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Definition of a Small Core Transcriptional Circuit Regulated by AML1-ETO [ChIP-seq, Cut&Run]

ABSTRACT: Transcription factors regulate gene networks controlling normal hematopoiesis and are frequently deregulated in acute myeloid leukemia (AML). Critical to our understanding of the mechanism of cellular transformation by oncogenic transcription factors is the ability to define their direct gene targets. However, gene network cascades can change within minutes to hours, making it difficult to distinguish direct from secondary or compensatory transcriptional changes by traditional methodologies. Utilizing CRISPR-based genome editing, we inserted a degron tag into the endogenous AML1-ETO locus of Kasumi-1 cells, as well as overexpressed a degradable AML1-ETO protein in CD34+ human cord blood cells. This allowed rapid AML1-ETO protein degradation upon addition of a proteolysis targeting chimera (PROTAC). Furthermore, by combining rapid degradation with nascent transcript analysis (PRO-seq), RNA-seq and Cut&Run, we have defined the core AML1-ETO regulatory network. De-repression of this small set of genes set off a cascade of transcriptional events resulting in myeloid differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153279 | GEO | 2020/12/31

REPOSITORIES: GEO

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Definition of a Small Core Transcriptional Circuit Regulated by AML1-ETO [PRO-seq]

Project description:Transcription factors regulate gene networks controlling normal hematopoiesis and are frequently deregulated in acute myeloid leukemia (AML). Critical to our understanding of the mechanism of cellular transformation by oncogenic transcription factors is the ability to define their direct gene targets. However, gene network cascades can change within minutes to hours, making it difficult to distinguish direct from secondary or compensatory transcriptional changes by traditional methodologies. Utilizing CRISPR-based genome editing, we inserted a degron tag into the endogenous AML1-ETO locus of Kasumi-1 cells, as well as overexpressed a degradable AML1-ETO protein in CD34+ human cord blood cells. This allowed rapid AML1-ETO protein degradation upon addition of a proteolysis targeting chimera (PROTAC). Furthermore, by combining rapid degradation with nascent transcript analysis (PRO-seq), RNA-seq and Cut&Run, we have defined the core AML1-ETO regulatory network. De-repression of this small set of genes set off a cascade of transcriptional events resulting in myeloid differentiation.

2020-12-31 | GSE153267 | GEO

Definition of a Small Core Transcriptional Circuit Regulated by AML1-ETO [RNA-seq]

2020-12-31 | GSE153264 | GEO

Definition of a Small Core Transcriptional Circuit Regulated by AML1-ETO [ChIP-seq and CUT&RUN]

2020-12-31 | GSE160242 | GEO

Paired ChIP-Seq studies of Kasumi-1 t(8;21) AML cells

Project description:Nearly 10-15% of all acute myeloid leukemia (AML) cases are caused by a recurring chromosomal translocation between 8 and 21, t(8;21). The t(8;21) translocation generates the AML1-ETO leukemia fusion protein. AML1-ETO promotes leukemogenesis by transcriptionally dysregulating important cell-fate genes. Here, to better understand how AML1-ETO deregulates transcription, we performed paired ChIP-Seq analyses of sequence-specific transcription factors, coactivators, corepressors, HDACs, RNA Pol II and acetyl-histone marks in both control and AML1-ETO-depleted Kasumi-1 t(8;21) AML cells.

2020-02-14 | GSE131939 | GEO

Genome-wide studies identify a novel interplay between AML1 and AML1/ETO in t(8;21) acute myeloid leukemia

Project description:The AML1/ETO fusion protein is essential to the development of acute myeloid leukemia (AML), and is well recognized for its dominant-negative effect on the co-existing wild-type protein AML1. However, the involvement of wild-type AML1 in AML1/ETO-driven leukemogenesis remains elusive. Through chromatin immunoprecipitation sequencing, computational analysis plus a series of experimental validations, we report here that AML1 is able to orchestrate the expression of AML1/ETO targets regardless of being activated or repressed, via forming a complex with AML1/ETO and via recruiting the cofactor. 4 ChIP-seq assays were used to identify the high confidence binding regions of AML1-ETO and AML1 in t(8;21) AML Kasumi-1 cell lines. The anti-AML1 (N20) antibody targets the N-terminus of AML1 and recognizes both AML1 and AML1/ETO; the anti-AML1 (C19) antibody targets the C-terminus of AML1 and recognizes AML1 but not AML1/ETO; the anti-ETO (C20) antibody targets the C-terminus of ETO and specifically recognizes AML1/ETO. 2 ChIP-seq assays were used to identify the binding regions of AML1 in human macrophage U937 cell lines. And the total input was used as control.

2015-11-04 | E-GEOD-65427 | biostudies-arrayexpress

A Stable Transcription Factor Complex Nucleated by Dimeric AML1-ETO Controls Leukaemogenesis

Project description:AML1-ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukemia, is a transcription factor implicated in both gene repression and activation. We now show that, in leukemic cells, AML1-ETO resides in and functions through a stable protein complex (AETFC) that contains several hematopoietic transcription factors and cofactors. In conjunction with biochemical and leukemia pathological studies, the ChIP-seq and RNA-seq analyses of the AETFC components in leukemic cells reveal that these components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, colocalize genome-wide, cooperatively regulate gene expression, and contribute to leukemogenesis. RNA-seq analyses gene expression upon knockdown of each AETFC component, including AML1-ETO, HEB, E2A, LYL1, LDB1 and LMO2, and double-knockdown of HEB and E2A, in Kasumi-1 cells. ChIP-seq analyses of four AETFC components, namely AML1-ETO, HEB, E2A and LMO2, in Kasumi-1 cells.

2013-06-20 | E-GEOD-43834 | biostudies-arrayexpress

Kasumi-1 AML1-ETO knockdown samples

2009-05-01 | GSE15646 | GEO

RNAi profiling of human Kasumi-1 AML1-ETO knockdown samples

Project description:Kasumi-1 AML cells that were transfected in triplicate with AML1-ETO or luciferase siRNA constructs by either Amaxa nucleofection or Biorad siLentFect and incubated for 96 hours. Microarrays used to discover an AML1-ETO signature for a GE-HTS screen to identify AML1-ETO modulators. Experiment Overall Design: Kasumi-1 AML cells incubated for 96 hours after they were transfected in triplicate with AML1-ETO or luciferase siRNA constructs by either Amaxa nucleofection or Biorad siLentFect along with three control samples not transfected with a construct.

2009-05-11 | E-GEOD-15646 | biostudies-arrayexpress

Genome-wide map of JMJD1C binding in Kasumi-1 cells [ChIP-seq]

Project description:The AML1-ETO fusion protein, a transcription factor generated by the t(8;21) translocation in acute myeloid leukaemia (AML), dictates a leukemic program by increasing self-renewal and inhibiting differentiation. Here we demonstrate that the histone demethylase JMJD1C functions as a co-activator for AML1-ETO and is required for its transcriptional program. JMJD1C is directly recruited by AML1-ETO to its target genes and regulates their expression by maintaining low H3K9me2 levels. Analyses in JMJD1C knockout mice also establish a JMJD1C requirement for AML1-ETOâs ability to increase proliferation. We also show a critical role for JMJD1C in the survival of multiple human AML cell lines, suggesting that it is required for leukemic programs in different AML cell types through its association with key transcription factors. Examination of JMJD1C and LYL1 chromatin binding in Kasumi-1 cells, HL-60 cells, NB-4 cells and THP-1 cells, including ChIP-seqs of JMJD1C and LYL1, and input DNAs for Kasumi-1, HL-60, NB4.

2015-11-02 | E-GEOD-63484 | biostudies-arrayexpress

MEIS2 is a novel oncogenic partner in AML1-ETO positive AML [RNA-Seq human]

Project description:MEIS2 collaborates with AML1-ETO in inducing acute myeloid leukemia in a murine bone marrow transplantation model RNA-seq to evaluate consequence of MEIS2 Knock-down on the transcriptional profle of the t(8;21) positive Kasumi-1 cell line

2016-07-04 | E-GEOD-81328 | biostudies-arrayexpress

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