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C/EBPα overexpression overrides epigenetic reprogramming by RUNX1-ETO and RUNX1-EVI1 [ChIP-seq]

ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous disease caused by recurrent mutations in the transcription regulatory machinery. As a result, malignant myeloid cells display abnormal growth and are blocked in differentiation. One type of recurrent mutations affects RUNX1 which is subject to mutations and translocations, the latter giving rise to fusion proteins with aberrant transcriptional activities. We recently compared the mechanism by which the products of the t(8;21) and the t(3;21) translocation RUNX1-ETO and RUNX1-EVI1 globally reprogram the epigenome. We demonstrated that a main component of the block in differentiation in both types of AML is direct repression of the gene encoding for the crucial myeloid regulator C/EBPα by both fusion proteins. We also showed that CEBPA upregulation is required for the release of the differentiation block after oncogene knock-down. In the study presented here we examined at the global level the response of t(8;21) and t(3;21) cells to C/EBPα overexpression. We show that C/EBPα overexpression does not change oncoprotein expression or globally displace these proteins from their binding sites, but up-regulates a core set of common target genes important for myeloid differentiation and interferes with leukemic growth, highlighting CEBPA regulated pathways as targets for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE102697 | GEO | 2018/04/30

REPOSITORIES: GEO

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C/EBPα overexpression overrides epigenetic reprogramming by RUNX1-ETO and RUNX1-EVI1 [RNA-seq]

Project description:Acute myeloid leukemia (AML) is a heterogeneous disease caused by recurrent mutations in the transcription regulatory machinery. As a result, malignant myeloid cells display abnormal growth and are blocked in differentiation. One type of recurrent mutations affects RUNX1 which is subject to mutations and translocations, the latter giving rise to fusion proteins with aberrant transcriptional activities. We recently compared the mechanism by which the products of the t(8;21) and the t(3;21) translocation RUNX1-ETO and RUNX1-EVI1 globally reprogram the epigenome. We demonstrated that a main component of the block in differentiation in both types of AML is direct repression of the gene encoding for the crucial myeloid regulator C/EBPα by both fusion proteins. We also showed that CEBPA upregulation is required for the release of the differentiation block after oncogene knock-down. In the study presented here we examined at the global level the response of t(8;21) and t(3;21) cells to C/EBPα overexpression. We show that C/EBPα overexpression does not change oncoprotein expression or globally displace these proteins from their binding sites, but up-regulates a core set of common target genes important for myeloid differentiation and interferes with leukemic growth, highlighting CEBPA regulated pathways as targets for therapeutic intervention.

2018-04-30 | GSE102730 | 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 (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

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

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 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

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-EVI1 disrupts lineage determination and the cell cycle by interfering with RUNX1 and EVI1 driven gene regulatory networks [RNA-seq]

Project description:Hematological malignancies are characterised by a block in differentiation, which is in many cases caused by recurrent mutations affecting the activity of hematopoietic transcription factors. RUNX1-EVI1 is a fusion protein formed by the t(3;21) translocation linking two transcription factors required for normal hematopoiesis. RUNX1-EVI1 is found in myelodysplastic syndrome, secondary acute myeloid leukemia, and blast crisis of chronic myeloid leukemia; with clinical outcomes being worse than in patients with RUNX1-ETO, RUNX1 or EVI1 mutations alone. As RUNX1-EVI1 is usually found as a secondary mutation, the molecular mechanisms underlying how RUNX1-EVI1 alone contributes to poor prognosis are not well understood. To address this question, we induced expression of RUNX1-EVI1 at the onset of hematopoiesis and in progenitor cells derived from an embryonic stem cell differentiation model. Induction resulted in disruption of the RUNX1-dependent endothelial-hematopoietic transition, blocked the cell cycle and undermined cell fate decisions in multipotent hematopoietic progenitor cells. Integrative analyses of gene expression with the chromatin and transcription factor binding landscape demonstrated that RUNX1-EVI1 binding caused the re-distribution of endogenous RUNX1 within the genome and interfered with both RUNX1 and EVI1 regulated gene expression programs. In summary, RUNX1-EVI1 expression alone leads to extensive epigenetic reprogramming which is incompatible with healthy blood production and thus is only compatible with a pre-transformed cellular context.

2020-04-17 | GSE143459 | GEO

RUNX1-EVI1 disrupts lineage determination and the cell cycle by interfering with RUNX1 and EVI1 driven gene regulatory networks [DNaseI-seq]

2020-04-17 | GSE143458 | GEO

RUNX1-EVI1 disrupts lineage determination and the cell cycle by interfering with RUNX1 and EVI1 driven gene regulatory networks [ChIP-seq]

2020-04-17 | GSE143457 | GEO

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]

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. 14 samples include: RUNX1 Kasumi-1, RUNX1/ETO control, RUNX1/ETO siMM, RUNX1/ETO siRE, RUNX1_non-t(8;21), H3K9Ac_siMM, H3K9Ac_siRE, POLII_siMM and POLII_siRE ChIP-Seq samples, and Kasumi-1, non-t(8;21), t(8;21) paitent#1, t(8;21) paitent#2 and CD34 normal DNasel HS samples.

2012-03-27 | E-GEOD-29222 | biostudies-arrayexpress

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