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RUNX1-ETO and RUNX1-EVI-1 differentially program the chromatin landscape in t(3 21) and t(8 21) AML but share global C/EBP-alpha dysfunction

ABSTRACT: RUNX1-ETO and RUNX1-EVI-1 differentially program the chromatin landscape in t(3 21) and t(8 21) AML but share global C/EBP-alpha dysfunction

PROVIDER: PRJNA343965 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR4291600.fastq.gz	Fastqsanger.gz
	SRR4291620.fastq.gz	Fastqsanger.gz
	SRR4291630_1.fastq.gz	Fastqsanger.gz
	SRR4291630_2.fastq.gz	Fastqsanger.gz
	SRR4291640_1.fastq.gz	Fastqsanger.gz

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RUNX1-ETO and RUNX1-EVI-1 differentially program the chromatin landscape in t(3;21) and t(8;21) AML but share global C/EBP-alpha dysfunction (RNA-Seq)

Project description:RUNX1 is a frequent target of translocations in acute myeloid leukemia whereby its DNA binding domain fuses to different epigenetic regulators. To assess how different RUNX1 fusion proteins interact with the epigenome we compared the global binding patterns and the chromatin landscape of t(8;21) and t(3;21) AML which express RUNX1-ETO and RUNX1-EVI-1, respectively. We found that differential prognosis for these types of AML is reflected in fundamental differences in gene expression, chromatin landscape, binding patterns of the fusion proteins and other transcription factors as identified by genome-wide digital footprinting in patients. As previously shown for RUNX1-ETO, knockdown of RUNX1-EVI-1 expression initiates differentiation of t(3;21) cells which is associated with up-regulation of genes vital for myeloid differentiation, including C/EBPα. Furthermore, by expressing either dominant-negative C/EBP or an inducible C/EBPα construct in t(3;21) cells we show that C/EBPα is necessary and sufficient for the differentiation response of these cells to RUNX1-EVI-1 knockdown.

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RUNX1-ETO and RUNX1-EVI-1 differentially program the chromatin landscape in t(3;21) and t(8;21) AML but share global C/EBP-alpha dysfunction (ChIP-Seq)

2017-06-26 | GSE87283 | GEO

RUNX1-ETO and RUNX1-EVI-1 differentially program the chromatin landscape in t(3;21) and t(8;21) AML but share global C/EBP-alpha dysfunction (DNase-Seq)

2017-06-26 | GSE87284 | GEO

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Project description:RUNX1-ETO and RUNX1-EVI-1 differentially program the chromatin landscape in t(3 21) and t(8 21) AML but share global C/EBP-alpha dysfunction (RNA-Seq)

| PRJNA343968 | ENA

Homo sapiens

Project description:RUNX1-ETO and RUNX1-EVI-1 differentially program the chromatin landscape in t(3 21) and t(8 21) AML but share global C/EBP-alpha dysfunction (DNase-Seq)

| PRJNA343969 | ENA

Homo sapiens

Project description:RUNX1-ETO and RUNX1-EVI-1 differentially program the chromatin landscape in t(3 21) and t(8 21) AML but share global C/EBP-alpha dysfunction (ChIP-Seq)

| PRJNA343970 | ENA

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.

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RUNX1 isoforms in leukemogenesis

Project description:Aneuploidy and structural aberrations affecting chromosome 21 (Hsa21) are the most frequent in cytogentic events in acute myeloid leukemia. However, it remains unclear why leukemic blasts select for amplifications of Hsa21 or parts of it and why children with Down syndrome (i.e. trisomy 21) are at a high risk of developing leukemia. Here, we propose that disequilibrium of the RUNX1 isoforms and resultant RUNX1A dominance are key to trisomy 21-associated leukemogenesis. Using a Hsa21-focussed CRISPR-Cas9 screen, we uncovered a strong and specific RUNX1 dependency in myeloid leukemia associated with Down syndrome (ML-DS). High levels of RUNX1A – as seen in ML-DS – synergized with the pathognomonic Gata1s mutation in ML-DS pathogenesis, an effect that was reversed upon restoration of the normal RUNX1A:RUNX1C equilibrium. Mechanistically, RUNX1A displaces RUNX1C from its endogenous binding sites and recruits the MYC cofactor MAX to induce oncogenic programs and perturb normal differentiation. This presents a therapeutic vulnerability that can be exploited by interfering with MYC:MAX dimerization. Our study highlights the importance of alternative splicing in leukemogenesis, and paves the way for developing specific and targeted therapies for ML-DS as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.

2023-05-10 | PXD030616 | Pride

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

Project description:RUNX1-ETO orchestrates dynamic enhancer promoter communication in t(8 21) Acute Myeloid Leukaemia

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RUNX1 reshapes the epigenetic landscape at the onset of hematopoiesis

Project description:Cell fate decisions during hematopoiesis are governed by lineage-specific transcription factors, such as RUNX1, SCL/TAL1, FLI1 and C/EBP family members. In order to gain insight about how these transcription factors regulate the activation of hematopoietic genes during embryonic development, we measured the genome-wide dynamics of transcription factor assembly on their target genes during the RUNX1-dependent transition from hemogenic endothelium to hematopoietic progenitors. Using a RUNX1-/- embryonic stem cell differentiation model expressing an inducible RUNX1 gene, we show that in the absence of RUNX1, SCL/TAL1, FLI1 and C/EBP-beta prime hematopoietic genes and that this early priming is required for correct temporal expression of the myeloid master regulator PU.1 and its downstream targets. After induction, RUNX1 binds to numerous new sites, initiating a local increase of histone acetylation and rapid global alterations in the binding patterns of SCL/TAL1 and FLI1. The acquisition of hematopoietic fate controlled by RUNX1 therefore does not represent the establishment of a new regulatory layer on top of a pre-existing hemogenic endothelium program but instead entails global reorganization of lineage-specific transcription factor assemblies. Microarray expression data obtained from differentiating murine hematopoietic cells, 3 independent biological replicates (measured twice) from iRUNX1 culture -/+DOX induction

2013-02-11 | E-GEOD-39662 | biostudies-arrayexpress

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