Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The homeobox transcription factor HB9 induces senescence and blocks differentiation in hematopoietic stem and progenitor cells

ABSTRACT: The translocation t(7;12)(q36;p13) occurs in infants and very young children with AML and usually has a fatal prognosis. Whereas the transcription factor ETV6, located at chromosome 12p13, has largely been studied in different leukemia types, the influence of the translocation partner HB9 (chr. 7q36), is still unknown. This is particularly surprising as ectopic expression of HB9 is the only recurrent molecular hallmark of translocation t(7;12) AML. We investigated the influence of HB9 as a potential oncogene on cell proliferation and cell cycle in vitro, as well as on hematopoietic stem cell differentiation in vivo using murine and human model systems. We show, that HB9 induces premature senescence in human HT1080 and murine NIH3T3 cells, providing for the first time evidence for an oncogenic potential of HB9. Furthermore, HB9-transduced primary murine hematopoietic stem and progenitor cells underwent a profound differentiation arrest and accumulated at the megakaryocyte/erythrocyte progenitor stage, resulting in a premalignant myeloid cell population in vivo. Concomitantly, HB9 expression upregulates erythropoiesis-related genes in primary human hematopoietic stem and progenitor cells, and enriches gene expression profiles for cell cycle and mitosis-related biological processes. In summary, the novel findings of HB9 dependent premature senescence and perturbed hematopoietic differentiation shed light on the oncogenic properties of HB9 in translocation t(7;12) AML and offer novel targets for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117060 | GEO | 2018/07/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

An induced pluripotent stem cell t(7;12)(q36;p13) acute myeloid leukemia model shows high expression of MNX1 and a block in differentiation of the erythroid and megakaryocytic lineages

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 mechanisms for leukemogenesis induced by t(7;12) is not understood, in part because of the lack of efficient methods to reconstruct the leukemia-associated genetic aberration with correct genomic architecture and regulatory elements. We therefore created induced pluripotent stem cell (iPSC) lines that carry the translocation t(7;12) using CRISPR/Cas9. These t(7;12) iPSC showed propensity to differentiate into all three germ layers, confirming retained stem cell properties. The potential for differentiation into hematopoietic stem and progenitor cells (HSPC) was shown by expression of CD34, CD43 and CD45. Compared with the parental iPSC line, a significant decrease in cells expressing CD235a and CD41a was seen in the t(7;12) iPSC derived HSPC (iHSPC), suggesting a block in differentiation. Moreover, colony formation assay showed an accumulation of cells at the erythroid and myeloid progenitor stages. Gene expression analysis revealed significant down-regulation of genes associated with myeloid differentiation and megakaryocyte differentiation pathways. Compared with the parental iHSPC the t(7;12) iHSPC expressed high levels of MNX1, a characteristic strongly associated with pediatric AML with t(7;12). Thus, we have created an iPSC t(7;12) leukemia model that has strong similarities with the t(7;12) AML subtype and therefore constitutes a valuable tool for further studies of the mechanisms for leukemia development to find new treatment options.

2022-04-30 | GSE182168 | GEO

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

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 | GSE244446 | GEO

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

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

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

The protein interactomes of Acute Myeloid Leukemia-associated oncogenic fusion proteins predict potential mechanisms of action

Project description:TurboID (biotin proximity ligase) was fused to AML-associated oncofusions (PML::RARA, RUNX1::RUNX1T1, CBFB::MYH11), wildtype NPM1, or mutated NPMc and expressed in murine hematopoietic stem/progenitor cells using MSCV-based retroviruses to identify key interacting proteins in primary hematopoietic cells.

2023-08-07 | MSV000092615 | MassIVE

Next Generation Sequencing of mouse hematopoietic cells retrovirally transfected with MNX1 or empty vector (Ctr) from fetal liver or mouse bone marrow and treated with or without pan-inhibitor against SAM-dependent methyltransferases Sinefungin

2022-06-14 | GSE202137 | GEO

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

2022-06-14 | GSE205697 | GEO

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

2022-06-14 | GSE205696 | GEO