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RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8 21) AML (ATAC-Seq)

ABSTRACT: RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8 21) AML (ATAC-Seq)

PROVIDER: PRJNA639043 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12002912.fastq.gz	Fastqsanger.gz
	SRR12002913.fastq.gz	Fastqsanger.gz
	SRR12002914.fastq.gz	Fastqsanger.gz

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RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML (RNA-Seq)

Project description:Acute myeloid leukemia development occurs in a step-wise fashion whereby an original driver mutation is followed by additional mutations. The first type of mutations tends to be in genes encoding members of the epigenetic/transcription regulatory machinery (i.e. RUNX1, DNMT3, TET2), while the secondary mutations often involve genes encoding members of signalling pathways that cause uncontrolled growth of such cells such as the growth factor receptors c-KIT of FLT3. Patients usually present with both types of mutations, but it is currently unclear how both mutational events shape the epigenome in developing AML cells. To this end we generated an in vitro model of t(8;21) AML by expressing its driver oncoprotein RUNX1-ETO with or without a mutated (N822K) KIT protein. The expression of N822K–c-KIT strongly increases the self-renewal capacity of RUNX1-ETO expressing cells. Global analysis of gene expression changes and alterations in the epigenome show that N822K–c-KIT expression profoundly influences the open chromatin landscape and transcription factor binding. However, our experiments also show that double mutant cells still differ from their patient derived counterparts, highlighting the importance of studying patient cells to obtain a true picture of how gene regulatory networks have been reprogrammed during tumourigenesis.

2021-04-01 | GSE152334 | GEO

RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML (ChIP-Seq)

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RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML (ATAC-Seq)

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RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8 21) AML

Project description:RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8 21) AML

| PRJNA639040 | ENA

RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8 21) AML (RNA-Seq)

Project description:RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8 21) AML (RNA-Seq)

| PRJNA639045 | ENA

RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8 21) AML (ChIP-Seq)

Project description:RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8 21) AML (ChIP-Seq)

| PRJNA639044 | 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.

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.

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

2019-04-12 | GSE117105 | 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

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