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SRP067537
Mus musculus
24 Downloadable Samples
Illumina HiSeq 2500
Description
One of the most common genetic alterations in acute myeloid leukemia is the internal tandem duplication (ITD) in the FLT3 receptor for cytokine FLT3 ligand (FLT3L). The constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on normal hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. We report that young pre-leukemic mice with the Flt3ITD knock-in allele manifest an expansion of all DCs including classical (cDCs) and plasmacytoid (pDCs). The expansion originated in DC progenitors, occurred in a cell-intrinsic manner and was further enhanced in Flt3ITD/ITD mice. The mutation caused the downregulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Flt3ITD mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T cells (Tregs). Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity in the absence of Tregs. Thus, the FLT3-ITD mutation directly affects DC development, thereby indirectly modulating T cell homeostasis and supporting Treg expansion. This effect of FLT3-ITD may subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner. Overall design: Sorted splenic dendritic cell subsets from either Flt3+/+ or Flt3ITD/+ mice were sequenced for mRNA profiling. For each subset per genotype contains 2-3 replicates, all from independent experiments.
Publication Title
Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The development, homeostasis and function of B lymphocytes involve multiple rounds of B cell receptor (BCR)-controlled proliferation and prolonged maintenance. We analyzed the role of transcription factor Zfx, a recently identified regulator of stem cell maintenance, in B cell development and homeostasis. Conditional Zfx deletion in the bone marrow blocked B cell development at the pre-BCR selection checkpoint. Zfx deficiency in peripheral B cells caused impaired generation of the B-1 cell lineage, accelerated B cell turnover, depletion of mature recirculating cells, and delayed T-dependent antibody responses. Zfx-deficient B cells showed normal proximal BCR signaling, but impaired BCR-induced proliferation and survival. This was accompanied by aberrantly enhanced and prolonged integrated stress response, and delayed induction of Cyclin D2 and Bcl-xL proteins. Thus, Zfx restrains the stress response and couples antigen receptor signaling to B cell expansion and maintenance during development and peripheral homeostasis.
Publication Title
Transcription factor Zfx controls BCR-induced proliferation and survival of B lymphocytes.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus, Homo sapiens
- 7 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Continuous expression of the transcription factor e2-2 maintains the cell fate of mature plasmacytoid dendritic cells.
Sample Metadata Fields
Specimen part, Cell line, Time
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Stem cells (SC) exhibit a unique capacity for self-renewal in an undifferentiated state. It is unclear whether the self-renewal of pluripotent embryonic SC (ESC) and of tissue-specific adult SC such as hematopoietic SC (HSC) is controlled by common mechanisms. The deletion of transcription factor Zfx impaired the self-renewal but not the differentiation capacity of murine ESC; conversely, Zfx overexpression facilitated ESC self-renewal by opposing differentiation. Furthermore, Zfx deletion abolished the maintenance of adult bone marrow HSC, but did not affect erythromyeloid progenitors or fetal HSC. In both ESC and HSC, Zfx activated a common set of direct target genes. In addition, the loss of Zfx resulted in the induction of immediate-early and/or stress-inducible genes in both SC types but not in their differentiated progeny. These studies identify the first shared transcriptional regulator of ESC and HSC, suggesting a common molecular basis of self-renewal in embryonic and adult SC.
Publication Title
Zfx controls the self-renewal of embryonic and hematopoietic stem cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 3 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Dendritic cells play a vital role in initiating robust immunity against pathogens as well as maintaining immunological tolerance to self antigens, food antigens and intestinal commensals. However, the intracellular signaling networks that program DCs to become tolerogenic are largely unknown. To address this, we analyzed gene expression profiles using microarray analysis of purified intestinal lamina propria DCs (CD11c+ CD11b+ DCs and CD11c+ CD11b- DCs) and compared it to splenic DCs (CD11c+ DC), from mice.
Publication Title
Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Plasmacytoid dendritic cells (pDCs) rapidly produce type I interferon (IFN-I) in response to viruses and are essential for antiviral immune responses. Although related to classical dendritic cells (cDCs) in their development and expression profile, pDCs possess many distinct features. Unlike cDCs, pDCs develop in the bone marrow (BM) and emerge into peripheral lymphoid organs and tissues as fully differentiated cells. We now report that pDCs specifically express Runx2, a Runt family transcription factor that is essential for bone development. Runx2-deficient murine pDCs developed normally in the BM but were greatly reduced in the periphery. The defect was cell-intrinsic and was associated with the retention of mature Ly49Q+ pDCs in the BM. Runx2 was required for the expression of several pDC-enriched genes including chemokine receptors Ccr2 and Ccr5. Mature pDCs expressed high levels of Ccr5 at the surface, and Ccr5-deficient pDCs in a competitive setting were reduced in the periphery relative to the BM. Thus, Runx2 is required for the emergence of mature BM pDCs into the periphery, in a process that is partially dependent on Ccr5. These results establish Runx2 as a lineage-specific regulator of immune system development.
Publication Title
Transcription factor Runx2 controls the development and migration of plasmacytoid dendritic cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Dendritic cells play a vital role in initiating robust immunity against pathogens as well as maintaining immunological tolerance to self antigens, food antigens and intestinal commensals. However, the intracellular signaling networks that program DCs to become tolerogenic are largely unknown. To address this, we analyzed gene expression profiles using microarray analysis of purified intestinal lamina propria DCs (CD11c+ CD11b+ DCs and CD11c+ CD11b- DCs) from mice.
Publication Title
Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 1 Downloadable Sample
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Dendritic cells (DCs) play a vital role in innate immunity. Transcriptome of DCs isolated from mouse spleen was obtained and deposited here.
Publication Title
Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 14 Downloadable Samples
- Illumina HiSeq 2500
Description
Adult hematopoiesis has been studied in terms of progenitor differentiation potentials, whereas its kinetics in vivo is poorly understood. We combined inducible lineage tracing of endogenous adult hematopoietic stem cells (HSC) with flow cytometry and single-cell RNA sequencing to characterize early steps of hematopoietic differentiation in the steady state. Labeled cells, comprising primarily long-term HSC and some short-term HSC, produced megakaryocytic lineage progeny within one week, in a process that required only 2-3 cell divisions. Erythroid and myeloid progeny emerged simultaneously by 2 weeks, and included a progenitor population with expression features of both lineages. Myeloid progenitors at this stage showed diversification into granulocytic, monocytic and dendritic cell types, and rare intermediate cell states could be detected. In contrast, lymphoid differentiation was virtually absent within the first 3 weeks of tracing. These results show that continuous differentiation of HSC rapidly produces major hematopoietic lineages and cell types, and reveal fundamental kinetic differences between megakaryocytic, erythroid, myeloid and lymphoid differentiation. Overall design: We combined inducible lineage tracing of endogenous adult hematopoietic stem cells (HSC) with flow cytometry and single-cell RNA sequencing to characterize early steps of hematopoietic differentiation in the steady state.
Publication Title
Kinetics of adult hematopoietic stem cell differentiation in vivo.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of antibodies to self-nucleic acids, immune complex deposition and tissue inflammation such as glomerulonephritis. Innate recognition of molecular complexes containing self-DNA and RNA and the ensuing production of type I interferons (IFN) contribute to SLE development. Plasmacytoid dendritic cells (pDCs) have been proposed as a relevant source of pathogenic IFN in SLE; however, their net contribution to the disease remains unclear. We addressed this question using haplodeficiency of the pDC-specific transcription factor E2-2 (Tcf4), which causes a specific impairment of pDC function in otherwise normal animals. We report that Tcf4+/- animals were significantly protected from SLE-like disease caused by the overexpression of the endosomal RNA sensor Tlr7. The protection was also observed after the monoallelic deletion of Tcf4 specifically in the dendritic cell lineage. Furthermore, Tcf4 haplodeficiency in the B6.Sle1.Sle3 multigenic model of SLE ameliorated key disease manifestations including anti-DNA antibody production, immune activation and glomerulonephritis. These results provide genetic evidence that pDCs are critically involved in SLE pathogenesis, confirming their potential utility as therapeutic targets in the disease.
Publication Title
Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus.
Sample Metadata Fields
Sex, Specimen part
View Samples