Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA357268 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5104160.fastq.gz | Fastqsanger.gz | |||
| SRR5104170.fastq.gz | Fastqsanger.gz | |||
| SRR5104180_1.fastq.gz | Fastqsanger.gz | |||
| SRR5104180_2.fastq.gz | Fastqsanger.gz | |||
| SRR5104161.fastq.gz | Fastqsanger.gz |
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Project description:Loss of function mutations of the histone acetyltransferase CREBBP have recently been described at high frequencies across a spectrum of lymphoid malignancies. The multiple effects of this epigenetic regulator on developmental and homeostatic processes have been extensively studied, however, exactly how CREBBP functions as a tumour suppressor remains unclear. Here we use a murine model to demonstrate that loss of Crebbp in haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphoproliferative disorders (LPD). We identify a pre-malignant (PM) B220+ Mac1+ stem cell which ultimately transforms to LPD and shed light on the mechanisms of malignant evolution by comparing lymphoid progenitors, pre-malignant and malignant cells at the clonal, transcriptional, epigenetic and genetic levels. We demonstrate that loss of Crebbp in HSPCs facilitates the development of lymphoid malignancies by generating a hyperproliferative population of lymphoid progenitors with an altered response to DNA-damage and enhanced self-renewal properties. Global genomic profiling revealed that epigenetic alterations observed in lymphoid progenitors correlated highly with transcriptional changes observed in frank LPD. Taken together, these findings define the tumour suppressor functions of Crebbp and shed light on the cellular origins and subsequent evolution of lymphoid malignancies.
2017-12-13 | GSE92344 | GEO
Project description:Development and differentiation of early innate lymphoid progenitors
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Project description:Inactivating mutations of the gene encoding for the CREBBP acetyltransferase are highly frequent in diffuse large B cell lymphoma (DLBCL, 30% of cases) and follicular lymphoma (FL, 60% of cases), the two most common cancers derived from the germinal-center (GC). However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Using functional epigenomics and mouse genetics, here we define the program modulated by CREBBP in primary human GC B cells and show that CREBBP regulates enhancer/super-enhancer networks, with specific roles in GC/post-GC cell fate decisions. Conditional GC-specific deletion of Crebbp in the mouse perturbs the expression of a limited set of genes involved in the regulation of signal transduction (BCR, TLR and CD40), lineage specification (NF-κB and BCL6) and terminal B cell differentiation (PRDM1, IRF4). Consistently, Crebbp-deficient B cells exhibit proliferative advantage and show impaired plasma cell differentiation. While GC-specific loss of Crebbp was not sufficient to initiate malignant transformation, compound Crebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics ofFL and DLBCL, display an increased incidence of clonal lymphoid malignancies recapitulating the features of the human diseases. These findings establish CREBBPas a haploinsufficient tumor suppressor gene in GC B cells and provide insights into the mechanisms and targets by which loss of CREBBP contributes to lymphomagenesis.
2017-01-11 | GSE89688 | GEO
Project description:Inactivating mutations of the gene encoding for the CREBBP acetyltransferase are highly frequent in diffuse large B cell lymphoma (DLBCL, 30% of cases) and follicular lymphoma (FL, 60% of cases), the two most common cancers derived from thegerminal-center (GC). However, the role of CREBBP inactivation in lymphomagenesisremains unclear. Using functional epigenomics and mouse genetics, here we definethe program modulated by CREBBP in primary human GC B cells and show thatCREBBP regulates enhancer/super-enhancer networks, with specific roles in GC/post-GC cell fate decisions. Conditional GC-specific deletion of Crebbp in the mouseperturbs the expression of a limited set of genes involved in the regulation of signaltransduction (BCR, TLR and CD40), lineage specification (NF-κB and BCL6) andterminal B cell differentiation (PRDM1, IRF4). Consistently, Crebbp-deficient B cellsexhibit proliferative advantage and show impaired plasma cell differentiation. WhileGC-specific loss of Crebbp was not sufficient to initiate malignant transformation,compound Crebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics ofFL and DLBCL, display an increased incidence of clonal lymphoid malignanciesrecapitulating the features of the human diseases. These findings establish CREBBPas a haploinsufficient tumor suppressor gene in GC B cells and provide insights intothe mechanisms and targes by which loss of CREBBP contributes to lymphomagenesis.
2017-01-11 | GSE88799 | GEO
Project description:We found that BAP1 (BRCA1 Associated Protein-1) shows loss of heterozygosity in over 25% of pancreatic cancer patients and functions as tumor suppressor. Conditional deletion of Bap1 in murine pancreas led to genomic instability, accumulation of DNA damage, and an inflammatory response that evolved to pancreatitis with full penetrance. Concomitant expression of oncogenic KrasG12D led to malignant transformation and development of invasive and metastatic pancreatic cancer. At the molecular level, BAP1 maintains the integrity of the exocrine pancreas by regulating genomic stability and its loss confers sensitivity to radio- and platinum-based therapies.
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Project description:Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly.
2005-08-16 | E-SMDB-3450 | biostudies-arrayexpress
Project description:The transcription factor B Cell CLL/Lymphoma 11B (BCL11B) is indispensable for T lineage development of lymphoid progenitors. Here we show that chimeric antigen receptor (CAR) expression early in ex vivo generated lymphoid progenitors suppresses Bcl11b, leading to suppression of T cell-associated gene expression and acquisition of natural killer (NK) cell-like properties. These results give important insights into differentiation of murine and human lymphoid progenitors driven by synthetic CAR transgene-expression and inform the potential use of ex vivo generated CARiK cells as a broadly applicable product for targeted immunotherapy.
2019-12-31 | GSE135015 | GEO
Project description:Abstract:
The cancer stem cell hypothesis has gained currency in recent times but concerns remain about its scientific foundations because of significant gaps that exist between research findings and comprehensive knowledge about cancer stem cells (CSCs). In this light, a mathematical model that considers hematopoietic dynamics in the diseased state of the bone marrow and peripheral blood is proposed and used to address findings about CSCs. The ensuing model, resulting from a modification and refinement of a recent model, develops out of the position that mathematical models of CSC development, that are few at this time, are needed to provide insightful underpinnings for biomedical findings about CSCs as the CSC idea gains traction. Accordingly, the mathematical challenges brought on by the model that mirror general challenges in dealing with nonlinear phenomena are discussed and placed in context. The proposed model describes the logical occurrence of discrete time delays, that by themselves present mathematical challenges, in the evolving cell populations under consideration. Under the challenging circumstances, the steady state properties of the model system of delay differential equations are obtained, analyzed, and the resulting mathematical predictions arising therefrom are interpreted and placed within the framework of findings regarding CSCs. Simulations of the model are carried out by considering various parameter scenarios that reflect different experimental situations involving disease evolution in human hosts.
Model analyses and simulations suggest that the emergence of the cancer stem cell population alongside other malignant cells engenders higher dimensions of complexity in the evolution of malignancy in the bone marrow and peripheral blood at the expense of healthy hematopoietic development. The model predicts the evolution of an aberrant environment in which the malignant population particularly in the bone marrow shows tendencies of reaching an uncontrollable equilibrium state. Essentially, the model shows that a structural relationship exists between CSCs and non-stem malignant cells that confers on CSCs the role of temporally enhancing and stimulating the expansion of non-stem malignant cells while also benefitting from increases in their own population and these CSCs may be the main protagonists that drive the ultimate evolution of the uncontrollable equilibrium state of such malignant cells and these may have implications for treatment.
2019-10-02 | MODEL1910020002 | BioModels
Project description:Collombet2016 - Lymphoid and myeloid cell
specification and transdifferentiation
This model is described in the article:
Logical modeling of lymphoid
and myeloid cell specification and transdifferentiation
Samuel Collombet, Chris van Oevelen,
Jose Luis Sardina Ortega, Wassim Abou-Jaoudé, Bruno Di
Stefano, Morgane Thomas-Chollier, Thomas Graf, and Denis
Thieffry
Proceedings of the National Academy of
Sciences of the United States of America
Abstract:
Blood cells are derived from a common set of hematopoietic
stem cells, which differentiate into more specific progenitors
of the myeloid and lymphoid lineages, ultimately leading to
differentiated cells. This developmental process is controlled
by a complex regulatory network involving cytokines and their
receptors, transcription factors, and chromatin remodelers.
Using public data and data from our own molecular genetic
experiments (quantitative PCR, Western blot, EMSA) or
genome-wide assays (RNA-sequencing, ChIP-sequencing), we have
assembled a comprehensive regulatory network encompassing the
main transcription factors and signaling components involved in
myeloid and lymphoid development. Focusing on B-cell and
macrophage development, we defined a qualitative dynamical
model recapitulating cytokine-induced differentiation of common
progenitors, the effect of various reported gene knockdowns,
and the reprogramming of pre-B cells into macrophages induced
by the ectopic expression of specific transcription factors.
The resulting network model can be used as a template for the
integration of new hematopoietic differentiation and
transdifferentiation data to foster our understanding of
lymphoid/myeloid cell-fate decisions.
This model is hosted on
BioModels Database
and identified by:
MODEL1610240000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-06-08 | MODEL1610240000 | BioModels
Project description:Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly. 3 old mice and 5 young mice were assayed
2007-12-19 | E-GEOD-4332 | biostudies-arrayexpress