Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA207975 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we use pre-malignant cells from different Cebpa mutant acute myeloid leukemia (AML) models. We have used conditional KO models (CreLoxP) and isolated hematopoietic cells shortly after induction of recombination, in order to look at pre-leukemic cells, which have acquired the first hit, but not yet undergone full malignant transformation. We have sorted granulocyte-macrophage progenitors (GMPs) and the more immature population pre-granulocyte-macrophages (preGMs) from pre-leukemic mice. We analyzed gene-expression profiles in order to find deregulated genes, which make the cells more prone to undergo transformation.
2013-07-08 | E-GEOD-47813 | biostudies-arrayexpress
Project description:The key myeloid transcription factor (TF) CEBPA is frequently mutated in acute myeloid leukemia (AML), but the molecular ramifications of this leukemic driver mutation remain elusive. To investigate CEBPA mutant AML, we compared gene expression changes in human CEBPA mutant AML and in the corresponding CebpaLp30 mouse model, and identified a conserved cross-species transcriptional program. ChIP-seq revealed aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. One leukemic-enhancer upstream of Nt5e, encoding CD73, was physically and functionally linked to this conserved AML gene, and could be activated by CEBPA. Targeting of CD73-adenosine signaling increased AML survival in transplanted mice. Our data indicate a first-in-class link between a TF cancer driver mutation and a druggable, direct transcriptional target.
2019-08-08 | PXD011359 | Pride
Project description:In this study, we use pre-malignant cells from different Cebpa mutant acute myeloid leukemia (AML) models. We have used conditional KO models (CreLoxP) and isolated hematopoietic cells shortly after induction of recombination, in order to look at pre-leukemic cells, which have acquired the first hit, but not yet undergone full malignant transformation.
2013-07-08 | GSE47813 | GEO
Project description:Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients that shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, while the rest presented with silencing of this gene and co-expression of certain T cell markers. DNA methylation studies revealed that these two groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA silenced leukemias also displayed marked hypermethylation when compared with normal CD34+ hematopoietic cells, while CEBPA mutant cases showed only mild changes in DNA methylation when compared to these normal progenitors. Biologically, CEBPA silenced leukemias presented with a decreased response to myeloid growth factors in vitro. Experiment Overall Design: Direct comparison of gene expression in leukemic blasts from 8 patients with Acute Myeloid Leukemia (AML) carrying a CEBPA mutation and 8 patients with AML without CEBPA mutation but with silencing of CEBPA expression, and with 9 samples of T Acute Lymphoblastic Leukemia (T-ALL) patients.
2009-01-24 | E-GEOD-14479 | biostudies-arrayexpress
Project description:Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients that shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, while the rest presented with silencing of this gene and co-expression of certain T cell markers. DNA methylation studies revealed that these two groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA silenced leukemias also displayed marked hypermethylation when compared with normal CD34+ hematopoietic cells, while CEBPA mutant cases showed only mild changes in DNA methylation when compared to these normal progenitors. Biologically, CEBPA silenced leukemias presented with a decreased response to myeloid growth factors in vitro. Keywords: DNA methylation profiling Direct comparison of DNA methylation in leukemic blasts from 8 patients with Acute Myeloid Leukemia (AML) carrying a CEBPA mutation and 8 patients with AML without CEBPA mutation but with silencing of CEBPA expression. Two control groups are included: 8 CD34+ bone marrow samples from healthy donors and 9 samples of T Acute Lymphoblastic Leukemia (T-ALL) patients.
2010-05-07 | E-GEOD-14417 | biostudies-arrayexpress
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
| S-EPMC8784167 | biostudies-literature
Project description:Translational research is commonly performed in the C57B6/J mouse strain, chosen for its genetic homogeneity and phenotypic uniformity. Here, we evaluate the suitability of the white-footed deer mouse (Peromyscus leucopus) as a model organism for aging research, offering a comparative analysis against C57B6/J and diversity outbred (DO) Mus musculus strains. Our study includes comparisons of body composition, skeletal muscle function, and cardiovascular parameters, shedding light on potential applications and limitations of P. leucopus in aging studies. Notably, P. leucopus exhibits distinct body composition characteristics, emphasizing reduced muscle force exertion and a unique metabolism, particularly in fat mass. Cardiovascular assessments showed changes in arterial stiffness, challenging conventional assumptions and highlighting the need for a nuanced interpretation of aging-related phenotypes. Our study also highlights inherent challenges associated with maintaining and phenotyping P. leucopus cohorts. Behavioral considerations, including anxiety-induced responses during handling and phenotyping assessment, pose obstacles in acquiring meaningful data. Moreover, the unique anatomy of P. leucopus necessitates careful adaptation of protocols designed for Mus musculus. While showcasing potential benefits, further extensive analyses across broader age ranges and larger cohorts are necessary to establish the reliability of P. leucopus as a robust and translatable model for aging studies.
| S-EPMC11335981 | biostudies-literature
Project description:The CCAAT enhancer binding protein alpha (C/EBPalpha) transcription factor plays a key role in the regulation of growth and differentiation of the granulocytic lineage in the hematopoietic system and CEBPA (encoding C/EBPalpha) is often mutated or deregulated in AML patients. Consistently, mice lacking C/EBPalpha have no mature neutrophils and die within a few hours. However, homozygous knockin mice in which wild type Cebpa has been replaced with a mutant allele (BRM2), which abolish the growth-repressing ability of C/EBPalpha, are viable, but at 8 weeks of age they display myeloid dysplasia with absence of neutrophil granulocytes. Strikingly, in older CebpaBRM2/BRM2 knockin mice the myeloid dysplastic phenotype progress into other myeloid malignancies such as myeloid proliferative syndrome and acute myeloid leukemia-like malignancy. This strongly suggests that secondary mutations in other loci must occur when developing leukemia in the CebpaBRM2/BRM2. In order to identify genes that cooperate with Cebpa mutations in the development of leukemia in CebpaBRM2/BRM2 mice a so-called retroviral insertion mutagenesis screen was performed. Inbred newborn CebpaBRM2/BRM2 and wildtype mice were injected with SRS19-6 retrovirus, which incorporated into the genome and resulted in activation of oncogenes and leukemic progression. When leukemia was evident the mice were euthanized and analyzed. As expected the CebpaBRM2/BRM2 mice had a shorter latency than wildtype mice (186 vs. 276 days). The mice had enlarged spleen, thymus, and/or lymph nodes and were thoroughly investigated by histology, flow cytometry and southern in order to determine the leukemic phenotypes. Most of the CebpaBRM2/BRM2 mice developed an AML-like phenotype, whereas T cell leukemias were most prominent in wildtype mice, showing that mutating Cebpa specifically directs leukemic progression towards a myeloid direction. Genomic instability was analyzed by CGH. Finally, the retroviral insertion loci were identified through a splinkerette-aided PCR strategy. This led to the identification of several novel putative and previously unexplored oncogenes, which might collaborate with mutated Cebpa in the development of AML. Keywords: Disease state analysis
2008-06-01 | GSE8032 | GEO
Project description:The CCAAT enhancer binding protein alpha (C/EBPalpha) transcription factor plays a key role in the regulation of growth and differentiation of the granulocytic lineage in the hematopoietic system and CEBPA (encoding C/EBPalpha) is often mutated or deregulated in AML patients. Consistently, mice lacking C/EBPalpha have no mature neutrophils and die within a few hours. However, homozygous knockin mice in which wild type Cebpa has been replaced with a mutant allele (BRM2), which abolish the growth-repressing ability of C/EBPalpha, are viable, but at 8 weeks of age they display myeloid dysplasia with absence of neutrophil granulocytes. Strikingly, in older CebpaBRM2/BRM2 knockin mice the myeloid dysplastic phenotype progress into other myeloid malignancies such as myeloid proliferative syndrome and acute myeloid leukemia-like malignancy. This strongly suggests that secondary mutations in other loci must occur when developing leukemia in the CebpaBRM2/BRM2. In order to identify genes that cooperate with Cebpa mutations in the development of leukemia in CebpaBRM2/BRM2 mice a so-called retroviral insertion mutagenesis screen was performed. Inbred newborn CebpaBRM2/BRM2 and wildtype mice were injected with SRS19-6 retrovirus, which incorporated into the genome and resulted in activation of oncogenes and leukemic progression. When leukemia was evident the mice were euthanized and analyzed. As expected the CebpaBRM2/BRM2 mice had a shorter latency than wildtype mice (186 vs. 276 days). The mice had enlarged spleen, thymus, and/or lymph nodes and were thoroughly investigated by histology, flow cytometry and southern in order to determine the leukemic phenotypes. Most of the CebpaBRM2/BRM2 mice developed an AML-like phenotype, whereas T cell leukemias were most prominent in wildtype mice, showing that mutating Cebpa specifically directs leukemic progression towards a myeloid direction. Genomic instability was analyzed by CGH. Finally, the retroviral insertion loci were identified through a splinkerette-aided PCR strategy. This led to the identification of several novel putative and previously unexplored oncogenes, which might collaborate with mutated Cebpa in the development of AML. Keywords: Disease state analysis In order to identify genes that cooperate with Cebpa mutations in the development of leukemia in CebpaBRM2/BRM2 mice a so-called retroviral insertion mutagenesis screen was performed. Inbred newborn CebpaBRM2/BRM2 and wildtype mice were injected with SRS19-6 retrovirus, which incorporated into the genome and resulted in activation of oncogenes and leukemic progression. When leukemia was evident the mice were euthanized and analyzed. GDNA from tumour tissues were analyzed by CGH using tail gDNA as reference.
2008-05-31 | E-GEOD-8032 | biostudies-arrayexpress
Project description:BackgroundCopy number variation is an important dimension of genetic diversity and has implications in development and disease. As an important model organism, the mouse is a prime candidate for copy number variant (CNV) characterization, but this has yet to be completed for a large sample size. Here we report CNV analysis of publicly available, high-density microarray data files for 351 mouse tail samples, including 290 mice that had not been characterized for CNVs previously.ResultsWe found 9634 putative autosomal CNVs across the samples affecting 6.87% of the mouse reference genome. We find significant differences in the degree of CNV uniqueness (single sample occurrence) and the nature of CNV-gene overlap between wild-caught mice and classical laboratory strains. CNV-gene overlap was associated with lipid metabolism, pheromone response and olfaction compared to immunity, carbohydrate metabolism and amino-acid metabolism for wild-caught mice and classical laboratory strains, respectively. Using two subspecies of wild-caught Mus musculus, we identified putative CNVs unique to those subspecies and show this diversity is better captured by wild-derived laboratory strains than by the classical laboratory strains. A total of 9 genic copy number variable regions (CNVRs) were selected for experimental confirmation by droplet digital PCR (ddPCR).ConclusionThe analysis we present is a comprehensive, genome-wide analysis of CNVs in Mus musculus, which increases the number of known variants in the species and will accelerate the identification of novel variants in future studies.
| S-EPMC4490682 | biostudies-literature