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Gene expression profiling of control and Meis1 deleted bone marrow

ABSTRACT: The transcription factor Meis1 is preferentially expressed in hematopoietic stem cells (HSCs) and over-expressed in certain leukemias. However, the functions of Meis1 in hematopoiesis remain largely unknown. Using inducible knock-out mice, we found that Meis1 is required for the maintenance of hematopoiesis under stress and over long term while steady-state hematopoiesis was sustained in the absence of Meis1. Bone marrow cells of Meis1 deficient mice showed reduced colony formation, contained significantly fewer numbers of long- term HSCs and these Meis1-deficient HSCs exhibited loss of quiescence. Further, we found that Meis1 deletion led to the accumulation of reactive oxygen species (ROS) in HSCs and decreased expression of genes implicated in hypoxia response. Finally, ROS scavenging by N-acetyl cysteine or stabilization of hypoxia-signaling by knockdown of the VHL protein led to reversal of the effects of Meis1-deletion. Taken together, these results demonstrate that Meis1 protects and preserves HSCs by restricting oxidative metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE41133 | GEO | 2012/09/26

SECONDARY ACCESSION(S): PRJNA175874

REPOSITORIES: GEO

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Gene expression profiling of control and Meis1 deleted bone marrow

Project description:The transcription factor Meis1 is preferentially expressed in hematopoietic stem cells (HSCs) and over-expressed in certain leukemias. However, the functions of Meis1 in hematopoiesis remain largely unknown. Using inducible knock-out mice, we found that Meis1 is required for the maintenance of hematopoiesis under stress and over long term while steady-state hematopoiesis was sustained in the absence of Meis1. Bone marrow cells of Meis1 deficient mice showed reduced colony formation, contained significantly fewer numbers of long- term HSCs and these Meis1-deficient HSCs exhibited loss of quiescence. Further, we found that Meis1 deletion led to the accumulation of reactive oxygen species (ROS) in HSCs and decreased expression of genes implicated in hypoxia response. Finally, ROS scavenging by N-acetyl cysteine or stabilization of hypoxia-signaling by knockdown of the VHL protein led to reversal of the effects of Meis1-deletion. Taken together, these results demonstrate that Meis1 protects and preserves HSCs by restricting oxidative metabolism. Lineage negative cells were harvested from Meis1-flox/CreER or control mice and incubated with 4-OHT for 48 hours. Total RNA was extracted and used for the profiling experiment.

2012-09-26 | E-GEOD-41133 | biostudies-arrayexpress

Gene expression signatures of Meis1 conditional knockout hematopoietic stem cells

Project description:Meis1 encodes a TALE family homeodomain protein that was first identified as a common retroviral integration site in mouse BHX2 myeloid leukemia. It functions as a DNA binding co-factor of Hox proteins through interacting with Pbx, a member of another TALE family protein. Moreover, Meis1 homozygous knockout mice are embryonic lethal, showing significant defects in vasculogenesis, eye development and hematopoiesis. Severe defects were also observed in adult hematopoiesis by conditional inactivation of Meis1 in vivo. Meis1 is critical to maintain the balance between enter and exit from cell cycles of hematopoietic stem cells (HSCs), indicating that Meis1 regulates self-renewal and quiescence of HSCs. Total RNA was isolated from KSL cells obtained from poly(I:C)-treated Mx1-Cre Meis1fl/fl and sham-treated Meis1fl/fl mice.

2013-12-01 | E-GEOD-38336 | biostudies-arrayexpress

Gene expression signatures of Meis1 conditional knockout hematopoietic stem cells

2013-12-01 | GSE38336 | GEO

MEIS1-HLF axis regulates oxidative metabolism and is essential for MLL-fusion gene leukemia

Project description:The pathogenesis of MLL-fusion gene leukemias has been linked to upregulated expression of HOX genes and of the HOX-cofactor Meis1.The functions of the HOX/MEIS1 complex in leukemia however remain unclear. Here, we used inducible MEIS1-knockout mice coupled with MLL-AF9 knockin mice to decipher the role of MEIS1 in leukemia. We found that MEIS1 was critically required for established leukemia. Further, MEIS1 loss led to increased oxygen flux and apoptosis, while hypoxia reversed these effects. Finally, we identify HLF as a downstream mediator of MEIS1 in leukemia. Overexpression of HLF prevents oxygen flux and rescues the leukemia phenotype in MEIS1-deficient cells. Thus, the oncogenic effects of MEIS1 are at least partly mediated by an HLF-driven hypoxic state.

2015-05-21 | GSE58732 | GEO

MEIS1 regulates hematopoiesis in hPSCs

Project description:MEIS1 regulates hematopoiesis in hPSCs

| PRJNA357013 | ENA

Identification of gene targets of Meis1

2012-08-03 | GSE34543 | GEO

Meis1 deficiency effect on thymic epithelial cells

Project description:Analysis of thymic epithelial cells lacking Meis1 gene using K14-CreERT2 Meis1fl/fl mice. Meis1 is a TALE class homeodomain transcription factor that critically regulates numerous embryonic developmental processes. Results provide insight into the role of Meis1 in the maintenance of postnatal thymic epithelial cells. Meis1-regulated gene expression in CD45- EpCAM+ mouse thymic epithelial cells was measured at 4 days after the induction of Meis1 deletion. Two independent experiments (pools of 6 mice; 2 pools per genotype) were performed.

2012-11-30 | E-GEOD-30824 | biostudies-arrayexpress

Identification of gene targets of Meis1

Project description:The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Our present study suggested it exerts two distinguishable effects in differentiating ES cells. First, it increases the numbers of hematopoietic progenitors and extends their persistence in culture. Second, Meis1 skews hematopoietic differentiation by suppressing erythroid while enhancing megakaryocytic progenitor differentiation. To identify the underlying transcriptional bases of these actions, we carried out microarray analysis to compare the various populations of cells developing in ES differentiation cultures in the presence and absence of Meis1 induction. ES cells with dox-inducible Meis1 (A2lox.Meis1) were differentiated as embryoid bodies (EBs) for 6 days before plating on OP9-GFP cell monolayers and cytokines, and treated with (+) or without (-) doxycycline (dox). Cells were purified by cell sorting on day 7 or 8 into various populations based on levels of CD41 expression: GFP-CD41-, GFP-CD41+ (day 7) and GFP-CD41-,GFP-CD41int, and GFP-CD41hi (day 8). Gene expression of these purified populations was determined by microarray analysis.

2012-08-02 | E-GEOD-34543 | biostudies-arrayexpress

Meis1 genomics

Project description:Meis1 function in leukemogenesis

| PRJEB50012 | ENA

Hoxa9/meis1-transgenic zebrafish develops acute myeloid leukemia-like disease with rapid onset and high-penetrance

Project description:HOXA9/MEIS1 plays a synergistic causative role and overexpresses frequently in acute myeloid leukemia (AML). Hoxa9/Meis1 transgenic murine results in rapid leukemic transformation of primary bone marrow cells. However, murine model is not suitable to perform a high-throughput phenotypic screen in vivo and identify compounds for AML therapy. A transgenic zebrafish overexpresses hoxa9/meis1 need to generate. We have engineered an inducible transgenic line Tg (drl:hoxa9;hsp70:meis1) harboring hoxa9/meis1 under the draculin (drl) promoter. The downregulation of runx1, c-myb, mpx, mfap4, and gata1 in Tg (drl:hoxa9;hsp70:meis1) embryos indicated enforced hoxa9/meis1 perturbs embryonic hematopoiesis. Importantly, adult Tg (drl:hoxa9;hsp70:meis1) develops malignant myeloid disease with an abundance of myeloid precursor cells, anemia, and high mortality after a latency period (~5-months-aged) with comparable to murine model and human AML patients. Genome-wide transcription changes analysis indicated arrested differentiation genes such as gata2b, notch1b, and gfi1ab are upregulated. Leflunomide, inhibitor of enzyme dihydroorotate dehydrogenase (DHODH) which is a potential option for differentiation therapy of AML, relieves defective hematopoiesis in transgenic embryos and larvae. Collectively, we have identified an inducible malignant myeloid disease transgenic zebrafish model similar to AML and provided a unique opportunity for high-throughput in vivo chemical screening for AML therapy and study the related mechanisms.

2022-09-01 | GSE204744 | GEO

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