Gene expression profile of normal v early MDS v non-MDS anemia bone marrow CD34 cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE2779 | GEO | 2005/08/05
SECONDARY ACCESSION(S): PRJNA92315
REPOSITORIES: GEO
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Project description:Early, low risk IPSS (International Prognostic Scoring System) myelodysplasia (MDS) is a heterogeneous disorder where the molecular and cellular haematopoietic defects are poorly understood. To gain insight into this condition, we analyzed gene expression profiles of marrow CD34+ progenitor cells from normal karyotype, low blast count MDS patients, age-matched controls and patients with non-MDS anaemia. The aim of the study was to further understanding of the cellular defect in MDS and to identify biomarkers of disease Experiment Overall Design: Bone marrow (BM) CD34 cells were purified from patients with MDS, non-MDS anemia and from normal donors. Total RNA was extracted from Tri-reagent and quality verified on by capillary electrophoresis (Agilent). RNA was amplified by the Affymetrix small sample protocol. cRNA was hybridised to Affymetrix U133A chips under standard conditions. Initial data was analysed in MAS 5.0
2007-09-20 | E-GEOD-2779 | biostudies-arrayexpress
Project description:Recurrent mutations in ASXL1 are found in various hematological malignancies and are associated with poor prognosis. In particular, ASXL1 mutations are frequently found in patients with hematological malignancies associated with myelodysplasia including myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia. Although loss-of-function ASXL1 mutations promote myeloid transformation, a large subset of ASXL1 mutations is thought to result in stable truncation of ASXL1. Here we demonstrate that C-terminal truncating ASXL1 mutations (ASXL1-MT) inhibit myeloid differentiation and induce MDS-like disease in mice, displaying all the features of human MDS including multi-lineage myelodysplasia, pancytopenia and occasional progression to overt leukemia. Concerning the molecular mechanisms, ASXL1-MT derepressed expression of Hoxa9 and miR-125a through inhibiting PRC2-mediated methylation of H3K27. miR-125a targeted expression of a surface receptor Clec5a, which was found to supports for myeloid differentiation. In addition, HOXA9 expression was high in MDS patients with ASXL1 mutations while Clec5a expression was generally low in MDS patients. Thus, ASXL1-MT induced MDS-like disease in mice via derepression of Hoxa9 and miR-125a, and Clec5a downregulation. Our data provide evidence for a novel axis of MDS pathogenesis (ASXL1 mutations-upregulation of HoxA9 and miR-125a-downregulation of Clec5a) and implicate both ASXL1 mutants and miR-125a as therapeutic targets in MDS.
2013-07-31 | GSE49118 | GEO
Project description:Recurrent mutations in ASXL1 are found in various hematological malignancies and are associated with poor prognosis. In particular, ASXL1 mutations are frequently found in patients with hematological malignancies associated with myelodysplasia including myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia. Although loss-of-function ASXL1 mutations promote myeloid transformation, a large subset of ASXL1 mutations is thought to result in stable truncation of ASXL1. Here we demonstrate that C-terminal truncating ASXL1 mutations (ASXL1-MT) inhibit myeloid differentiation and induce MDS-like disease in mice, displaying all the features of human MDS including multi-lineage myelodysplasia, pancytopenia and occasional progression to overt leukemia. Concerning the molecular mechanisms, ASXL1-MT derepressed expression of Hoxa9 and miR-125a through inhibiting PRC2-mediated methylation of H3K27. miR-125a targeted expression of a surface receptor Clec5a, which was found to supports for myeloid differentiation. In addition, HOXA9 expression was high in MDS patients with ASXL1 mutations while Clec5a expression was generally low in MDS patients. Thus, ASXL1-MT induced MDS-like disease in mice via derepression of Hoxa9 and miR-125a, and Clec5a downregulation. Our data provide evidence for a novel axis of MDS pathogenesis (ASXL1 mutations-upregulation of HoxA9 and miR-125a-downregulation of Clec5a) and implicate both ASXL1 mutants and miR-125a as therapeutic targets in MDS. BM cells derived from mock-transplanted mice and ASXL1-MT transplanted mice were incubated with biotinylated antibodies for CD3e, B220, and TER-119, followed by incubation with streptavidin Micro Beads (Miltenyi Biotec). The marker-negative fraction was separated with LS Columns (Miltenyi Biotec). Using the sorted-BM cells, we compared the expression proliles between 3 sorted-BM cells with mock and 3 sorted-BM cells with ASXL1-MT. Total RNA was extracted by Trizol reagent (Invitrogen) according to the manufacturer’s protocol. Double-stranded cDNA was synthesized from 5 μg of total RNA with oligo (dT)24 T7 primer, amplified with T7 RNA polymerase up to approximately 50 μg of cRNA, and hybridized to Affymetrix Mouse Expression array 430A, which contains 45000 probe sets for 39000 transcripts and variants from over 34000 well-characterized mouse genes (Affymetrix). After washing and staining, the arrays were scanned on the GeneChip system confocal scanner (Affymetrix). The intensity for each feature of the array was captured with Affymetrix Microarray Suite (MAS) Version 5.0 software. Gene set enrichment analysis was performed by using Gene Ontology gene sets from the Molecular Signatures Database (http://www.broad.mit.edu/gsea/msigdb/).
2013-07-31 | E-GEOD-49118 | biostudies-arrayexpress
Project description:In this study, to obtain a complete registry of genetic lesions in MDS and to identify novel therapeutic targets, we performed SNP array analysis and whole exome analysis for novel mutations using high-throughput sequencing technologies. In whole exome analysis, paired CD3-positive T cells were used as a normal control. By comparing sequences in tumors and paired T cells, 268 non-synonymous somatic mutations were confirmed with an overall true positive rate of 53.9 %, including 206 missense, 25 nonsense, and 10 splice site mutations, and 27 frameshift-causing insertions/deletions (indels). The mutations of the known gene targets, however, accounted for only 12.3 % of all detected mutations (N = 33), and the remaining 235 mutations involved previously unreported genes. Combined with the genomic copy number profile obtained by SNP array karyotyping, this array of somatic mutations provided a landscape of myelodysplasia genomes. Copy number analysis of Affymetrix 250K SNP arrays was performed for 29 MDS or related neoplasms and paired 29 germline samples.
2011-09-11 | E-GEOD-31174 | biostudies-arrayexpress
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.
2011-01-01 | E-GEOD-21261 | biostudies-arrayexpress
Project description:lncRNAs not only participate in normal hematopoiesis but also contribute to the pathogenesis of acute leukemia. However, their clinical and prognostic relevance in MDS remains unclear to date. In this study, we profiled the lncRNA expressions in 176 adult patients with primary MDS with Affymetrix GeneChip Human Transcriptome Array 2.0, and identified the lncRNAs whose expression levels were significantly associated with overall survival (OS). We then constructed a risk scoring system with the weighted sum of these lncRNAs. Patients with higher lncRNA scores had a significantly shorter OS and a higher five-year leukemic transformation rate compared with those with lower scores.
2018-02-13 | GSE97064 | GEO
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.
2011-01-01 | GSE21261 | GEO
Project description:Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic progenitors characterized by ineffective hematopoiesis and high propensity to leukemias. Although a number of gene targets have been identified, in many MDS cases, particular genetic targets are unknown. In this study, we performed genome-wide profiling of copy number (CN) abnormalities and allelic imbalances in MDS genomes in order to clarify the distribution of LOH (loss of heterozygosity) and identify their target genes. We analyzed a total of 171MDS and MDS/MPD specimens, including 7 RA/RARS, 23 RCMD/RCMD-RS, 6 5q-syndrome, 30 RAEB-1, 40 RAEB-2, 4 therapy related-MDS/AML, 5 MDSu, 17 CMML-1, 16 CMML-2, 24 overt AML, using high-density SNP arrays. The data were analyzed by CNAG/AsCNAR software we specifically developed for allele-specific CN analysis and sensitive LOH detection. MDS showed characteristic CN profiles in SNP array analysis. Of particular interest is the finding of high frequency of CN-neutral LOH (Uniparental disomy,UPD), which were observed in 51 of 171 (30%) MDS cases. They preferentially involved 1p, 1q, 4q, 7q, 11q, 17p and other chromosomal segments, which were associated with homozygous mutations of both loss-of-function mutations and gain-of function mutations of tumor suppressor genes and cellular oncogenes, including TP53 (17p UPD), AML1/RUNX1 (21q UPD), Nras and cMPL (1p UPD), JAK-2 (9p UPD), and FLT3 (13q UPD). Next we tried to identify a new gene target in 11q UPD, which was most common UPD region in this study and many of these cases were CMML with a normal karyotype. The minimum 11q UPD segment is about 2Mb which existed in 11q23. We sequenced coding exons of c-cbl and detected homozygous mutations in 8 of 9 MDS cases with 11q UPD (CMML= 5, RAEB= 3, overt leukemia= 1), but very rare in cases without 11q UPD (1/162), demonstrating that the mutation is tightly linked to 11q UPD. These mutations were 8 point mutations and 1 micro-deletion, they were accumulated in the linker or RING domain. These c-cbl mutants can transform NIH3T3 in a dominant manner and these mutants are phosphorylated and activate PI3K-Akt pathway. To investigate the functions of these mutants in hematopoietic cells, we introduced these mutants into c-kit(+)Sca1(+)Lin(-) murine bone marrow cells, it prolonged replating capacity of these hematopoietic progenitors. Keywords: SNP-chip To identify oncogenic lesions in MDS, we performed a genome-wide analysis of primary MDS samples using high-density SNP arrays (Affymetrix GeneChip).
2010-04-09 | E-GEOD-15187 | biostudies-arrayexpress
Project description:Aplastic anaemia (AA) is a form of bone marrow failure (BMF) resulting in significant cytopenias and may progress with clonal evolution to myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). MicroRNA expression is dysregulated in MDS/AML but there are limited studies on its role in the pathogenesis of AA. Using stored BM samples (n=81) from 2006-2019 from 52 patients, we demonstrate key differences in miRNA expression between AA patients at diagnosis and de novo MDS patients (n=21). The five most significantly upregulated miRNA in MDS patients (downregulated in AA) were miR-130a-3p, miR-221-3p, miR-126-3p, miR-27b-3p and miR-196b-5p (adj p<0.001). However, at the time of AA clonal progression to secondary MDS/AML, no significant miRNA differences were identified suggesting that the underlying mechanistic pathways are similar between AA progression to MDS/AML and de novo MDS. At diagnosis, miR-127-3p, miR-1271-5p, miR-301b-5p, miR-3934-5p and miR-4531 (adj p=0.081) were upregulated in those whose AA eventually progressed in comparison to those without eventual clonal progression. Using KEGG pathway analysis derived from miRPathDBv2.0, cytokine-cytokine receptor interaction, TGF-, MAP kinase, prolactin, Hippo, neurotrophin and FOXO signalling pathways were enriched in AA patients with clonal progression to MDS/AML; these pathways were similarly enriched in the de novo MDS cohort. These studies highlight the differing miRNA expression profiles in AA and MDS and in AA clonal evolution to MDS/AML.
2023-09-02 | GSE242216 | GEO
Project description:An increasing body of work reveals aberrant hypermethylation of genes occurring in and potentially contributing to the pathogenesis of myeloid malignancies. Several of these diseases, such as myelodysplastic syndromes (MDS), are responsive to DNA methyltransferase inhibitors. In order to determine the extent of promoter hypermethylation in such tumors we compared the distribution of DNA methylation of 14,000 promoters in MDS and secondary AML patients enrolled in a phase I trial of 5-azacytidine and the histone deacetylase inhibitor entinostat against de novo AML patients and normal CD34+ bone marrow cells. The MDS and secondary AML patients displayed more extensive aberrant DNA methylation involving thousands of genes than did the normal CD34+ bone marrow cells or de novo AML blasts. Aberrant methylation in MDS and secondary AML tended to affect particular chromosomal regions, occurred more frequently in Alu poor genes, and included prominent involvement of genes involved in the WNT and MAPK signaling pathways. DNA methylation was also measured at days 15 and 29 after the first treatment cycle. DNA methylation was reversed at day 15 in a uniform manner throughout the genome, and this effect persisted through day 29, even without continuous administration of the study drugs. Keywords: DNA methylation profiling Direct comparison of DNA methylation in bone marrow samples from patients with Myelodysplastic syndrome or secondary Acute Myeloid Leukemia (AML) at baseline and after in vivo treatment with 5-azacytidine + etinostat. A comparison to de novo normal karyotype AML was also performed. Two control groups were included: one consisting of 8 CD34+ bone marrow samples from healthy donors and a second one consisting of matched CD34+ and CD34- fractions from the bone marrows of 4 healthy donors.
2010-05-15 | E-GEOD-17328 | biostudies-arrayexpress