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RUNX1-ETO translocations must proceed CSF3R mutations to promote acute myeloid leukemia development

ABSTRACT: RUNX1-ETO translocations must proceed CSF3R mutations to promote acute myeloid leukemia development

PROVIDER: PRJNA905820 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22421702.fastq.gz	Fastqsanger.gz
	SRR22421703.fastq.gz	Fastqsanger.gz
	SRR22421704.fastq.gz	Fastqsanger.gz
	SRR22421705.fastq.gz	Fastqsanger.gz
	SRR22421706.fastq.gz	Fastqsanger.gz

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Similar Datasets

RUNX1-ETO translocations must proceed CSF3R mutations to promote acute myeloid leukemia development

Project description:Acute myeloid leukemia (AML) is a deadly blood cancer character by an overproduction of immature myeloid cells. AML has a high degree of genetic diversity, and the presence or absence of particular genetic alterations can greatly impact prognosis. In AML, patients with CSF3R mutations exhibit high relapse rates and poor overall survival. A recent study found that 90.5% of patients with CSF3R mutations had cooccurring RUNX1-ETO (8;21), CBFB-MYH11, or CEBPA mutations7. The RUNX1-ETO and CBFB-MYH11 translocations disrupt the core binding factor complex, an important transcriptional regulator in myeloid development. In this study, we evaluated how RUNX1-ETO modifies CSF3RT618I-driven transcriptional changes to promote the production of myeloblasts in AML. We find that RUNX1-ETO accelerates CSF3R-driven oncogenesis both in vitro and in vivo. Furthermore, RUNX1-ETO impairs the ability of CSF3R to drive myeloid differentiation associated transcriptional programs resulting in the production of immature myeloblasts which characterize this disease.

2023-10-11 | GSE218829 | GEO

RUNX1::ETO translocations must precede CSF3R mutations to promote acute myeloid leukemia development.

Project description: Not available

| S-EPMC10544281 | 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

The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle regulation to Drive Leukemic Transformation [HiC]

Project description:Oncogenic transcription factors such as the leukaemic fusion protein RUNX1/ETO constitute cancer-specific but highly challenging therapeutic targets, whose functions depend on pharmacologically tractable downstream pathways. Here we interrogated the transcriptional network of RUNX1/ETO in an in vitro/in vivo RNAi screen and identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO drives CCND2 expression by binding to a regulatory element upstream of the CCND2 promoter. Both knockdown of CCND2 and treatment with the CDK4/6 inhibitor palbociclib inhibited leukemic expansion patient-derived AML cells and impaired engraftment of immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO drives leukaemia by directly promoting cell cycle progression and establish inhibition of G1 CCND-CDK complexes as a promising therapeutic strategy for RUNX1/ETO-driven AML.

2019-04-12 | GSE117107 | GEO

The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle regulation to Drive Leukemic Transformation [ChIP]

2019-04-12 | GSE117105 | GEO

CSF3R T618I collaborates with RUNX1-RUNX1T1 to expand hematopoietic progenitors and sensitizes to GLI-inhibition

Project description:Activating CSF3R mutations are recurrent in AML with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations of CSF3R and the t(8;21) associated RUNX1-RUNX1T1 fusion remains unclear. In CD34+ hematopoietic stem and progenitor cells from healthy donors, double oncogene expression led to a clonal advantage, increased self-renewal potential, as well as blast-like morphology and distinct immunophenotype. Gene expression profiling revealed hedgehog-signaling as a potential mechanism, with upregulation of GLI2 constituting a putative pharmacological target. Both primary hematopoietic cells and the t(8;21) positive AML cell line SKNO-1 showed increased sensitivity to the GLI-inhibitor GANT61 when expressing CSF3R T618I. Our findings suggest that during leukemogenesis the RUNX1-RUNXT1 fusion and CSF3R mutation act in a synergistic manner to alter hedgehog signaling which can be exploited therapeutically.

2023-10-18 | GSE230755 | GEO

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

RUNX1/ETO role's in hematopoietic system

Project description:RUNX1/ETO role's in hematopoietic system

| PRJNA271475 | ENA

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.

2017-06-26 | GSE87285 | GEO

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