MDS and DNA repair defects in Crebbp+/- mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE18061 | GEO | 2012/01/01
SECONDARY ACCESSION(S): PRJNA119327
REPOSITORIES: GEO
Similar Datasets
Project description:Myelodysplastic syndrome (MDS) is considered a disease of hematopoietic stem cell (HSC) origin. To begin to unravel the molecular mechanisms underlying the deregulation of HSCs in MDS, we performed comparative gene expression profiling on Crebbp+/- and wild type HSCs. We chose to isolate HSCs from the fetal liver (FLHSC) because at this stage there were no differences in cell number between Crebbp+/- and wild type fetal livers, suggesting no overt hematopoietic differences. Thus, any change in gene expression found in Crebbp+/- FLHSCs is likely to reflect the initially compromised genetic program of HSC regulation, as opposed to that of Crebbp+/- HSCs in adult bone marrow, where secondary changes in gene expression may also occur as compensatory mechanisms for a compromised or failing hematopoietic system. We used day 14.5 post coitus FLHSC (Sca-1+,Lin-,AA4.1+,c-Kit++) from wild type (wt) and Crebbp heterozygous (ht) embryos to examine changes in gene expression before overt myelodysplastic disease manifestation. Total RNA from wt and Crebbp+/- FLHSCs was isolated, PCR-amplified using the Ovation RNA amplification system and hybridized to Affymetrix Mouse 430 2.0 expression microarrays.
2012-01-01 | E-GEOD-18061 | biostudies-arrayexpress
Project description:The presence of unspliced transcripts in hematopoietic stem cells (HSCs) and the proposed association of CREBBP with the constitutive production of unspliced RNA and with pre-mRNA processing prompted us to examine more closely an anomaly we had noted in microarray-based gene expression studies but had previously attributed to experimental noise. We noticed that more than half of the probe sets down-regulated in Crebbp+/- fetal liver HSCs (FLHSCs) relative to wild-type (WT) mapped entirely within introns, rather than detecting exonic or spliced sequences. We therefore set out to test whether this might be evidence that reduced CREBBP levels selectively alter the generation of full-length, unspliced pre-mRNA. We also asked whether this process might be associated with differentiation since self-renewal and lineage commitment are the both responses for which HSCs are primed. Total RNA from wild-type, Crebbp+/-, Ep300+/-, Cdkn1a-/- FLHSCs and from wild type and Crebbp+/- mouse embryonic fibroblasts (MEFs) was isolated and hybridized to Affymetrix Mouse 430 2.0 expression microarrays. Fetal liver HSC RNA was amplified using the Ovation kit prior to hybridization. cell type comparison
2011-08-24 | E-GEOD-27987 | biostudies-arrayexpress
Project description:Adult and fetal hematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anemia and prenatal death. RISP null fetal HSCs displayed impaired respiration resulting in a decreased NAD+/NADH ratio. RISP null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation concomitant with increases in 2-hydroxyglutarate (2-HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration resulting in loss of quiescence resulting in severe pancytopenia and lethality. Thus, respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence.
2017-09-13 | PXD006054 | Pride
Project description:Gene expression analysis on purified human long-term hematopoietic stem cells (LT-HSC; CD34+CD38-CD90+) and short-term HSC (ST-HSC; CD34+CD38-CD90-) derived from healthy control patients and patients with myelodysplastic syndrome (MDS)
2012-08-01 | GSE38955 | GEO
Project description:Mutations of RUNX1 are detected in patients with myelodysplastic syndrome (MDS). In particular, C-terminal truncation mutations lack a transcription regulatory domain and have increased DNA binding through the runt homology domain (RHD). The expression of the RHD, RUNX1(41-214), in mouse hematopoietic cells induced progression to MDS and acute myeloid leukemia (AML). Analysis of pre-myelodysplastic animals revealed expansion of c-Kit+Sca-1+Lin- (KSL) cells and skewed differentiation to myeloid at the expense of the lymphoid lineage. These abnormalities correlate with the phenotype of Runx1-deficient animals, as expected given the reported dominant-negative role of C-terminal mutations over the full-length RUNX1. However, MDS is not observed in Runx1-deficient animals. Gene expression profiling revealed that RUNX1(41-214) KSLs have an overlapping yet distinct gene expression profile from Runx1-deficient animals. Moreover, an unexpected parallel was observed between the hematopoietic phenotype of RUNX1(41-214) and aged animals. Genes deregulated in RUNX1(41-214), but not in Runx1-deficient animals, were inversely correlated with the aging gene signature of hematopoietic stem cells (HSC), suggesting that disruption of the expression of genes related to normal aging by RUNX1 mutations contributes to development of MDS. The data presented here provide insights into the mechanisms of development of MDS in HSCs by C-terminal mutations of RUNX1. Gene expression analysis were performed on c-Kit+/Sca-1+/Lin-/IL7Ra- (KSL) cells sorted from RUNX1(41-214)-expressing and Runx1-knockout (Runx1floxed/floxed MxCre+/-) and control mice (Runx1floxed/floxedMxCre-/-).
2012-11-29 | E-GEOD-40155 | biostudies-arrayexpress
Project description:X-chromosome aneuploidies have long been associated with human cancers, but causality has not been established. In mammals, X-chromosome inactivation (XCI) is triggered by Xist RNA to equalize gene expression between the sexes. Here we delete Xist in the blood compartment of mice and demonstrate that mutant females develop a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome (mixed MPN/MDS) with 100% penetrance. Significant disease components include primary myelofibrosis, leukemia, histiocytic sarcoma, and vasculitis. Xist-deficient hematopoietic stem cells (HSC) show aberrant maturation and age-dependent loss. Reconstitution experiments indicate that MPN/MDS and myelofibrosis are of hematopoietic rather than stromal origin. We propose that Xist loss results in X-reactivation and consequent genome-wide changes that lead to cancer, thereby causally linking the X-chromosome to cancer in mice. Thus, Xist RNA is not only required to maintain XCI but also suppresses cancer in vivo. We carried out expression profiling in hematopoietic cells isolated from Xist-deficient female mice before disease (2 months old) and during myeloprolifeative neoplasm/myelodysplastic syndrome (MPN/MDS) and chronic myelomonocytic leukemia (CMML)-like disease (6 and 12 months old) and compared profiles of purified bone marow HSCs (KLS+CD34-), splenic B-cells (B220+), myeloid cells (CD11b+), and erythroid cells (Ter119+) against those of corresponding cell types from age-matched wild-type female mice. We conditionally targeted Xist locus in the blood compartment of mice by crossing Xist2lox/2lox mice (129Sv/Jae; Csankovszki et al., 1999) with Vav.Cre mice (B6.Cg-Tg (Vav1-cre)A2Kio/J; Jackson Laboratory). We used hematopoietic cells that were isolated from Xist-deficient and wild-type female progeny to analyze changes in gene expression due to loss of Xist.
2013-02-20 | E-GEOD-43961 | biostudies-arrayexpress
Project description:Myelodysplastic syndromes (MDS) are incurable neoplasms that arise from early hematopoietic stem cells (HSCs). We used single cell RNA sequencing (scRNA-seq) to evaluate mechanisms of resistance to venetoclax-based therapies.
2023-11-30 | GSE241417 | GEO
Project description:Myelodysplastic syndromes (MDS) are a group of incurable hematopoietic stem cell (HSC) neoplasms characterized by peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia. MDS represent the final stage in a continuum of HSCs’ genetic and functional alterations and are preceded by a premalignant phase, clonal cytopenia of undetermined significance (CCUS). Dissecting the mechanisms of CCUS maintenance may uncover therapeutic targets to delay or prevent malignant transformation. Here, we demonstrate that DNMT3A and TET2 mutations, the most frequent mutations in CCUS, induce aberrant HSCs’ differentiation towards the myeloid lineage at the expense of erythropoiesis by upregulating IL-1b–mediated inflammatory signaling and that canakinumab rescues red blood cell transfusion dependence in early-stage MDS patients with driver mutations in DNMT3A and TET2. This study illuminates the biological landscape of CCUS and offers an unprecedented opportunity for MDS intervention during its initial phase, when expected survival is prolonged.
2024-03-20 | GSE237148 | GEO
Project description:Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from the AGM, FL and BM. Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive line from Fetal Calvaria (OP9) and non-supportive stromal clones from fetal liver (BFC). Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from fetal liver. We took advantage of stromal clones established from the AGM, FL and BM and tested for their ability to support or not HSCs ex vivo. RNA were extracted from confluent stromal cultures or sorted cells and used for hybridization of Affymetrix (mouse gene 1.0 ST) microarrays.
2014-03-01 | E-GEOD-44181 | biostudies-arrayexpress
Project description:X-chromosome aneuploidies have long been associated with human cancers, but causality has not been established. In mammals, X-chromosome inactivation (XCI) is triggered by Xist RNA to equalize gene expression between the sexes. Here we delete Xist in the blood compartment of mice and demonstrate that mutant females develop a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome (mixed MPN/MDS) with 100% penetrance. Significant disease components include primary myelofibrosis, leukemia, histiocytic sarcoma, and vasculitis. Xist-deficient hematopoietic stem cells (HSC) show aberrant maturation and age-dependent loss. Reconstitution experiments indicate that MPN/MDS and myelofibrosis are of hematopoietic rather than stromal origin. We propose that Xist loss results in X-reactivation and consequent genome-wide changes that lead to cancer, thereby causally linking the X-chromosome to cancer in mice. Thus, Xist RNA is not only required to maintain XCI but also suppresses cancer in vivo. We carried out expression profiling in hematopoietic cells isolated from Xist-deficient female mice before disease (2 months old) and during myeloprolifeative neoplasm/myelodysplastic syndrome (MPN/MDS) and chronic myelomonocytic leukemia (CMML)-like disease (6 and 12 months old) and compared profiles of purified bone marow HSCs (KLS+CD34-), splenic B-cells (B220+), myeloid cells (CD11b+), and erythroid cells (Ter119+) against those of corresponding cell types from age-matched wild-type female mice.
2013-02-20 | GSE43961 | GEO