likeness to treat AML. In summary, AML shows dependency on IQGAP1 and UR778Br, identified through in-silico studies, selectively targeted AML cells while sparing normal marrow.
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Project description:Acute myeloid leukemia is a clinically and genetically heterogenous disease characterized by bone marrow infiltration with immature leukemic blasts that cause bone marrow failure. Patient age, comorbidities and genomic disease characteristics have a profound impact on patient outcome. Here, we present an integrated Multi-Omics analysis of protein and gene expression as well as cytogenetics and mutations to capture the rewiring of intracellular protein networks that is most likely caused by genomic aberrations. Because protein networks are downstream of genomic aberrations, we hypothesized that our Multi-Omics approach may add to the current AML classification by identifying proteomic AML subtypes with specific clinical and molecular features that could identify therapeutic vulnerabilities and aid in the identification of predictive biomarkers
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Project description:Overexpression of miR-181a in AML blasts: DNA Microarray was performed to compare overall gene expression profiles of KG-1 Anti-miR-CT and U937 Anti-miR-CT cells compared respectively to KG-1 Anti-miR-181a and U937 Anti-miR-181a.
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