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Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7 12)(q36 p13)

ABSTRACT: Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7 12)(q36 p13)

PROVIDER: PRJNA1022491 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26213523_1.fastq.gz	Fastqsanger.gz
	SRR26213523_2.fastq.gz	Fastqsanger.gz
	SRR26213524_1.fastq.gz	Fastqsanger.gz
	SRR26213524_2.fastq.gz	Fastqsanger.gz
	SRR26213525_1.fastq.gz	Fastqsanger.gz

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Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13) [HiC]

Project description:Acute myeloid leukemia (AML) with translocation t(7;12)(q36;p13) is a subgroup that occurs only in infants or very young children and is characterised by a poor outcome. Deep molecular characterization has been hampered by the rarity of this AML subtype and the lack of model systems. Approximately 50% of AML with t(7;12)(q36;p13) express an MNX1::ETV6 oncofusion transcript, but there is no evidence for the presence of an oncofusion protein. However, a universal feature is the strong RNA and protein expression of MNX1, a homeobox transcription factor that is normally not transcribed in haematopoietic cells. Here we use whole genome sequencing data to precisely map the translocation breakpoints on chromosomes 7 and 12 in these pediatric AML patients to a region downstream of MNX1 on chromosome 7 and either introns 1 or 2 of ETV6 on chromosome 12. We confirm the tight correlation of MNX1 overexpression in t(7;12)(q36;p13) AML in our own samples and three additional cohorts of pediatric AML. Using a CRISPR-engineered iPSC cell line, ChiPSC22t(7;12), harbouring the t(7;12)(q36;p13) translocation, we unravel an enhancer-hijacking event leading to MNX1 overexpression. Identification of hematopoietic enhancer regions in hematopoietic stem and progenitor cells derived from differentiated ChiPSC22t(7;12) cells allowed us to demonstrate their importance for MNX1 expression in knock-out experiments and by measuring the promoter-enhancer distance in confocal microscopy. In contrast to the prevailing dogma in AML, suggesting that translocations lead to the creation of oncofusion genes, t(7;12)(q36;p13) AML is characterized by an enhancer-hijacking event driving MNX1, a novel leukemia oncogene and the haploinsufficiency of ETV6.

2024-08-21 | GSE244277 | GEO

Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13) [4C-Seq]

2024-08-21 | GSE244275 | GEO

Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13) [ATAC-Seq]

2024-08-21 | GSE244274 | GEO

Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13) [ACT-Seq]

2024-08-21 | GSE244446 | GEO

Mnx1 Induces Leukemia Transformation Through Altering Histone Methylation in a Model of Pediatric t(7;12) Acute Myeloid Leukemia

Project description:Acute myeloid leukemia (AML) in children with cytogenetic aberrations like translocation t(7;12)(q36;p13) is associated with inferior outcome. The translocation can lead to a fusion transcript MNX1::ETV6 but also to activation of MNX1 transcription. We generated an AML mouse model by transplantation of fetal liver cells with ectopic expression of MNX1. AML was highly penetrant in immunocompromised and less penetrant in immunocompetent mice. Transforming capacity was restricted to fetal liver cells and could not achieved with adult bone marrow cells, in concordance with the clinical finding that t(7;12)(q36;p13) is mostly restricted to infants. Ectopic expression of MNX1 led to increased H3K4methylation and reduced H3K27me3, possibly through its interaction with methyl transferases. MNX1 expression was accompanied with changes in genome wide chromatin accessibility , increased DNA damage, depletion in the LSK population and skewing toward the myeloid lineage. These effects, together with leukemia development, could be prevented by the S-adenosylmethionine analogue Sinefungin that acts as a SAM competitor and a pan methyltranferases inhibitor. Expression profiles of a human iPSC AML model with t(7;12) and of TARGET pediatric AML and TCGA patients support the rationale for targeting MNX1 and downstream pathways.

2024-09-30 | PXD034416 | Pride

Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7 12)(q36 p13) [4C-Seq]

Project description:Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7 12)(q36 p13) [4C-Seq]

| PRJNA1022053 | ENA

Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7 12)(q36 p13) [ATAC-Seq]

Project description:Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7 12)(q36 p13) [ATAC-Seq]

| PRJNA1022052 | ENA

Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7 12)(q36 p13) [ACT-Seq]

Project description:Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7 12)(q36 p13) [ACT-Seq]

| PRJNA1023180 | ENA

Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-08-21 | GSE244379 | GEO

Epigenetic profiling of mouse hematopoietic cells retrovirally transfected with MNX1 or empty vector (Ctr) from fetal liver or mouse bone marrow [ACT-seq]

Project description:Acute myeloid leukemia (AML) results from aberrant hematopoietic processes and these changes are frequently initiated by chromosomal translocations. One particular subtype, AML with translocation t(7;12)(q36;p13), is found in children diagnosed before two years of age. The chromosomal breakage points of the t(7;12) have consistently been found to be located after exon 1 in the Motor neuron and pancreas homeobox 1 (MNX1) gene in chromosome 7, and after exon 2 in the ETV6 gene in chromosome 12. The aim of this study is the investigation of the leukomogenic potenial of MNX1 overexpression and MNX1-ETV6 fusion using mouse models, in addition to the molecular pathway through which MNX1 is inducing leukemia.

2022-06-14 | GSE205696 | GEO

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