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Activity of a stem cell enhancer influences stem cell programs and clinical outcome in leukaemia

ABSTRACT: Chip-chip data from primary human AML patient blasts, normal CD34+ HSCs, normal neutrophils and normal T cells with H3K9 and H3K27 antibodies. Gene expression profiling from primary human AML patient blasts and CD34+ normal cells. Analysis of the chromatin landscape of the ERG locus using H3K9 and H3K27 as markers of euchromatin and heterochromatin respectively. Analysis of ERG expression in AML patients with normal CD34+ HSCs as control. Correlation of the activity of a stem cell enhancer at the ERG locus in AML primary patient blasts with their transcriptome and clinical outcome data.

ORGANISM(S): Homo sapiens

SUBMITTER: Weng Khong Lim

PROVIDER: E-GEOD-38865 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia.

Diffner Eva E Beck Dominik D Gudgin Emma E Thoms Julie A I JA Knezevic Kathy K Pridans Clare C Foster Sam S Goode Debbie D Lim Weng Khong WK Boelen Lies L Metzeler Klaus H KH Micklem Gos G Bohlander Stefan K SK Buske Christian C Burnett Alan A Ottersbach Katrin K Vassiliou George S GS Olivier Jake J Wong Jason W H JW Göttgens Berthold B Huntly Brian J BJ Pimanda John E JE

Blood 20130117 12

Aberrant transcriptional programs in combination with abnormal proliferative signaling drive leukemic transformation. These programs operate in normal hematopoiesis where they are involved in hematopoietic stem cell (HSC) proliferation and maintenance. Ets Related Gene (ERG) is a component of normal and leukemic stem cell signatures and high ERG expression is a risk factor for poor prognosis in acute myeloid leukemia (AML). However, mechanisms that underlie ERG expression in AML and how its expr ...[more]

PMID: 23327922

Similar Datasets

Activity of a stem cell enhancer influences stem cell programs and clinical outcome in leukaemia

Project description:Chip-chip data from primary human AML patient blasts, normal CD34+ HSCs, normal neutrophils and normal T cells with H3K9 and H3K27 antibodies. Gene expression profiling from primary human AML patient blasts and CD34+ normal cells. Analysis of the chromatin landscape of the ERG locus using H3K9 and H3K27 as markers of euchromatin and heterochromatin respectively. Analysis of ERG expression in AML patients with normal CD34+ HSCs as control.

2013-04-04 | GSE38865 | GEO

Genome wide screen reveals WNT11, a noncanonical WNT gene, as a target of ETS transcription factor ERG

Project description:ERG is a transcription factor that is involved in leukomogenesis and its mRNA overexpression has been associated with poor prognosis in a subset of patients with T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Herein, a genome-wide screen of ERG target genes was conducted by chromatin immunoprecipitation-on-chip (ChIP-chip) in Jurkat cells. 342 significant annotated regions were derived from ChIP-chip experiments. Seventeen candidate promoter regions resulted in at least two-fold enrichment by quantitative PCR. Notably, ERG potential targets included WNT signaling genes: WNT2, WNT9A, WNT11, CCND1, and FZD7. Functionally, expression of WNT11 was downregulated with siRNA ERG knockdown and substantially upregulated in a tet-on ERG-inducible assay in K562 cells. To investigate a role for ERG in WNT signaling, a WNT agonist was used to inhibit glycogen synthase kinase (GSK-3). This treatment resulted in an ERG-dependent proliferative growth advantage in the tet-on ERG-inducible system. Lastly, chromatin immunoprecipitation assays of primary leukemia blasts confirmed WNT11 promoter enrichment dependent on ERG mRNA expression. In conclusion, ERG transcriptional networks in leukemia are revealed. Specifically, WNT11 emerged as a target of ERG. We propose that overexpression of ERG in acute leukemia may lead to a proliferative advantage upon activation of WNT signals. ChIP-chip with ERG antibody C20 and combined C17/20 and nonspecificic IgG in Jurkat

2010-12-10 | E-GEOD-21495 | biostudies-arrayexpress

The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia

Project description:In this work we dissect the functional role of the HOXB-AS3 long non coding RNA in patients with NPM1-mutated (NPM1mut) acute myeloid leukemia (AML). We show that HOXB-AS3 regulates the proliferative capacity of NPM1mut AML blasts in vitro and in vivo. HOXB-AS3 was found to interact with the ErbB3-binding protein 1 (EBP1) and guide EBP1 to the ribosomal DNA locus. Via this mechanism HOXB-AS3 regulates ribosomal RNA transcription and de novo protein synthesis. We propose that in the context of NPM1 mutations, HOXB-AS3 overexpression acts as a compensatory mechanism, which allows adequate protein production in leukemic blasts.

2019-10-16 | PXD015520 | Pride

Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia

Project description:Here we show that pan-haematopoietic ERG expression driven by the Vav promoter induces an early progenitor myeloid leukemia in transgenic mice. Integrated genome-scale analysis of gene expression and ERG binding profiles revealed that ERG activates a transcriptional program similar to human AML stem/progenitor cells and human AML with high ERG expression. We further show that ERG induces expression of the Pim1 kinase oncogene through a novel enhancer element validated in transgenic mice, and Pim1 inhibition disrupts growth and induces apoptosis of ERG-driven leukemic cells. In addition, ERG indirectly induces the RAS pathway and direct RAS inhibition by a RAS inhibitor blocks growth of leukemia cells in vitro and in vivo. Thus, integrative genomic analysis of transgenic ERG leukemias reveals mechanisms and potential therapeutic targets of high ERG expressing AML. Spleen cells were fixed with 1% formaldehyde and ChIP assays were performed as previously described (Wilson NK et al., 2010 Cell Stem Cell) using polyclonal antibodies against ERG-1/2/3 (clone C-17, Sc354X, Santa Cruz) and control nonspecific rabbit IgG (I5006, Sigma).

2013-08-30 | E-GEOD-46554 | biostudies-arrayexpress

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

Oncogenic RAS primes primary acute myeloid leukemia blasts for differentiation

Project description:RAS mutations are frequently found among AML patients, generating a constitutively active signaling protein changing cellular proliferation, differentiation and apoptosis. We previously showed that treatment of AML patients with high-dose cytarabine (HDAC) is preferentially beneficial for those with an oncogenic RAS mutation. By applying a murine AML model, we could ascribe this effect to a RAS-driven, p53-dependent induction of differentiation. Here, we sought to confirm the correlation between RAS status and differentiation of blasts obtained from AML patients. The expression signature of primary AML blasts expressing oncogenic RAS where compared to blasts with wtRAS. Blasts where obtained from peripheral blood or bone marrow samples from patients with CBFbeta-MYH11 translocations and with or without an additional NRAS point mutation. As a reference, the Kasumi-1 acute myeloid leukemia cell line was used.

2015-11-20 | E-MTAB-2090 | biostudies-arrayexpress

Integrated nuclear proteomics and transcriptomics identifies new high frequency dysregulated targets in acute myeloid leukemia

Project description:Acute myeloid leukemia (AML) is characterized by developmental arrest which is thought to arise from transcriptional dysregulation of myeloid development programs. Here, we have analyzed the transcriptome of AML blasts in comparison with normal human CD34+ cells using the HTA 2.0 gene chip. We have compared 18 minimally differentiated AML blasts with cord blood derived normal human CD34+ cells - this study is performed as a parallel analysis to compliment the nuclear proteomic studies.

2019-10-02 | E-MTAB-3873 | biostudies-arrayexpress

Human AML secretome and exosomes and correlation with Anti-Apoptotic Index, part 3

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. We hypothesized that expression of apoptosis-related proteins in AML blasts, and possibly also in bystander cells in the bone marrow, is regulated by extracellular factors present in the AML microenvironment. Tumor cell communication with its microenvironment is emerging as an important determinant playing multiple roles in cancer. Both soluble factors and extracellular vesicles (EVs), most notably exosomes, have been shown to influence cellular processes of malignant and normal cells in the tumor microenvironment. We performed a proteomics analysis of the whole secretome as well as of EVs secreted by AML blasts to pinpoint released protein factors that might mediate apoptosis-resistance.

2016-02-03 | PXD001487 | Pride

miR-181a modulates Acute Myeloid Leukemia susceptibility to natural killer cells

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.

2014-12-30 | E-MTAB-2837 | biostudies-arrayexpress

The co-receptor Neuropilin-1 enhances proliferation in inv(16) acute myeloid leukemia via VEGF signaling

Project description:Oncogenic programs regulate the proliferation and maintenance of cancer stem cells, and can define pharmacologic dependencies. In acute myeloid leukemia (AML) with the chromosome inversion 16 (inv(16)), the fusion CBF::MYH11 oncoprotein regulates pathways associated with leukemia stem cell activity. Here we demonstrate that expression of Neuropilin-1 (NRP1) is regulated by the fusion oncoprotein, and promotes AML expansion. Mechanistically, we show that the NRP1 locus has open chromatin in inv(16) AML, and that CBF::MYH11 modulates the local function of the transcription factors ERG, GATA2 and RUNX1 to sustain NRP1 levels. We found that ERG activates NRP1 expression, and that CBF::MYH11 knockdown represses ERG expression, thereby allowing the repressive activity of GATA2/RUNX1 at three NRP1 enhancers. Functionally, we demonstrate that NRP1 enhances the expansion of leukemic cells in vitro and in mice, and that this activity is dependent on its VEGFR-associated FV/FVIII domain. Finally, we show that treatment with VEGF inhibitor axitinib reduces AML cell growth and delays median leukemia latency in vivo. Our findings reveal that the NRP1/VEGF axis mediates proliferation in inv(16) AML blasts, and suggest that targeting NRP1 function could be promising in combination AML therapy.

2024-11-18 | GSE215613 | GEO

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