Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptomic and epigenomic profiling of SETDB1 mediated repression in Acute Myeloid Leukemia

ABSTRACT: Epigenetic regulators play a critical role in normal and malignant hematopoiesis. We recently showed that the Histone 3 Lysine 9 (H3K9) methyltransferase SETDB1 negatively regulates the expression of the pro-leukemic genes HoxA9 and its cofactor Meis1 through deposition of promoter H3K9 trimethylation (H3K9me3) in MLL-AF9 AML cells. Here, we investigated the microbiological impact of altered SETDB1 expression in AML cells. We explored changes in transcription using RNA-seq, promoter associated histone modifications using ChIP-seq, and chromatin accessibility using ATAC-seq. Next generation sequencing of AML cells with or without overexpression of SETDB1 shows that high expression of SETDB1 induces repressive changes to the promoter epigenome and downregulation of genes linked with AML, including Dock1 and the MLL-AF9 target genes Hoxa9, Six1, and others. These data reveal novel targets of SETDB1 in AML that point to a role for SETDB1 in negatively regulating pro-leukemic target genes and suppressing AML.

ORGANISM(S): Mus musculus

PROVIDER: GSE136850 | GEO | 2019/10/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The Polycomb Repressive Complex 2 Is Required For MLL-AF9 Leukemia

Project description:This SuperSeries is composed of the following subset Series: GSE34959: Expression profiling of primary wild type (WT), Ezh2-null and Eed-null murine MLL-AF9 AML GSE34961: Expression profiling of secondary wild type (WT) and Ezh2-null murine MLL-AF9 AML GSE34962: Epigenetic profiling of WT and Ezh2-null MLL-AF9 murine leukemic cells Refer to individual Series

2012-02-22 | E-GEOD-34963 | biostudies-arrayexpress

RNA-seq profiling of murine Tet-off MLL-AF9; NRAS acute myeloid leukemia at different timepoints upon doxycycline-induced MLL-AF9 down-regulation.

Project description:Using an acute myeloid leukemia (AML) mouse model driven by tet-regulated MLL-AF9 (fusion between the gene MLL1 (KMT2A/MLL) and MLLT3 (AF9)) co-expressed with oncogenic NRASG12D (Tet-off MLL-AF9), we investigated the effect of modulating the expression of the MLL-AF9 fusion oncogene on the transcriptome and proteome of established murine AML. Treatment in vitro or in vivo of these Tet-off MLL-AF9 AMLs with doxycycline (DOX) results in the efficient down-regulation of the expression of the driver oncogene MLL-AF9. RNA sequencing analysis was performed on primary Tet-Off MLL-AF9 AML cells obtained from the spleen of leukemic animals and cultured in vitro for either 2 or 4 days in the presence of doxycycline (1μg/ml) (DOX= down-regulation of MLL-AF9) or left untreated (UT).

2021-12-31 | GSE108326 | GEO

Hes1 is responsible for Notch signaling-mediated suppression of acute myeloid leukemia development

Project description:In leukemogenesis Notch signaling can be up- and down-regulated in a context-dependent manner. Here we report that deletion of hairy and enhancer of split-1 (Hes1) promotes acute myeloid leukemia (AML) development induced by the MLL-AF9 fusion protein. Subsequently, the FMS-like tyrosine kinase 3 (FLT3) was up-regulated in mouse cells of a Hes1- or RBP-J-null background. MLL-AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL-AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL-AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development by down-regulating FLT3 expression. 4 samples are analyzed, two pairs of MLL-AF9/Hes1-/- and MLL-AF9/Hes1+/+ leukemic bone marrows.

2017-05-02 | E-GEOD-50234 | biostudies-arrayexpress

Tetraspanin 3 is Required for the Development and Propagation of Acute Myelogenous Leukemia

Project description:Msi2 is a critical regulatior of myeoid leukemia, and these data identify genes that are changed following Msi2 deletion in bcCML and de novo AML stem cells. Leukemic stem cells were extracted from wild-type and Msi2 mutant MLL-AF9 driven AML and BCR-ABL/NUP98-HOXA9 driven bcCML, in triplicate. RNA was extracted and hybridized on Affymetrix microarrays. The mouse strain was a genetic trap Msi2 mutant made by Center for Animal Resources and Development (CARD) of Kumamoto University. They call their strain B6;CB-Msi2Gt(pU-21T)2Imeg, see also http://cardb.cc.kumamoto-u.ac.jp/transgenic/strainsDetailAction.do?strainId=834

2015-06-04 | E-GEOD-69512 | biostudies-arrayexpress

The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells (ChIP-Seq data)

Project description:Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogues active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia which may be selectively targeted to therapeutic effect. To investigate the effects of Kdm1a KD on histone modifications, we performed chromatin immunoprecipitation followed by next-generation sequencing (ChIP-Seq) in control and Kdm1a KD MLL-AF9 AML cells for dimethyl-H3K4 and dimethyl-H3K9, as well as for trimethyl-H3K4 and trimethyl-H3K9. Dimethyl-H3K4 and dimethyl-H3K9 are targeted for demethylation by KDM1A. For each of these histone modifications, we compared the mean ChIP-Seq signal across and around protein coding genes bound by the MLL-AF9 oncoprotein (Bernt et al., 2011) with the mean signal from genes not bound by MLL-AF9 expressed at high, middle or low levels.

2012-03-28 | E-GEOD-36346 | biostudies-arrayexpress

The Growth factor independence 1 (GFI1) 36N variant predisposes to Acute Myeloid Leukemia (AML) by inducing epigenetic changes at the Hoxa9 locus

Project description:GFI136N is a coding Single Nucleotide Polymorphism (SNP) in the gene GFI1 that increases the risk for Acute myeloid leukemia (AML) by 60%. It is present in 3-5% of Caucasians and has a prevalence of 12% among AML patients. We generated knockin mice expressing either the human GFI136N variant or the more common GFI136S form and observed that GFI136N, in contrast to GFI136S, lacked the ability to bind to the Gfi1 target gene and leukemia associated transcription factor Hoxa9 in myeloid precursors and failed to initiate the histone modifications that regulate HoxA9 expression. Consistent with this, GFI136N heterozygous AML patients showed increased HOXA9 expression compared to control patients. In the knockin mice, granulo-monocytic pogenitors (GMPs), a bone marrow subset from which AML can arise, show a proliferative expansion in the presence of the GFI136N variant. Finally, the GFI136N variant increased colony formation and proliferation of myeloid precursors induced by the onco-fusion proteins MLL/AF9 or AML1/Eto9a and accelerated the onset of a KRAS-driven myelo-proliferative disease. Our data suggest that GFI136N predisposes to AML by deregulating the expression of Hoxa9, a locus highly relevant for AML, thereby inducing a pre-leukemic state in myeloid precursors that can give rise to AML. 3 samples (2 histone modifications, 1 transcription factor)

2012-12-04 | E-GEOD-31657 | biostudies-arrayexpress

Loss of MBD2 Attenuates MLL-AF9-Driven Leukemogenesis By Reducing Leukemic Cell Cycling via CDKN1C

Project description:Emerging evidence supports that MBD2, a DNA methylation reader, often participated in the transcriptional silencing of hypermethylated genes in cancer cells. Nevertheless, the role of MBD2 in AML remains elusive. Herein, by using MLL-AF9 murine model and human AML cell line, we observed that loss of MBD2 could delay the initiation and propagation of leukemia through serial transplantation experiments. MBD2 depletion significantly reduced the leukemia burden by decreasing the frequency of leukemic stem cells (LSCs), coupled with inhibiting leukemia proliferation, thereby allowing leukemia blasts develop to a more mature state reflecting normal myelopoiesis. Both gene expression analyses and bioinformatic studies revealed that MBD2 negatively modulated the genes related to myeloid differentiation and was necessary to sustain MLL-AF9 oncogenic induced gene programs. We further demonstrated that MBD2 could promote LSC cell cycle progression through epigenetic regulation of CDKN1C transcription by binding to its promoter region. Taken together, our data suggested that MBD2 promotes AML development and could be a therapeutic target of myeloid malignancies.

2022-02-11 | GSE166610 | GEO

Genes differentially expressed in MLL-AF9-transduced versus HOXA9/MEIS1-transduced LSK cells

Project description:HOXA9 and MEIS1 are essential downstream effectors of the MLL-AF9 oncoprotein during leukaemia induction. Leukaemia derived from MLL-AF9-transduced LSK cells has a more aggressive phenotype than that derived from HOXA9/MEIS1-transduced LSK cells. To determine differential gene expression that contributes to increased aggressiveness in MLL-AF9-induced leukaemia, microarray was performed on LSK cells transduced with MLL-AF9 versus HOXA/MEIS1 oncogenes.

2019-07-03 | E-MTAB-7355 | biostudies-arrayexpress

miRNAs differentially expressed in MLL-AF9-transduced versus HOXA9/MEIS1-transduced LSK cells

Project description:HOXA9 and MEIS1 are essential downstream effectors of the MLL-AF9 oncoprotein during leukemia induction. Leukemia derived from MLL-AF9-transduced LSK cells has a more aggressive phenotype than that derived from HOXA9/MEIS1-transduced LSK cells. To determine differential miRNA expression that contributes to increased aggressiveness in MLL-AF9-induced leukemia, miRCURY LNA microRNA Array was performed on LSK cells transduced with MLL-AF9 versus HOXA/MEIS1 oncogenes.

2019-07-03 | E-MTAB-7356 | biostudies-arrayexpress

Abnormal intragenic transcriptional activation in the BRE gene in MLL-rearranged and MOZ-CBP+ AML

Project description:High BRE gene expression in MLL-AF9+ acute myeloid leukemia (AML) is associated with a favorable prognosis, while high MECOM expression confers a very poor prognosis. ChIP-seq and RNA-seq experiments on primary human MLL-AF9+ AML samples showed more pronounced signals in samples with high MECOM expression, explaining its high expression. Between samples from the two MLL-AF9+ AML subgroups, promoter marks were located at the same position at the MECOM locus. In contrast, intragenic active promoter marks in BRE were exclusively present in samples with outlier high BRE expression. 5’ RACE and RNA-seq showed biallelic transcription of a novel BRE transcript starting adjacent to the active promoter marks followed by downstream exons. RT-qPCR detected the novel BRE transcript in >50% of adult and childhood MLL-rearranged (n=56) but also MOZ-CBP+ AML (n=20), while it was virtually absent in other samples (n=145, p<0.0001). The novel BRE transcript and active promoter marks were also absent from large publicly available datasets, underlining the uniqueness of this novel BRE transcript. Genome-wide analyses of MLL-AF9+ samples showed abnormal intragenic H3K4me3 marks in 90 genes exclusively in high BRE samples. Of these genes, expression of exons downstream versus upstream was most discriminative for BRE. Luciferase reporter assays using the intragenic BRE promoter showed that it was transactivated by MLL-AF9. The new BRE transcript may encode a BRE isoform that lacks part of the N-terminus. Importantly, we detected a new in frame CHORD1-BRE fusion in a case with relapsed AML. The BRE fusion occurred in the same region as intragenic transcription activation in BRE in MLL-AF9+ AML. This work identifies strong abnormal intragenic transcription activation resulting in the formation of a new BRE transcript in MLL-AF9+ and MOZ-CBP+ AML. Future studies should reveal whether alternate BRE contributes to AML pathogenesis.

2017-12-20 | GSE89336 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data