EGAS00001000264-sc-20140514 - samples
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ABSTRACT:
PROVIDER: EGAD00001000847 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, leukemia predisposition, and skeletal abnormalities. We aim to characterise the structural effects of SDS in patients with this disorder by exome sequencing.
| EGAS00001000264 | EGA
Project description:Mutations in the DNAJC21 gene were recently described in Shwachman-Diamond syndrome (SDS), a bone marrow failure syndrome with high predisposition for myeloid malignancies. To study the underlying biology in hematopoiesis regulation and disease, we generated the first in vivo model of Dnajc21 deficiency using zebrafish. Zebrafish dnajc21 mutants phenocopy key SDS patient phenotypes such as cytopenia, reduced growth and defective ribosome biogenesis. We show that cytopenia results from impaired hematopoietic differentiation and cell proliferation, and is accompanied by an expansion of hematopoietic stem and progenitor cells during both embryonic and adult hematopoiesis. The introduction of a tp53 point mutation in the dnajc21 mutants results in myelodysplastic syndrome with erythroid dysplasia as early as four months of age. Using transcriptomic and metabolomic analyses, we show that Dnajc21 regulates various metabolic pathways including nucleotide biosynthesis. Chemical modulation of the pyrimidine biosynthesis pathway in dnajc21 mutants reveals an association with neutrophil differentiation, suggesting a novel mechanism in dnajc21-mutant SDS biology.
2023-03-01 | GSE225613 | GEO
Project description:Oncogenic signaling of the niche can have a severe effect on the hematopoietic compartment and could contribute or play an active role during the development of human leukemia predisposition syndromes. To provide insights into the mechanisms that underlie this concept, as well as their relevance to disease, this study uses the leukemia predisposition syndrome Shwachman-Diamond syndrome (SDS) as a model. This leukemia predisposition syndrome is established by constitutive homozygous or compound heterozygous loss-of-function mutations in the gene SBDS. SDS is characterized by skeletal defects and a striking predisposition for the development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Loss of Sbds in the hematopoietic compartment does not results in the induction of MDS or AML, however, could have an indirect effect on the hematopoietic system through the disruption of niche cells.<br>This submission concerns itself with gene expression profiling of transgenic mice. Osterix1 (Osx) is a zinc-finger transcriptional factor essential for osteoblast differentiation in mice and is expressed in cells of the mesenchymal lineage. A bacterial artificial chromosome (BAC) was modified such that it expressed the green fluorescent protein (GFP)::Cre recombinase (GFP::Cre) fusion protein. The artificial construct was inserted into the Osterix gene (Osx1, Sp7), enabling fusion gene GFP::Cre to be expressed from the Osx promotor (Osx1-GFP::Cre) and thereby creating transgenic mice. Cells isolated from these mice are therefore termed Osx::GFP cells. The Osx-GFP-Cre mice were crossed with Sbds f/f (flox/flox, loxp sites are inserted into the gene Sbds enabling the deletion of the region located between these loxp sites) mice to generate the transgenic Osx-GFP-Cre Sbds f/f (OCS) mice. Hence cells expressing the Osx/Sp7 gene therefore express the GFP::Cre fusion protein which enables the prospective isolation of GFP+ cells and it enables the deletion of the Sbds gene through the Cre-mediated recombination of the loxp sites.</br><br> OCS mice have skeletal defects similar to those observed in the human leukemia predisposition syndrome SDS. To obtain a detailed understanding of the underlying mechanisms Osx::GFP+ cells were prospectively isolated from bone cells suspensions, through fluorescence activated cell sorting (FACS), derived from OCS mice. Mutant OCS mice have a homozygous deletion of the Sbds gene in mesenchymal cells (e.g., osteoblasts), while wildtype mice have normal Sbds alleles. The gene expression profiles (GEPs) of both groups of mice were directly compared to determine major transcriptional changes.</br>
2016-09-22 | E-MTAB-5023 | biostudies-arrayexpress
Project description:Although anemia is common in Shwachman-Diamond syndrome (SDS), the underlying mechanism remains unclear. We asked whether SBDS, which is mutated in most SDS patients, is critical for erythroid development. We found that SBDS expression is high early during erythroid differentiation. Inhibition of SBDS in CD34+ hematopoietic stem cells and early progenitors (HSC/Ps) and K562 cells led to slow cell expansion during erythroid differentiation. Induction of erythroid differentiation resulted in markedly accelerated apoptosis in the knockdown cells; however, proliferation was only mildly reduced. The percentage of cells entering differentiation was not reduced. Differentiation also increased the oxidative stress in SBDS-knockdown K562 cells, and antioxidants enhanced the expansion capability of differentiating SBDS-knockdown K562 cells and colony production of SDS patient HSC/Ps. Erythroid differentiation also resulted in reduction of all ribosomal subunits and global translation. Furthermore, stimulation of global translation with leucine improved the erythroid cell expansion of SBDS-knockdown cells and colony production of SDS patient HSC/Ps. Leucine did not reduce the oxidative stress in SBDS-deficient K562 cells. These results demonstrate that SBDS is critical for normal erythropoiesis. Erythropoietic failure caused by SBDS-deficiency is at least in part related to elevated ROS levels and translation insufficiency since antioxidants and leucine improved cell expansion.
2011-09-14 | GSE32057 | GEO
Project description:Shwachman-Diamond syndrome (SDS) is a bone marrow failure (BMF) syndrome associated with an increased risk of myelodysplasia and leukemia. The molecular mechanisms of SDS are not fully understood. We report that primitive hematopoietic cells from SDS patients present with a reduced activity of the small Rho GTPase Cdc42 and concomitantly a reduced frequency of HSCs polar for polarity proteins. The level of apolarity of SDS HSCs correlated with the magnitude of HSC depletion in SDS patients. Importantly, exogenously provided Wnt5a or GDF11 that elevates the activity of Cdc42 restored polarity in SDS HSCs and increased the number of HSCs in SDS patient samples in surrogate ex vivo assays. Single cell level RNA-Seq analyses of SDS HSCs and daughter cells demonstrated that SDS-HSC treated with GDF11 are transcriptionally more similar to control than to SDS-HSCs. Treatment with GDF11 reverted pathways in SDS HSCs associated with rRNA processing and ribosome function, but also viral infection and immune function, p53-dependent DNA damage, spindle checkpoints, and metabolism, further implying a role of these pathways in HSC failure in SDS. Our data suggest that HSC failure in SDS is driven at least in part by low Cdc42 activity in SDS HSCs. Our data thus identify novel rationale approaches to attenuate HSCs failure in SDS.
2020-09-18 | GSE158140 | GEO
Project description:Monosomy 7 or deletion of 7q (del(7q)) frequently arise in inherited and acquired bone marrow failure, and are associated with progression to high grade Myelodysplastic Syndrome (MDS) and acute leukemia. Current non-transplant approaches to treat marrow failure may be complicated by potential stimulation of clonal outgrowth. To study the biological consequences of del(7q) within the context of a failing marrow, we utilized induced pluripotent stem cells (iPSCs) derived from patients with Shwachman Diamond Syndrome (SDS) and genomically engineered a deletion of (7q). Deletion of 7q failed to confer a relative fitness advantage in either pluripotent SDS iPSC or in iPSC-derived SDS CD34+ cells. The TGF-beta pathway was the top differentially regulated pathway in transcriptome analysis with the TGF pathway found activated in SDS-iPSCs, compared to SDS-del(7q) iPSCs. Increased phosphorylation of SMAD2 in SDS-iPSCs was reduced following del(7q) and increased upon restoration of 7q diploidy, in support of an effect of 7q dosage on the activation status of the TGF-beta pathway in SDS. Inhibition of the TGF-beta pathway rescued hematopoiesis in SDS-iPSCs and in primary bone marrow cells from SDS patients without improving hematopoiesis of the SDS-del(7q) cells. Together, these results utilizing an iPSC model of MDS in BMF identified a targetable vulnerability for potential therapeutic strategies to ameliorate bone marrow failure without promoting outgrowth of the del7q clone.
2019-07-26 | GSE118377 | GEO
Project description:Monosomy 7 or deletion of 7q (del(7q)) frequently arise in inherited and acquired bone marrow failure, and are associated with progression to high grade Myelodysplastic Syndrome (MDS) and acute leukemia. Current non-transplant approaches to treat marrow failure may be complicated by potential stimulation of clonal outgrowth. To study the biological consequences of del(7q) within the context of a failing marrow, we utilized induced pluripotent stem cells (iPSCs) derived from patients with Shwachman Diamond Syndrome (SDS) and genomically engineered a deletion of (7q). Deletion of 7q failed to confer a relative fitness advantage in either pluripotent SDS iPSC or in iPSC-derived SDS CD34+ cells. The TGF-beta pathway was the top differentially regulated pathway in transcriptome analysis with the TGF pathway found activated in SDS-iPSCs, compared to SDS-del(7q) iPSCs. Increased phosphorylation of SMAD2 in SDS-iPSCs was reduced following del(7q) and increased upon restoration of 7q diploidy, in support of an effect of 7q dosage on the activation status of the TGF-beta pathway in SDS. Inhibition of the TGF-beta pathway rescued hematopoiesis in SDS-iPSCs and in primary bone marrow cells from SDS patients without improving hematopoiesis of the SDS-del(7q) cells. Together, these results utilizing an iPSC model of MDS in BMF identified a targetable vulnerability for potential therapeutic strategies to ameliorate bone marrow failure without promoting outgrowth of the del7q clone.
2019-07-26 | GSE118372 | GEO
Project description:To define the mechanistic basis of clonal hematopoiesis in Shwachman-Diamond syndrome (SDS), we investigated somatic mutations acquired by patients with SDS followed longitudinally. This dataset includes the initial discovery cohort whole exome sequencing from bone marrow samples used to identify novel somatic mutations in patients with SDS. Paired fibroblasts serve as a germline control.
| EGAS00001004880 | EGA
Project description:Unique traits of pluripotent stem cells are not fully known. Using thermal proteome profiling, we identified reduced stability of ribosomes in induced pluripotent cells (iPSCs) compared to that in somatic cells. Also, iPSCs exhibited lower protein synthesis rate and lower expression of a ribosome maturation factor, the Shwachman-Bodian-Diamond Syndrome protein (SBDS). Differentiation of iPSCs led to upregulation of SBDS and knock-down of SBDS slowed the differentiation while increasing expression of master pluripotency markers NANOG and Oct-4. Mutations in the SBDS gene have been shown to impair ribosome assembly and to inhibit differentiation of hematopoietic stem cells causing the Shwachman- Diamond syndrome. Physiological SBDS-dependent destabilization of ribosomes appears to be a tool for translational control providing robustness to the state of pluripotency.
2021-10-05 | PXD014830 | Pride
Project description:Unique traits of pluripotent stem cells are not fully known. Using thermal proteome profiling, we identified reduced stability of ribosomes in induced pluripotent cells (iPSCs) compared to that in somatic cells. Also, iPSCs exhibited lower protein synthesis rate and lower expression of a ribosome maturation factor, the Shwachman-Bodian-Diamond Syndrome protein (SBDS). Differentiation of iPSCs led to upregulation of SBDS and knock-down of SBDS slowed the differentiation while increasing expression of master pluripotency markers NANOG and OCT4. Mutations in the SBDS gene have been shown to impair ribosome assembly and to inhibit differentiation of hematopoietic stem cells causing the Shwachman-Diamond syndrome. Physiological SBDS-dependent destabilization of ribosomes appears to be a tool for translational control providing robustness to the state of pluripotency.
2021-10-05 | PXD015874 | Pride