Investigating microenvironment in MDS
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA925555 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23142900_1.fastq.gz | Fastqsanger.gz | |||
| SRR23142900_2.fastq.gz | Fastqsanger.gz | |||
| SRR23143000_1.fastq.gz | Fastqsanger.gz | |||
| SRR23143000_2.fastq.gz | Fastqsanger.gz | |||
| SRR23142901_1.fastq.gz | Fastqsanger.gz |
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Project description:To characterize the molecular changes in myelodysplastic syndromes (MDS) and to explore novel genetic abnormalities occurring in these disorders through a genome-wide study in a series of MDS and MDS/MPN patients. A total of 285 abnormalities were identified in 71 patients. Three high-risk MDS cases displayed chromothripsis. In addition, cryptic deletions were identified in genomic regions where MDS-related genes, such as DNMT3A (2p23.3), TET2 (4q24), RUNX1 (21q22) and BCOR (Xp11.4), are located.
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Project description:Altered bone marrow hematopoiesis and immune suppression is a hallmark of myelodysplastic syndrome (MDS). While the bone marrow microenvironment influences malignant hematopoiesis, the mechanism leading to MDS-associated immune suppression is unknown. We tested whether mesenchymal stromal cells (MSCs) contribute to this process. Here, we developed a model to study cultured MSCs from MDS patients compared to similar aged matched normal controls for regulation of immune function. MSCs from MDS patients (MDS-MSC) and healthy donor MSC (HD-MSC) exhibited a similar in vitro phenotype and neither had a direct effect on NK cell function. However, when MDS and HD-MSCs were cultured with monocytes, only the MDS-MSCs acquired phenotypic and metabolic properties of myeloid-derived suppressor cells (MDSCs), with resulting suppression of NK cell function, along with T cell proliferation. A unique MSC transcriptome was observed in MDS-MSCs compared to HD-MSCs, including increased expression of the reactive oxygen species (ROS) regulator, ENC1. High ENC1 expression in MDS-MSC induced suppressive monocytes with increased INHBA, a gene that encodes for a member of the TGF? superfamily of proteins. These monocytes also had reduced expression of the TGF? transcriptional repressor MAB21L2, further adding to their immune suppressive function. Silencing ENC1 or inhibiting ROS production in MDS-MSCs abrogated the suppressive function of MDS-MSC conditioned monocytes. In addition, silencing MAB21L2 in healthy MSC conditioned monocytes mimicked the MDS-MSC suppressive transformation of monocytes. Our data demonstrate that MDS-MSCs are responsible for inducing an immune suppressive microenvironment in MDS through an indirect mechanism involving monocytes.
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Project description:Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal stem cell disorders. We hypothesize that gene expression changes in the bone marrow (BM) microenvironment might play a fundamental role in the development and progression of MDS. The goal of the present study is to investigate the differences in gene expression profiles of BM mesenchymal stromal cells (MSCs) between MDS patients and normal individuals, as well as between MDS subtypes. To this end, we applied global gene expression profiling on BM MSCs from adult de novo MDS patients and from controls. The results suggest that gene expression of the MDS BM microenvironment is difference from control BM. In particular, interferon signaling pathway was shown to be up-regulated in MDS BM. The results also showed altered expression according to disease progression. The present study provides evidence supporting MDS as an immune disease and suggests that BM MSCs are a possible therapeutic target in MDS.
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Project description:Single Cell RNA-Sequencing was performed on enzymatically digested and magnetically depleted CD45- cells from the bone marrow aspirates of MDS and AML patients.
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Project description:Loss of function TET2 mutations are frequently seen in myelodysplastic syndrome (MDS) patients. Previous studies have demonstrated that TET2 deficiency enhances maintenance of MDS hematopoietic stem and progenitor cells (HSPCs). Nonetheless, the pathogenic role of TET2 in MDS progression remains elusive. Here, we demonstrate Tet2 knockout (KO) markedly accelerated malignant transformation in Nup98-HoxD13 (NHD13) transgenic mice and promotes leukemogenesis of HoxA9 transduction/transplant mice. Consistently, low TET2 level cooperating with high HOXA9 level predicts poor outcome of MDS patients. Notably, Tet2 KO conferred a clonal advantage to the HSPCs of NHD13 mice. Whole-exome sequencing revealed that Tet2 KO facilitates accumulation of mutations at genes associated with leukemogenesis, including Arih2, whose loss of function promotes MDS cells proliferation. Using 5-hydroxymethylcytosine immunoprecipitation coupled with high-throughput sequencing analysis, we found while Tet2 deletion decreased overall 5hmC levels, it also increased 5hmC distribution at certain mutation loci such as Arih2. Vitamin C treatment, which mimics Tet2/Tet3 restoration, blocked disease progression in Tet2-deficient NHD13 mice. Collectively, our findings demonstrate that TET2 activity governs occurrence of secondary mutations in MDS HSPCs, providing a rationale for enhancing TETs function to block MDS-malignant transformation.
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Project description:Full Title: Multilineage Dysplasia (MLD) in AML correlates with MDS-related cytogenetic abnormalities and a prior history of MDS or MDS/MPN but has no independent prognostic relevance: A comparison of 408 cases classified as “AML not otherwise specified” or “AML with myelodysplasia-related changes” The WHO classification of acute myeloid leukemia (AML) is hierarchically structured and integrates genetic information, data on patients’ history, and multilineage dysplasia (MLD). The category “AML with MDS-related changes” (AML-MRC) is separated from AML not otherwise specified (AML-NOS) by the presence of either MLD, MDS-related cytogenetics or MDS history. To clarify whether MLD alone is clinically relevant, we analyzed 408 adult patients categorized as AML-MRC or AML-NOS. EFS (Median 13.8 months vs. 16.0 months) and 3-year-OS (45.8% vs. 53.9%) did not differ significantly between patients with MLD and without. However, MLD correlated with pre-existing MDS (p<0.001) and MDS-related cytogenetics (p=0.035). Patients with MLD as sole AML-MRC criterion (AML-MLD-sole; n=90) had less frequently FLT3-ITD (p=0.032), and a lower median age than AML-NOS (n=232), but EFS, OS, and WBC did not differ significantly. Contrarily, patients with AML-NOS plus AML-MLD-sole (n=323) versus patients with MDS history or MDS-related cytogenetics (n=85) had better EFS (16.9 vs. 10.7 months; p=0.005) and 3-year-OS (55.8% vs. 32.5%; p=0.001). Gene expression profiles were measured for a subset of 96 patients. Analysis of the expression data showed distinct clusters for AML-MLD-sole and AML-NOS versus AML with MDS-related cytogenetics or MDS history. Thus, MLD demonstrated no independent clinical impact, while cytogenetics and MDS history were of prognostic relevance. This data suggest modifications in a revised WHO proposal. All 96 bone marrow samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation.
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Project description:To investigated dysregulated miRNAs in human MDS patients, we performed miRNA-sequencing (miRNA-seq) of serum EVs from 38 MDS patients and 8 healthy subjects. The miRNA profile in EVs from MDS patients was distinctly clustered from that in healthy individuals. In addition, the miRNAs significantly upregulated in the MDS group target pathways linked to cell survival, proliferation, and MSC differentiation, indicating that they have remarkably similar properties to miRNAs in murine EVs from MDS cells. These results suggest that miRNAs play an essential role in the MSC impairment observed in MDS.
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