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Unknown,Transcriptomics,Genomics,Proteomics

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Dnmt3a haploinsufficiency transforms Flt3-ITD myeloproliferative disease into a rapid, spontaneous, and fully-penetrant acute myeloid leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Nathan Salomonis

PROVIDER: E-GEOD-77849 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia.

Meyer Sara E SE Qin Tingting T Muench David E DE Masuda Kohei K Venkatasubramanian Meenakshi M Orr Emily E Suarez Lauren L Gore Steven D SD Delwel Ruud R Paietta Elisabeth E Tallman Martin S MS Fernandez Hugo H Melnick Ari A Le Beau Michelle M MM Kogan Scott S Salomonis Nathan N Figueroa Maria E ME Grimes H Leighton HL

Cancer discovery 20160325 5

<h4>Unlabelled</h4>Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3(ITD)) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells re ...[more]

PMID: 27016502

Similar Datasets

Dnmt3a haploinsufficiency transforms Flt3-ITD myeloproliferative disease into a rapid, spontaneous, and fully-penetrant acute myeloid leukemia (Single Cell RNA-Seq)

Project description:Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human acute myeloid leukemia (AML) cases with a 5-year overall survival of approximately 30%. In CN-AML with poorer prognosis, mutations in the de novo DNA methyltransferase (DNMT3A) and the FMS-like tyrosine kinase 3 (Flt3) commonly co-occur (1-3). We demonstrate that mice with Flt3-internal-tandem duplication (Flt3ITD) and inducible deletion of Dnmt3a spontaneously develop a rapidly-lethal, completely-penetrant, and transplantable AML of normal karyotype. These murine AML retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3-ITD/DNMT3A-mutant primary human and murine AML demonstrate a similar pattern of global DNA methylation. In the murine model, rescuing DNMT3A expression was accompanied by DNA re-methylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Differentially methylated genomic regions were associated with changes in the expression of nearby genes. Moreover, dissection of the cellular architecture of the AML model using single-cell RNA-Seq, flow cytometry and colony assays identified clonogenic subpopulations that differentially express genes that are sensitive to the methylation of nearby genomic loci and varied in response to Dnmt3a levels. Thus, Dnmt3a haploinsufficiency transforms Flt3ITD myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation. To identify the gene expression changes associated with Dnmt3a loss of function in human and murine Flt3-ITD and Dnmt3a-mutant AML (Single Cell RNA-Seq).

2016-03-27 | E-GEOD-77847 | biostudies-arrayexpress

Dnmt3a haploinsufficiency transforms Flt3-ITD myeloproliferative disease into a rapid, spontaneous, and fully-penetrant acute myeloid leukemia (Bulk RNA-Seq)

2016-03-27 | E-GEOD-77846 | biostudies-arrayexpress

A multi-scale approach reveals that NFkB cRel enforces a B-cell decision to divide.

Project description:The transcriptomes of individual small and large B cells after 24 h of stimulation were sequenced and genes upregulated in small or large cells were found and analyzed to provide a global charactarization of transcription patterns in growing B cells. We identified 5 large and 5 small viable B cells from images of the C1 IFC containing captured cells. We prepared libraries for the 10 individual cells, a positive bulk control (containing diluted bulk cDNA), a negative control containing only the ERCC spikeins, and a 0h bulk control.

2015-02-18 | E-GEOD-64156 | biostudies-arrayexpress

Synovial microenvironment-influenced mast cells promote the progression of rheumatoid arthritis

Project description:Mast cells are phenotypically and functionally highly heterogeneous, and their state is possibly controlled by their local microenvironment. Therefore, concrete analyses are needed to understand whether mast cells act as powerful motivators or dispensable bystanders in specific diseases. Here, we evaluated the correlation between synovial mast cells and rheumatoid arthritis (RA) disease severity, and the efficacy of therapeutic interventions against mast cells. We showed that degranulation of mast cells in inflammatory synovial tissues of RA patients was induced via MAS-related G protein-coupled receptor X2 (MRGPRX2), and the expression of MHC class II (MHC II) and costimulatory molecules on mast cells were upregulated. These unique signaling response led to mast cell activation and promoted T cell responses, resulting in the progression of RA. Collagen-induced arthritis mouse models treated with a combination of anti-IL-17A and cromolyn sodium, a mast cell membrane stabilizer, showed significantly reduced clinical severity and decreased bone erosion. The findings of the present study suggest that synovial microenvironment-influenced mast cells contribute to RA and may provide a novel mast cell-targeting therapy for RA.

2024-01-07 | PXD038584 | Pride

Th single cell RNA-Seq

Project description:Th2 cells regulate helminth infections, allergic disorders, tumor immunity and pregnancy by secreting various cytokines. It is likely that there are undiscovered Th2-signaling molecules. While steroids are known to be immunoregulators, de novo steroid production from immune cells has not been previously characterised. We demonstrate production of the steroid pregnenolone by Th2 cells in vitro, and in vivo in a helminth infection model. To identify gene-expression identify of these steroidogenic-Th2 cells, we performed single-cell RNA-sequencing.

2014-04-25 | E-MTAB-2512 | biostudies-arrayexpress

Single cell global gene profiling reveals molecular and functional platelet bias of aged hematopoietic stem cells

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2016-03-24 | E-GEOD-70657 | biostudies-arrayexpress

Tbx3 controls Dppa3 levels to regulate exit from pluripotency towards mesodermal lineage

Project description:Tbx3, a member of the T-box family, plays important roles in development, stem cells, nuclear reprogramming and cancer. Loss of Tbx3 induces differentiation in mouse embryonic stem cells (mESCs). However, we show that mESCs exist in an alternate stable pluripotent state in the absence of Tbx3. In-depth transcriptome analysis of this mESC state reveals Dppa3 as a direct downstream target of Tbx3. Also Tbx3 facilitates the cell fate transition from pluripotent cells to mesoderm progenitors by directly repressing Wnt pathway members required for differentiation. Wnt signaling regulates differentiation of mESCs into mesoderm progenitors and helps maintain a naïve pluripotent state. We show that Tbx3, a downstream target of Wnt signaling, fine-tunes these divergent roles of Wnt signaling in mESCs. In conclusion, we identify a signaling-TF axis that controls the exit of mESCs from a self-renewing pluripotent state towards mesoderm differentiation. ChIPSeq and RNASeq (population and single cell) was performed on the indicated cell lines. Replicates are indicated as needed. The mm9 genome assembly was used. For single cell mRNA-Seq preparation, SSEA1+DAPI- mESCs were sorted and collected.

2015-07-21 | E-GEOD-60066 | biostudies-arrayexpress

Deciphering the relationship between polycomb repression and stochastic gene expression from single-cell RNA-seq data

Project description:Polycomb repressive complexes are important histone modifiers, which silence gene expression, yet there exists a subset of polycomb-bound genes actively transcribed by RNA polymerase II. To investigate the switching between polycomb-repressed and active states, we sequence mRNA from OS25 mouse embryonic stem cells cultured in serum/LIF. To validate our finding that polycomb modulates stochastic gene expression and transcriptional bursting, we perform knockout experiments and we sequence mRNA from Ring1A knockout (untreated) and Ring1A/B double knockout cells with constitutive Ring1A knockout and tamoxifen-inducible conditional Ring1B knockout.

2017-06-01 | E-MTAB-5661 | biostudies-arrayexpress

Single-cell RNA-seq Reveals Unique Vascular Smooth Muscle Cell Phenotypes in Culture

Project description:Background. Heterogeneity in vascular smooth muscle cells (VSMCs) has been classically defined with a small set of predefined markers. Single cell genomics provides a unique unbiased approach to evaluate VSMC phenotypes. Objectives. The goal of this study was to define the heterogeneity of primary murine VSMCs grown in culture. VSMCs grown in culture are routinely used as a model of VSMCs in the vessel wall. We wanted to better understand the assumptions of this model. RNA sequencing was performed on single aortic VSMCs from 3-4 month old male mice at passages 1 and 2 (P1 and P2). Single cell contractility measurements were performed using Traction Force microscopy.

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Trancriptional comparison of Zbtb32-deficient and -sufficient cells

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-06-10 | E-GEOD-83194 | biostudies-arrayexpress