Nanoparticle-mediated Targeting of the Fusion Gene RUNX1/ETO in t(8;21)-positive Acute Myeloid Leukemia [CUT&RUN]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE217110 | GEO | 2022/11/09
REPOSITORIES: GEO
Similar Datasets
Project description:To investigate the therapeutic potential of targeting RUNX1/ETO with lipid nanoparticles encapsulating chemically modefied siRNA. Chromatin Accessibility (ATAC-seq) was performing on cells lines after lipid nanoparticles in vitro.
2022-11-09 | GSE217112 | GEO
Project description:To investigate the therapeutic potential of targeting RUNX1/ETO with lipid nanoparticles encapsulating chemically modefied siRNA. Gene expression profiling was performing on cells lines after lipid nanoparticles in vitro and on harvested cells from treated mice in vivo.
2022-11-09 | GSE217109 | GEO
Project description:Human histone deacetylase 3 (HDAC3) plays an important role in gene transcription in diseased human cells, such as leukemia. The t(8;21) chromosomal translocation is one of the most commonly observed genetic abnormalities associated with acute myeloid leukemia. This translocation generates the AML1-ETO fusion protein between the wild-type RUNX1 transcription factor and wild-type ETO transcriptional corepressor. To better understand the role of HDAC3 in t(8;21) leukemogenesis, the human HDAC3-containing complexes were isolated from stably-transfected HeLa cells by using anti-FLAG immunoprecipitation. The resulting complexes were resolved in SDS-PAGE. The components of the complexes were identified using LC-MS/MS. We report here that the human RUNX1 transcription is a component of the HDAC3 complexes. We demonstrate that HDAC3 and RUNX1 collaboratively repress AML1-ETO-mediated transcription. These results reveal new insight into how AML1-ETO, RUNX1, and HDAC3 crosstalk to deregulate gene transcription in t(8;21) leukemia cells.
2020-02-17 | PXD017230 | Pride
Project description:Acute myeloid leukaemia (AML) is caused by mutations in transcriptional and epigenetic regulator genes impairing myeloid differentiation. The t(8;21)(q22;q22) translocation generates the leukemogenic RUNX1-ETO fusion protein which interferes with the hematopoietic master regulator RUNX1. We previously showed that maintenance of t(8;21) AML is dependent on RUNX1-ETO as its depletion causes extensive changes in transcription factor binding and gene expression as well as myeloid differentiation. How changes in gene expression and binding events are connected within a transcriptional network is unclear. To this end, we assigned cis-regulatory elements to each other using promoter-capture chromosomal conformation assays in the presence and absence of RUNX1-ETO. From these data we constructed a RUNX1-ETO dependent dynamic transcriptional network maintaining AML. Integration of these data with gene expression and transcription factor binding data shows that RUNX1-ETO participates in interactions and that differential cis-element interactions are driven by alterations in the binding of RUNX1-ETO regulated transcription factors.
2019-11-11 | GSE121281 | GEO
Project description:Acute myeloid leukaemia (AML) is caused by mutations in transcriptional and epigenetic regulator genes impairing myeloid differentiation. The t(8;21)(q22;q22) translocation generates the leukemogenic RUNX1-ETO fusion protein which interferes with the hematopoietic master regulator RUNX1. We previously showed that maintenance of t(8;21) AML is dependent on RUNX1-ETO as its depletion causes extensive changes in transcription factor binding and gene expression as well as myeloid differentiation. How changes in gene expression and binding events are connected within a transcriptional network is unclear. To this end, we assigned cis-regulatory elements to each other using promoter-capture chromosomal conformation assays in the presence and absence of RUNX1-ETO. From these data we constructed a RUNX1-ETO dependent dynamic transcriptional network maintaining AML. Integration of these data with gene expression and transcription factor binding data shows that RUNX1-ETO participates in interactions and that differential cis-element interactions are driven by alterations in the binding of RUNX1-ETO regulated transcription factors.
2019-11-11 | GSE121280 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-11-09 | GSE217113 | GEO
Project description:The t(8;21) acute myeloid leukemia associated oncoprotein AML1-ETO is a transcription factor that aberrantly regulates the pathways that lead to myeloid differentiation. Here, we set out to investigate the effects of AML1-ETO on gene expression and the epigenome in patient blast cells. We identify two modules, one in which AML1-ETO binds promoter regions of active genes and one represented by non-promoter binding to accessible, yet inactive chromatin regions. Using genome-wide binding analysis and mass spectrometry interaction studies we identify ERG, FLI1, TAL1 and RUNX1 as common binding factors of all AML1-ETO occupied genomic regions, while LYL1 and LMO2 show preferential binding in the context of non promoter regions. Epigenetically, reduced histone acetylation levels at non-promoter regions seems HDAC dependent, as treatment with an HDACi increases acetylation and induces cell death. Both AML1-ETO modules are represented in most aberrantly regulated pathways, including many signaling pathways, self-renewal and apoptosis. For the latter, the expression of the wild type transcription factors RUNX1 and ERG is required, as alterations in expression are associated with the onset of an apoptosis program. Interestingly, upon RUNX1 or ERG knockdown this onset seems to be dependent on increased AML1-ETO expression as combinatorial knockdown of RUNX1/AML1-ETO or ERG/AML1-ETO results in rescue from apoptosis. Together our results show that the balanced interplay of the epigenetic environment and transcription factors retains an anti apoptotic phenotype in t(8;21) AML cells.
2016-11-15 | GSE76464 | GEO
Project description: Not available
| S-EPMC5457485 | biostudies-literature
Project description:The t(8;21) translocation fuses the DNA binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape we measured genome-wide RUNX1- and RUNX1/ETO bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide re-distribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML. This SuperSeries is composed of the following subset Series: GSE29222: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding [ChIP-Seq and DNAse-Hypersensitivity data] GSE29223: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding [expression array data] GSE34540: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding (ChIP-seq) GSE34594: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding (Illumina expression) Refer to individual Series
2012-03-26 | E-GEOD-29225 | biostudies-arrayexpress
Project description:The t(8;21) translocation fuses the DNA binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape we measured genome-wide RUNX1- and RUNX1/ETO bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide re-distribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML. This SuperSeries is composed of the SubSeries listed below.
2012-03-27 | GSE29225 | GEO