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Ena-DATASET-ErasmusMC-hema-25-08-2016-22:47:10:141-68 - samples

ABSTRACT: Highly purified mesenchymal cells (CD45-/7AAD-/CD235a-/CD31-/CD271+/CD105+) were prospectively FACS-isolated from bone marrow specimens of 3 Diamond-Blackfan anemia (DBA) cases. This data set, comprising 3 DBA cases, is used as complement to 45 low-risk myelodysplastic syndrome (LRMDS) and 4 Shwachman-Diamond syndrome (SDS) cases to demonstrate aberrant inflammatory signaling as a common mechanism in pre-leukemia syndromes to induce genotoxic stress in hematopoietic stem cells. In addition, this data set is used to determine different overlapping gene expression signatures in pre-leukemia syndromes compared to gene expression profiles of highly purified mesenchymal cells of healthy donors.

PROVIDER: EGAD00001002661 | EGA |

REPOSITORIES: EGA

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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>

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Ena-DATASET-ErasmusMC-hema-25-08-2016-22:47:10:141-68 - samples

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