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Nanoparticle-mediated Targeting of the Fusion Gene RUNX1/ETO in t(8;21)-positive Acute Myeloid Leukemia [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217109 | GEO | 2022/11/09

REPOSITORIES: GEO

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Nanoparticle-mediated Targeting of the Fusion Gene RUNX1/ETO in t(8;21)-positive Acute Myeloid Leukemia [CUT&RUN]

Project description:To investigate the therapeutic potential of targeting RUNX1/ETO with lipid nanoparticles encapsulating chemically modefied siRNA. Epegnomic profiling was performing on cells lines after lipid nanoparticles in vitro.

2022-11-09 | GSE217110 | GEO

Nanoparticle-mediated Targeting of the Fusion Gene RUNX1/ETO in t(8;21)-positive Acute Myeloid Leukemia [ATAC-seq]

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

Nanoparticle-mediated targeting of the fusion gene RUNX1/ETO in t(8;21)-positive acute myeloid leukaemia.

Project description:A hallmark of acute myeloid leukaemias (AMLs) are chromosomal rearrangements that give rise to novel leukaemia-specific fusion genes. Most of these fusion genes are both initiating and driving events in AML and therefore constitute ideal therapeutic targets but are challenging to target by conventional drug development. siRNAs are frequently used for the specific suppression of fusion gene expression but require special formulations for efficient in vivo delivery. Here we describe the use of siRNA-loaded lipid nanoparticles for the specific therapeutic targeting of the leukaemic fusion gene RUNX1/ETO. Transient knockdown of RUNX1/ETO reduces its binding to its target genes and alters the binding of RUNX1 and its co-factor CBFβ. Transcriptomic changes in vivo were associated with substantially increased median survival of a t(8;21)-AML mouse model. Importantly, transient knockdown in vivo causes long-lasting inhibition of leukaemic proliferation and clonogenicity, induction of myeloid differentiation and a markedly impaired re-engraftment potential in vivo. These data strongly suggest that temporary inhibition of RUNX1/ETO results in long-term restriction of leukaemic self-renewal. Our results provide proof for the feasibility of targeting RUNX1/ETO in a pre-clinical setting and support the further development of siRNA-LNPs for the treatment of fusion gene-driven malignancies.

| S-EPMC10079536 | biostudies-literature

HDAC3 preferentially binds to RUNX1 in t(8;21) AML cells and collaborates with RUNX1 to repress AML1-ETO-mediated transcriptional activation

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

RUNX1-ETO orchestrates dynamic enhancer promoter communication in t(8;21) Acute Myeloid Leukaemia (DNaseI-Seq)

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

RUNX1-ETO orchestrates dynamic enhancer promoter communication in t(8;21) Acute Myeloid Leukaemia (ChIP-Seq)

2019-11-11 | GSE121280 | GEO

Nanoparticle-mediated Targeting of the Fusion Gene RUNX1/ETO in t(8;21)-positive Acute Myeloid Leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-11-09 | GSE217113 | GEO

Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML.

Project description:The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here, we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA and DNA interactions with the broadly expressed Runt-related transcription factor 1 (RUNX1), we identified the long noncoding RNA (lncRNA) originating from the upstream regulatory element of PU.1 (LOUP). This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia (AML), wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein, RUNX1-ETO, limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell-type-specific RNAs and transcription factors, as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.

| S-EPMC8525335 | biostudies-literature

Epigenetic regulation of the apoptosis program in t(8;21) AMLs by an AML1-ETO, ERG and RUNX1 triad

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

RUNX1-ETO and RUNX1-EVI1 Differentially Reprogram the Chromatin Landscape in t(8;21) and t(3;21) AML.

Project description:Acute myeloid leukemia (AML) is a heterogeneous disease caused by mutations in transcriptional regulator genes, but how different mutant regulators shape the chromatin landscape is unclear. Here, we compared the transcriptional networks of two types of AML with chromosomal translocations of the RUNX1 locus that fuse the RUNX1 DNA-binding domain to different regulators, the t(8;21) expressing RUNX1-ETO and the t(3;21) expressing RUNX1-EVI1. Despite containing the same DNA-binding domain, the two fusion proteins display distinct binding patterns, show differences in gene expression and chromatin landscape, and are dependent on different transcription factors. RUNX1-EVI1 directs a stem cell-like transcriptional network reliant on GATA2, whereas that of RUNX1-ETO-expressing cells is more mature and depends on RUNX1. However, both types of AML are dependent on the continuous expression of the fusion proteins. Our data provide a molecular explanation for the differences in clinical prognosis for these types of AML.

| S-EPMC5457485 | biostudies-literature

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