The Mesenchymal Niche in Myelodysplastic Syndromes.
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ABSTRACT:
SUBMITTER: Friedrich C
PROVIDER: S-EPMC9320414 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The myelodysplastic syndromes are a diverse group of clonal stem cell disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and an increased propensity to evolve to acute myeloid leukemia. The molecular pathogenesis of these disorders is poorly understood, but recurring chromosomal abnormalities occur in approximately 50% of cases and are the focus of much investigation. The availability of newer molecular techniques has allowed the identification of additional genetic aberrations, including mutations and epigenetic changes of prognostic and potential therapeutic importance. This review focuses on the key role of cytogenetic analysis in myelodysplastic syndromes in the context of the diagnosis, prognosis, and pathogenesis of these disorders.
| S-EPMC4340482 | biostudies-literature
Project description:Control of oxidative stress in the bone marrow (BM) is key for maintaining the balance between self-renewal, proliferation, and differentiation of hematopoietic cells. Breakdown of this regulation can lead to diseases characterized by BM failure such as the myelodysplastic syndromes (MDS). To better understand the role of oxidative stress in MDS development, we compared protein carbonylation as an oxidative stress marker in BM of patients with MDS and control subjects, and also patients with MDS under treatment with the iron chelator deferasirox.
2019-10-30 | PXD013609 | Pride
Project description:Myelodysplastic syndromes (MDS) are a group of clonal disorders of hematopoietic stem cells. Mesenchymal stem cells (MSC) are the progenitors of the Bone Marrow (BM) stroma and have been involved in the physiopathology of MDS. The presence of cytogenetic aberrations on MSC from MDS patients is controversial. The aim of the study is to characterize BM derived MSC from patients with MDS using: kinetic studies, immunophenotyping, fluorescent in situ hybridisation (FISH) analysis and genetic changes by array based comparative genomic hybridization (array-CGH). 32 cases of untreated MDS were included in the study. MSC from MDS achieved confluence at a slower rate than donor-MSC, and the antigenic expression of CD105 and CD104 was also lower. Array-CGH studies showed DNA genomic changes that were proved not to be somatic, and gains were more frequent than looses. The results of array-CGH were confirmed by FISH. When an unsupervised hierarchical cluster analysis was performed two clusters were identified: one of them included the 5q- syndrome patients, while the other incorporated the rest of the MDS patients. Our results shows, for the first time, that MSC from MDS display genomic aberrations, assessed by array-CGH and FISH, some of them specially linked to particular MDS subtypes. Keywords: Genomic comparison between mesenchymal cells 32 BM cells from âde novoâ MDS, corresponding to 29 patients, were included in the study. Male/female ratio was 14/15 and median age was 70 years (range 34-89). MDS diagnosis was established by peripheral blood counts and morphology, BM morphology and cytogenetic analyses and classified according to the WHO proposals. 12 Patientsâ characteristics are summarized in table 1. Three patients were included twice in the study: at the diagnosis of one RA (case 2) and two Unclassifiable MDS (cases 29,30), and at the progression into RAEB-2 (cases 16, 20 and 18). None of them had received treatment during this period of time, other than supportive therapy. Normal BM samples were obtained from 15 healthy donors, 8 males and 7 females, with a median age of 57 (range 37-88). Written informed consent was obtained from all patients and donors according to ethical guidelines of our institution. Genomic-wide analysis of DNA copy number changes of MSC from 13 cases was performed using array-CGH. Slides containing 3032 BACs were produced in âCentro de Investigación del Cáncerâ (Salamanca, Spain). The particular BAC and P-1 derived artificial chromosome set used to produce this array is distributed to academic institutions by the Welcome Trust Sanger Institute (Cambridge, United Kingdom) and contains targets spaced at ï» 1 Mb density over full genome, a set of subtelomeric sequences for each chromosome arm, and a few hundred probes selected for their involvement in oncogenesis. The clone content is available in the âCytoviewâ windows of the Sanger Institute mapping database site, Ensembl (http://www.ensembl.org/). According to this database, clones were ordered along the chromosomes. These clones were isolated from their bacterial cultures with the relevant antibiotics and the DNA was extracted with standard protocol Welcome Trust Sanger Institute (Cambridge, UK). 10 ng of DNA (BAC/PAC) was used as a template for three DOP-PC. 22;23 These products were ethanol precipitated and dissolved in distilled water. A minimum of three replicates per clone were printed by Microgrid II (Biorobotics) on each slide (Ultragaps Coated Slides, Corning) using the aqueous dimethylsulfoxide buffer as spotting solution. Briefly, for labelling reactions, 1 μg of nonamplified genomic DNA, test and reference were digested separately with DpnII restriction enzyme (New England Biolabs, Beverly, MA). For microarray hybridization, the digested DNAs were separately labelled using random primers (Bioprimer labelling kit, Invitrogen) and cyanine dye-3-dCTP and cyanine dye-5-dCTP fluorescent dye to paired hybridisation samples (Amersham Biosciences). The incorporated of the label nucleotide was quantified using the Nanodrop spectrophotometer. Labelled test and reference DNAs were mixed equitably, co-precipitated in presence of Cot-1 human DNA (Roche, Indianapolis, IN) with ethanol, washed, and resuspended in hybridization solution (50% Formamide, 10% Dextran sulfate, 2X standard saline citrate, 10 mM Tris pH 7.6, 2.7% sodium dodecyl sulfate and 10 μg/ μl of yeast tRNA). DNA mixtures were hybridized to the arrays in the TECAN HS4800 Pro according to the manufacturerâs recommended protocol. Images and signal intensities were acquired using GenePix4000B (Axon Instruments, Burlingame, CA) dual laser scanner in combination with GenePixPro4.0 (Axon Instruments) imaging software. Image and Data analysis. Spot intensities measured by the GenePix Pro 4.1 software (Axon Instruments, Wetsbur BV, Leuden, The Netherland). Pixel intensities for each feature were integrated and median values were determined, and the local background was calculated. For each spot the intensities were corrected by subtracting the local background for both wavelengths, and only spots with signal intensities al least threefold above background signal intensities were included in the analysis. The median of the ratios of all spots was calculated and used to normalize all data points. From each feature, the log2 value of the average of the normalization ratios of the spots was calculated and used to display the data. In addition, fluorescence ratios were normalized for each microarray using the print-tip loess method and the background subtraction with the Diagnosis and Normalization Arrays Data tool. 24 The cut-off level was determined for each individual experiment after avering the ratios from the two color-swith hybridizations and subsequent for normalization, and calculate the mean and Standard derivations to define the cut-off level as means plus/minus two times the standard derivations. The clones that showed possible changes were submitted to the Database of Genomics Variants (http://projects.tcag.ca/variation/) and chromosomal Imbalances and Phenotype in Humans using Ensembl Resources (DECIPCHER: http: www sanger. ac.uk /PostGenomics/decipher/. Clustering Unsupervised clustering We converted the relative ratio value for each BAC clones in each sample to score of 1 (gain/amplified), 0 (no change), or -1 (loss) based on the 2 SD standards described above and analyzed with Cluster and TreeView) 25 (Cluster and TreeView software) based on the average linkage method with the centered correlation metric was used (or Pearson Uncentered). Supervised Sam analysis was used http://www-stat.stanford.edu/ tibs/SAM) 26 to identify BACs that segregate subgroups on MSC. BACs with an SD of zero across the data set before analysis were removed.
2010-05-25 | E-GEOD-10822 | biostudies-arrayexpress
Project description:Myelodysplastic syndromes (MDS) comprise a group of bone marrow diseases characterized by profound heterogeneity in morphologic presentation, clinical course, and cytogenetic features. Roughly 50% of patients display clonal chromosome abnormalities. In several multicentric studies, the karyotype turned out to be one of the most important prognostic parameters and was incorporated into statistical models aiming for a better prediction of the individual prognosis like the International Prognostic Scoring System. However, due to the profound cytogenetic heterogeneity, the impact of many rare abnormalities as well as combinations of anomalies occurring in a substantial portion of patients with MDS is still unknown and can only be delineated on the basis of large international multicentric cooperations. Recently, the German-Austrian MDS Study Group presented cytogenetic findings in 2,072 patients with MDS, which serve as a basis for the characterization of the cytogenetic subgroups discussed in this article. The availability of new therapeutic options for low- and high-risk MDS targeted against distinct entities characterized by specific chromosome abnormalities, like 5q-deletions, monosomy 7, and complex abnormalities underlines the important role of cytogenetics for the clinical management of MDS. This article thus focuses on the clinical and prognostic relevance, the molecular background, and therapeutic perspectives in these three cytogenetic subgroups.
| S-EPMC2413090 | biostudies-other
Project description:Mesenchymal stromal cells (MSC) are crucial components of the bone marrow (BM) microenvironment essential for regulating self-renewal, survival and differentiation of hematopoietic stem/progenitor cells (HSPC) in the stem cell niche. MSC are functionally and phenotypically altered in myelodysplastic syndromes (MDS), contributing to disease progression. MDS MSC do not harbor recurrent genetic alterations but have been shown to exhibit an altered methylome compared to MSC from healthy controls. We examined growth, differentiation and HSPC-supporting capacity of ex vivo expanded MSC from MDS patients in comparison to age-matched healthy controls after direct treatment in vitro with the hypomethylating agent azacitidine (AZA). We show that AZA exerts a direct effect on MSC by modulating their differentiation potential. Osteogenesis was significantly boosted in healthy MSC while adipogenesis was inhibited in both healthy and MDS MSC. In co-culture experiments, both AZA treated MDS MSC and healthy MSC exhibited enhanced support of non-clonal HSPC which was associated with increased cell cycle induction. Conversely, clonal MDS HSPC were inhibited by contact with AZA treated MSC. RNA-sequencing analyses of stromal cells revealed changes in pathways essential for HSPC support as well as in immune regulatory pathways. In sum, our data demonstrate that AZA treatment of stromal cells leads to upregulation of HSPC-supportive genes and cell cycle induction in co-cultured healthy HSPC, resulting in a proliferative advantage over clonal HSPC. Thus, restoration of functional hematopoiesis by AZA may be driven by activated stromal support factors in MSC providing cell cycle cues to healthy HSPC.
2018-12-19 | GSE112461 | GEO
Project description:We set a model to replicate the vascular bone marrow niche by using endothelial colony forming cells (ECFCs), and we used it to explore the vascular niche function in patients with low-risk myelodysplastic syndromes (MDS). Overall, we investigated 56 patients and we observed higher levels of ECFCs in MDS than in healthy controls; moreover, MDS ECFCs were found variably hypermethylated for p15INK4b DAPK1, CDH1, or SOCS1. MDS ECFCs exhibited a marked adhesive capacity to normal mononuclear cells. When normal CD34+ cells were co-cultured with MDS ECFCs, they generated significant lower amounts of CD11b+ and CD41+ cells than in co-culture with normal ECFCs. At gene expression profile, several genes involved in cell adhesion were upregulated in MDS ECFCs, while several members of the Wingless and int (Wnt) pathways were underexpressed. Furthermore, at miRNA expression profile, MDS ECFCs hypo-expressed various miRNAs involved in Wnt pathway regulation. The addition of Wnt3A reduced the expression of intercellular cell adhesion molecule-1 on MDS ECFCs and restored the defective expression of markers of differentiation. Overall, our data demonstrate that in low-risk MDS, ECFCs exhibit various primary abnormalities, including putative MDS signatures, and suggest the possible contribution of the vascular niche dysfunction to myelodysplasia.
| S-EPMC4468365 | biostudies-literature
Project description:Myelodysplastic syndromes are associated with a risk of severe infections. While neutropenia is likely to be the main predisposing factor, several other immune defects have been reported, including impaired neutrophil function, B-, T- and NK-cell defects and the possible consequences of iron overload due to red blood cell transfusions. The advanced age of most patients, their frequent comorbidities, and the fact that drugs such as hypomethylating agents and lenalidomide, which are effective in myelodysplastic syndromes but can transiently worsen neutropenia, may increase the risk of infection and their severity in this context. The majority of infections in myelodysplastic syndromes are bacterial, while the incidence of fungal infections is not well known and viral infections seem to be rare. No prophylactic measures against infections have demonstrated efficacy in myelodysplastic syndromes. However, pending more data, we propose here some recommendations for the management of patients with myelodysplastic syndromes. In the future, an important contribution can be made by prospective trials testing the efficacy of prophylactic and therapeutic approaches to infection in these patients, especially in the context of the new drugs available for myelodysplastic syndromes.
| S-EPMC3487546 | biostudies-literature
Project description:Myelodysplastic syndromes (MDS) are acquired clonal stem cell disorders exhibiting ineffective hematopoiesis, dysplastic cell morphology in the bone marrow, and peripheral cytopenia at early stages; while advanced stages carry a high risk for transformation into acute myeloid leukemia (AML). Genetic alterations are integral to the pathogenesis of MDS. However, it remains unclear how these genetic changes in hematopoietic stem and progenitor cells (HSPCs) occur, and how they confer an expansion advantage to the clones carrying them. Recently, inflammatory processes and changes in cellular metabolism of HSPCs and the surrounding bone marrow microenvironment have been associated with an age-related dysfunction of HSPCs and the emergence of genetic aberrations related to clonal hematopoiesis of indeterminate potential (CHIP). The present review highlights the involvement of metabolic and inflammatory pathways in the regulation of HSPC and niche cell function in MDS in comparison to healthy state and discusses how such pathways may be amenable to therapeutic interventions.
| S-EPMC8541058 | biostudies-literature
Project description:Myelodysplastic syndromes (MDSs) are heterogeneous for their morphology, clinical characteristics, survival of patients, and evolution to acute myeloid leukemia. Different prognostic scoring systems including the International Prognostic Scoring System (IPSS), the Revised IPSS, the WHO Typed Prognostic Scoring System, and the Lower-Risk Prognostic Scoring System have been introduced for categorizing the highly variable clinical outcomes. However, not considered by current MDS prognosis classification systems, gene variants have been identified for their contribution to the clinical heterogeneity of the disease and their impact on the prognosis. Notably, TP53 mutation is independently associated with a higher risk category, resistance to conventional therapies, rapid transformation to leukemia, and a poor outcome. Herein, we discuss the features of monoallelic and biallelic TP53 mutations within MDS, their corresponding carcinogenic mechanisms, their predictive value in current standard treatments including hypomethylating agents, allogeneic hematopoietic stem cell transplantation, and lenalidomide, together with the latest progress in TP53-targeted therapy strategies, especially MDS clinical trial data.
| S-EPMC8582368 | biostudies-literature
Project description:Myelodysplastic syndrome (MDS) are clonal stem cell diseases characterized mainly by ineffective hematopoiesis. Here, we present an approach that enables robust long-term engraftment of primary MDS stem cells (MDS-SCs) in mice by implantation of human mesenchymal cell-seeded scaffolds. Critically for modelling MDS, where patient sample material is limiting, mononuclear bone marrow cells containing as few as 104 CD34+ cells can be engrafted and expanded by this approach with the maintenance of the genetic make-up seen in the patients. Non-invasive high-resolution ultrasound imaging shows that these scaffolds are fully perfused. Our data shows that human microenvironment but not mouse is essential to MDS-SCs homing and engraftment. Notably, the alternative niche provided by healthy donor MSCs enhanced engraftment of MDS-SCs. This study characterizes a new tool to model MDS human disease with the level of engraftment previously unattainable in mice, and offers insights into human-specific determinants of MDS-SC microenvironment.
| S-EPMC7610449 | biostudies-literature