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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression patterns in response to IL-3 in human AML patient mononuclear cells

ABSTRACT: Aberrant activation of β-catenin is a common event in Acute Myeloid Leukemia (AML), and is recognized as an independent predictor of poor prognosis. Although increased β-catenin signaling in AML has been associated with AML1-ETO and PML-RARα translocation products, and activating mutations in the FLT3 receptor, it remains unclear which mechanisms activate β-catenin in AML more broadly. Here, we describe a novel link between interleukin-3 (IL-3) signaling and the regulation of β-catenin in myeloid transformation and AML. Using a murine model of HoxB8 and IL-3 cooperation we show that IL-3 modulates β-catenin protein levels, and Cre-induced deletion of β-catenin abolishes IL-3 dependent growth and colony formation. In the erythroleukemic cell line TF-1.8, we observed increased β-catenin protein levels and nuclear localization in response to IL-3, which correlated with transcriptional induction of β-catenin target genes. Furthermore, IL-3 promoted β-catenin accumulation in a subset of AML patient samples, and microarray gene expression analysis of these cells revealed induction of WNT/β-catenin and TCF4 transcriptional gene signatures in an IL-3 dependent manner. This study is the first to link β-catenin activation to IL-3 and suggests that targeting IL-3 signaling may be an effective approach for the inhibition of β-catenin activity in some patients with AML. AML patient samples (AML1-4) were cultured in the presence or absence of hIL-3 for 6 or 16h.

ORGANISM(S): Homo sapiens

SUBMITTER: Chung Kok

PROVIDER: E-GEOD-51402 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene expression patterns in response to IL-3 in human AML patient mononuclear cells

Project description:Aberrant activation of β-catenin is a common event in Acute Myeloid Leukemia (AML), and is recognized as an independent predictor of poor prognosis. Although increased β-catenin signaling in AML has been associated with AML1-ETO and PML-RARα translocation products, and activating mutations in the FLT3 receptor, it remains unclear which mechanisms activate β-catenin in AML more broadly. Here, we describe a novel link between interleukin-3 (IL-3) signaling and the regulation of β-catenin in myeloid transformation and AML. Using a murine model of HoxB8 and IL-3 cooperation we show that IL-3 modulates β-catenin protein levels, and Cre-induced deletion of β-catenin abolishes IL-3 dependent growth and colony formation. In the erythroleukemic cell line TF-1.8, we observed increased β-catenin protein levels and nuclear localization in response to IL-3, which correlated with transcriptional induction of β-catenin target genes. Furthermore, IL-3 promoted β-catenin accumulation in a subset of AML patient samples, and microarray gene expression analysis of these cells revealed induction of WNT/β-catenin and TCF4 transcriptional gene signatures in an IL-3 dependent manner. This study is the first to link β-catenin activation to IL-3 and suggests that targeting IL-3 signaling may be an effective approach for the inhibition of β-catenin activity in some patients with AML.

2014-02-13 | GSE51402 | GEO

The role of Gaq in MLL leukemogenesis

Project description:Beta-catenin has a central role for self-renewal of leukemic stem cells in Mixed Lineage Leukemia (MLL)-arranged acute myeloid leukemia (AML), however its upstream modulators that can enhance this pathway remain largely unexplored. Through genome-wide gene expression analysis, we identified a previously unknown role for the G protein Gaq in MLL-arranged AML. Inhibition of Gaq reduces the level of active beta-catenin expression and impairs the maintenance of MLL-rearranged AML. Our microarray analysis uncovers a novel functional role for Gaq in leukemia maintenance. GFP-positive leukemic cells flow-sorted by BD Influxâ¢ cell sorter from bone marrow of the primary AML mice induced by MLL-AF9 oncogene were lentivirally transduced with Gaq shRNA (TRCN0000295412, Sigma) or Scrambled control (SHC016, Sigma), and replated in methylcellulose supplemented with IL3. Each group contains triplicate samples.

2016-02-25 | E-MTAB-4078 | biostudies-arrayexpress

Characterisation of the Beta-Catenin cytoplasmic/nuclear interactome in leukaemia cells

Project description:Canonical Wnt/B-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia (AML) patients; however, some patients exhibit little or no β-catenin nuclear-localization even where cytosolic B-catenin is abundant. Differential propensity for nuclear-localized β-catenin is also observed in cell lines. To investigate the factors mediating the nuclear-localization of B-catenin we carried out a nuclear/cytoplasmic proteomic analysis of the B-catenin interactome in myeloid leukemia cells. From this we identified hundreds of putative novel B-catenin-interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear B-catenin, K562/HEL) versus Wnt-unresponsive cells (low nuclear B-catenin, ML1) suggested the established interactor, LEF1, is a key factor mediating the nuclear-localization of B-catenin in myeloid leukemia. The relative levels of nuclear LEF1 and B-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF1 knockdown inhibited B-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF1 overexpression was able to promote both nuclear-localization and B-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This study is the first to present a B-catenin interactome in hematopoietic cells and reveals LEF1 as a critical regulator of canonical Wnt signaling in myeloid leukemia.

2019-01-11 | PXD009305 | Pride

Human AML secretome and exosomes and correlation with Anti-Apoptotic Index, part 2

2016-02-03 | PXD003471 | Pride

PLCG1 is required for AML1-ETO leukemia stem cell self-renewal

Project description:In an effort to identify novel drugs targeting fusion-oncogene induced acute myeloid leukemia (AML), we performed high-resolution proteomic analysis. In AML1-ETO (AE) driven AML we uncovered a deregulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein which is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem- and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of Ca++-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO positive leukemic stem cells.

2021-11-04 | PXD026374 | Pride

Human AML secretome and correlation with Anti-Apoptotic Index, part 1

Project description:Expression of proteins regulating apoptosis (BCL-2, MCL-1, BCL-X and BAX) in acute myeloid leukemia (AML) blasts at diagnosis have been shown to be associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. This suggested a dynamic regulation of apoptosis. Herein, we further explored this aspect of apoptosis in AML. Firstly, the intra-individual ex vivo apoptosis-related profiles of normal lymphocytes and AML blasts showed a strong correlation, with expression values far beyond control lymphocytes. Secondly, we demonstrated that apoptosis-resistant primary AML blasts, as opposed to apoptosis-sensitive cells, were able to up-regulate BCL-2 expression in sensitive AML blasts in contact cultures (p=0.0067 and p=1.0 respectively). Using proteomics we further set out to identify novel proteins possibly engaged in apoptosis regulation. Proteomics analysis revealed that major functional protein clusters upregulated in secretomes of apoptosis-resistant AML, were presumably engaged in global gene regulation including mRNA splicing, protein translation and chromatin remodeling.

2016-02-03 | PXD001476 | Pride

The important role of GPR84 in MLL leukemogenesis

Project description:Beta-catenin signaling is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML), yet the upstream regulators that can augment this pathway are unknown. Through genome-wide gene expression analysis and functional studies, we identified an important role for GPR84 in MLL AML. Suppression of GPR84 significantly inhibited cell growth in pre-LSCs, reduced LSC frequency and impaired reconstitution of MLL AML. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a transduced hematopoietic stem cells (HSCs). Our microarray analysis demonstrated that GPR84 overexpression significantly up-regulated a small set of MLL-fusion targets and beta-catenin co-effectors, and down-regulated a hematopoietic cell cycle inhibitor. These data thus reveal a previously unrecognized role of GPR84 in the maintenance of fully developed AML by sustaining aberrant beta-catenin signaling in LSCs. HSC-derived Hoxa9/Meis1a pre-LSCs were transduced with GPR84 cDNA or empty vector, and replated in methylcellulose supplemented with cytokines. Each group contains triplicate samples.

2014-10-15 | E-MTAB-1932 | biostudies-arrayexpress

Identification of Lgr4 targets in mixed lineaged leukemia-arranged AML

Project description:Inhibition of leucine-rich repeat-containing G protein-coupled receptor 4 (Lgr4) prevents the development of Mixed Lineage Leukemia (MLL)-arranged AML in mice and suppresses activation of Wnt/beta-catenin signaling. To identify key downstream targets of Lgr4, we performed genome-wide gene expression analysis. Our microarray analysis and subsequent in vivo studies demonstrate a novel functional role for growth arrest and DNA damage-inducible 45 (Gadd45a) in promoting in vivo self-renewal of leukemic stem cells in MLL-rearranged AML. GFP-positive leukemic cells flow-sorted by BD Influx cell sorter from bone marrow of primary AML mice induced by MLL-AF9 oncogene were lentivirally transduced with Lgr4 shRNA (MSH040504-3-LVRU6MP, GeneCopoeia) or Scrambled control (CSHCTR001-LVRU6MP, GeneCopoeia), and replated in methylcellulose supplemented with IL3. Each group contains triplicate samples.

2023-08-30 | E-MTAB-4773 | biostudies-arrayexpress

Epigenetic minicircuitry of AML1-ETO/THAP10/MIR383 contributes t(8;21) AML leukemogenesis

Project description:AML1-ETO is regarded as an initial event and plays a pivotal role in t(8;21) acute myeloid leukemia (AML) which is a highly heterogeneous disease. DNA methylation patterns are frequently deregulated in t(8;21) AML, though little is known of the mechanisms through which specific gene sets become aberrantly methylated. Here, We found that the promoter DNA methylation signature of t(8;21) AML blasts differs from those of normal CD34+ bone marrow cells and other AMLs. This signature contains 408 differentially methylated genes, many of which are genes involved in cancer pathway and myeloid leukemia. Database systematic survey and differential methylated regions (DMR) analysis were performed. These study demonstrated that a novel hypermethylated zinc finger containing protein-THAP10 is a target gene and can be epigenetic silenced by AML1-ETO at transcriptional level in t(8;21) AML and silencing of THAP10 by AML1-ETO predicts a poor clinical outcome. Our findings also identified that THAP10 is a bona fide target of miR-383 which can be epigenetic activated by AML1-ETO. In this study, we provided evidence that epigenetic silencing of THAP10 is the mechanistic link between AML1-ETO fusion proteins and tyrosine kinase cascades. In addition, we showed that THAP10 is a nuclear protein which inhibits myeloid proliferation inhibition and promotes differentiation both in vitro and in vivo. Altogether, our results revealed an unexpected and important link between fusion protein AML1-ETO, mir-383, THAP10 and tyrosine cascades in t(8;21) AML.

2017-04-30 | GSE80508 | GEO

D9, a novel 3-Deazaneplanocin A (DZNep) analog, is efficacious in targeting acute myeloid leukemia (AML) (Sensitive vs Resistance)

Project description:We and others have previously reported that 3-Deazaneplanocin A (DZNep) is a histone methylation inhibitor that has a wide range anticancer effects in a variety of human cancers. Here, using acute myeloid leukemia as a model, we reported a less toxic analog of DZNep, named D9, that is shown to be efficacious in both cell lines and patient samples of AML. Gene expression analysis in a panel of AML cell lines treated with D9 identified a set of genes that is associated with D9 sensitivity and is implicated in multiple oncogenic signaling pathways. Moreover, we show that D9 is able to deplete the leukemia stem cells (LSC) and abolish chemotherapy-induced LSC enrichment, leading to dramatic elimination of AML cell survival and associated gene expression when combined with chemotherapy. Thus, D9 appears to be a robust epigenetic compound that may constitute a potential for AML therapy. We evaluated the overall effects of D9 on histone lysine methylations in AML cell lines and its relationship to apoptosis induction by D9. The results demonstrated that the both sensitive and resistant cell lines, treated with D9 for 48 and 72 hours, showed similar levels of suppression of histone lysine methylation. Thus, the differential sensitivities of AML cells to D9 is not due to its different ability to inhibit the bulk histone methylation but is more likely to be associated with the differential gene expression response to D9. To test this hypothesis, we treated three sensitive (MOLM-14, MV4-11 and TF-1) and three resistant (Mono-Mac-1, THP-1, and KG-1a) cell lines with D9 at 1 or 5 Î¼M for 48 hours and performed Illumina BeadChip transcriptom profiling analysis. Significance Analysis of Microarrays (SAM) analysis shows that D9 treatment resulted in transcriptional changes of 547 genes, including 327 upregulated genes and 220 downregulated genes in sensitive cell lines but not in resistant cell lines.

2015-12-31 | E-GEOD-59624 | biostudies-arrayexpress

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