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Destabilization of AETFC through C/EBPalpha-mediated repression of LYL1 contributes to t(8 21) leukemic cell differentiation

ABSTRACT: Destabilization of AETFC through C/EBPalpha-mediated repression of LYL1 contributes to t(8 21) leukemic cell differentiation

PROVIDER: PRJNA472044 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7182880_1.fastq.gz	Fastqsanger.gz
	SRR7182880_2.fastq.gz	Fastqsanger.gz
	SRR7182881_1.fastq.gz	Fastqsanger.gz
	SRR7182881_2.fastq.gz	Fastqsanger.gz
	SRR7182882_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Destabilization of AETFC through C/EBPalpha-mediated repression of LYL1 contributes to t(8;21) leukemic cell differentiation

Project description:In t(8;21) leukemic cells, the leukemogenic fusion protein AML1-ETO is stabilized and functions through the AML1-ETO-containing transcription factor complex (AETFC). Destabilization of AETFC thus provides a strategy to target AML1-ETO. In this study, we found that AETFC can be destabilized by a specific mechanism involving a direct repression of the core component LYL1 by C/EBPalpha at transcriptional level. We performed a ChIP-seq analysis of the genome-wide occupancy of C/EBPalpha and identifeid a -1 kb C/EBPalpha-binding site in the LYL1 locus that mediate this repression. As LYL1 acts as a linker between the AML1-ETO-E and LMO2-LDB1 parts of AETFC, depletion of LYL1 causes a destabilization of AETFC, which increases susceptibility of the leukemic cells to differentiation. Our results have provided a novel mechanism by which C/EBPalpha can directly destabilize AETFC, and have identified LYL1 as a new therapeutic target for treatment of t(8;21) leukemia.

2019-02-19 | GSE114642 | GEO

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML [RNA-seq]

Project description:Transcription factors (TFs) play critical roles in hematopoiesis, and their aberrant expression can lead to various types of leukemia. The t(8;21) leukemogenic fusion protein AML1-ETO (AE) is the most common fusion protein in acute myeloid leukemia and can enhance hematopoietic stem cell renewal while blocking differentiation. A key question in understanding AE-mediated leukemia is what determines the choice of AE to activate self-renewal genes or repress differentiation genes. Toward the resolution of this problem, we earlier showed that AE resides in the stable AETFC complex and that its components co-localize on up- or down-regulated target genes and are essential for leukemogenesis. In the current study, using biochemical and genomic approaches, we show that AE-containing complexes are heterogeneous, and that assembly of the larger AETFC (containing AE, HEB, E2A, LYL1, LMO2 and LDB2) requires LYL1. Furthermore, we provide strong evidence that the LYL1-containing AETFC preferentially binds to active enhancers and promotes AE-dependent gene activation. Moreover, we show that coactivator CARM1 interacts with AETFC and facilitates gene activation by AETFC. Collectively, this study describes a novel role of oncoprotein LYL1 in AETFC assembly and gene activation by recruiting CARM1 to chromatin for AML cell survival.

2022-11-10 | GSE207233 | GEO

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML [CHIP-seq]

2022-11-10 | GSE207232 | GEO

Destabilization of AETFC through C/EBPα-mediated repression of LYL1 contributes to t(8;21) leukemic cell differentiation.

Project description: Not available

| S-EPMC6880927 | biostudies-literature

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

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8 21) AML.

Project description:LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8 21) AML.

| PRJNA854203 | ENA

Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis

Project description:The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases. In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AETFC, that contains multiple transcription (co)factors. Among these AETFC components, HEB and E2A, two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA-binding capacity to AETFC, and are essential for leukemogenesis. However, the third E protein, E2-2, is specifically silenced in AML1-ETO–expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO–expressing leukemic cells, and this inhibition requires the bHLH DNA-binding domain. RNA-seq and ChIP-seq analyses reveal that, despite overlapping to some extent, the three E proteins differentially regulate many target genes, and, in particular, that E2-2 both redistributes AETFC to, and activates, some genes associated with dendritic cell differentiation. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene, THPO, is identified as a potential predictor of relapse. In a mouse model of human t(8;21) leukemia, E2-2 suppression accelerates leukemogenesis. Taken together, these results reveal that, in contrast to HEB and E2A, which facilitate AML1-ETO–mediated leukemogenesis, E2-2 compromises the function of AETFC and acts as a negative regulator of leukemogenesis. The three E proteins thus define a heterogeneity of AETFC, which improves our understanding of the precise mechanism of leukemogenesis and assists development of diagnostic/therapeutic strategies.

2018-12-14 | GSE114644 | GEO

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8 21) AML [RNA-seq]

Project description:LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8 21) AML [RNA-seq]

| PRJNA854206 | ENA

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8 21) AML [CHIP-seq]

Project description:LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8 21) AML [CHIP-seq]

| PRJNA854207 | ENA

LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML.

Project description:Transcription factors (TFs) play critical roles in hematopoiesis, and their aberrant expression can lead to various types of leukemia. The t(8;21) leukemogenic fusion protein AML1-ETO (AE) is the most common fusion protein in acute myeloid leukemia and can enhance hematopoietic stem cell renewal while blocking differentiation. A key question in understanding AE-mediated leukemia is what determines the choice of AE to activate self-renewal genes or repress differentiation genes. Toward the resolution of this problem, we earlier showed that AE resides in the stable AETFC complex and that its components colocalize on up- or down-regulated target genes and are essential for leukemogenesis. In the current study, using biochemical and genomic approaches, we show that AE-containing complexes are heterogeneous, and that assembly of the larger AETFC (containing AE, CBFβ, HEB, E2A, LYL1, LMO2, and LDB1) requires LYL1. Furthermore, we provide strong evidence that the LYL1-containing AETFC preferentially binds to active enhancers and promotes AE-dependent gene activation. Moreover, we show that coactivator CARM1 interacts with AETFC and facilitates gene activation by AETFC. Collectively, this study describes a role of oncoprotein LYL1 in AETFC assembly and gene activation by recruiting CARM1 to chromatin for AML cell survival.

| S-EPMC9586329 | biostudies-literature

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