Single cell RNA sequencing of paired myelodysplastic syndrome and secondary acute myeloid leukemia bone marrow aspirate samples
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE205490 | GEO | 2022/06/14
REPOSITORIES: GEO
Similar Datasets
Project description:Myelodysplastic syndromes (MDS) are a heterogenous group of hematopoietic stem cell disorders characterized by dysplastic blood cell formation and peripheral blood cytopenias. Up to 30% of patients with MDS will progress to a highly chemotherapy-resistant secondary acute myeloid leukemia (sAML). We identified mutations in U2AF1 in MDS patients and patients with U2AF1 mutations are at an increased risk of developing sAML. We identified mutations in U2AF1 in patients with MDS and hypothesized that U2AF1 mutations may represent a novel mechanism that could alter gene expression in MDS. To elucidate gene expression changes associated with U2AF1 mutations, we analyzed the global mRNA expression profile obtained from bone marrow CD34+ cells purified from 5 MDS patients with a U2AF1 mutation, 10 MDS patients without a mutation, and 4 normal donors.
2011-11-23 | E-GEOD-30195 | biostudies-arrayexpress
Project description:Myelodysplastic syndromes (MDS) are a heterogenous group of hematopoietic stem cell disorders characterized by dysplastic blood cell formation and peripheral blood cytopenias. Up to 30% of patients with MDS will progress to a highly chemotherapy-resistant secondary acute myeloid leukemia (sAML). We identified mutations in U2AF1 in MDS patients and patients with U2AF1 mutations are at an increased risk of developing sAML.
2011-11-23 | GSE30195 | GEO
Project description:Prior studies using DNA microarray platforms have shown alterations of gene expression profiles (GEPs) of marrow cells in myelodysplastic syndromes (MDS). Using the increased sensitivity and accuracy of high-throughput RNA sequencing (RNA-Seq) for detecting and quantifying mRNA transcripts, our study has demonstrated novel significant differences in GEPs between MDS and normal CD34+ marrow cells with 41 genes identified as disease classifiers. Additionally, two main clusters of GEPs distinguished patients based on their major clinical features, particularly between those whose disease remained stable (sMDS) vs patients whose illness transformed to acute myeloid leukemia within 12 months (tMDS). The genes whose expression was associated with disease outcome were involved in functional pathways and biologic processes highly relevant for MDS. Exomic analysis identified MDS-associated pathogenic mutations in virtually all patients tested. MDS subgroups with spliceosome mutations demonstrated distinct differential isoform usage and expression and consequent dysregulation of distinct biological functions. This combination of clinical, transcriptomic and exomic findings provides valuable molecular insights into the mechanisms underlying MDS and its progression to a more aggressive stage and also facilitates prognostic characterization of MDS patients.
2018-04-09 | GSE111085 | GEO
Project description:Single cell RNA sequencing of paired myelodysplastic syndrome and secondary acute myeloid leukemia bone marrow aspirate samples
| PRJNA847640 | ENA
Project description:Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response. We performed global methylation analysis of 75 patients with high risk MDS and secondary AML (sAML) who were included in CETLAM MDS-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetics. At diagnosis, no global methylation pattern allowed us to differentiate patients according to the cytological subtype, cytogenetics or treatment response. But we found a methylation signature defined by 200 probes, which allowed us to distinguish between responding and non-responding patients to azacitidine (AZA) treatment. Studying follow-up samples, we have confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to determine a methylation pattern predictive of progression or relapse. In conclusion, altered DNA methylation patterns at diagnosis, in a subset of determined CpGs, may serve as biomarker for predicting AZA response.
2021-01-27 | GSE152710 | GEO
Project description:Microarray analysis with 40,000 cDNA gene chip arrays determined differential gene expression profiles (GEPs) in CD34+ marrow cells from myelodysplastic syndrome (MDS) patients compared to normal individuals. Using focused bioinformatics analyses, we found 1175 genes significantly differentially expressed by MDS vs Normal, requiring a minimum of 39 genes to separately classify these patients. Major GEP differences were demonstrated between Normal and MDS patients and between several MDS subgroups: (1) those whose disease remained stable (sMDS) and those who subsequently transformed (tMDS) to acute myeloid leukemia (AML); (2) between del(5q) and other MDS patients. A 6-gene ‘poor risk’ signature was defined which was associated with AML transformation and provided additive prognostic information for IPSS Intermediate-1 patients. Over-expression of genes generating ribosomal proteins and for other signaling pathways was demonstrated in the tMDS patients. Comparison of del(5q) to the remaining MDS patients showed 1924 differentially expressed genes, with under-expression of 1014 genes, 11 of which were within the 5q31-32 Commonly Deleted Region. These data demonstrated (1) GEPs distinguishing MDS patients from normal and between those with differing clinical outcomes (tMDS vs sMDS) and cytogenetics [eg, del(5q)] ; and (2) molecular criteria refining prognostic categorization and associated biologic processes in MDS. Gene expression profiles from CD34+ cells of 35 MDS subjects and 6 Normals were compared.
2009-10-31 | E-GEOD-18366 | biostudies-arrayexpress
Project description:The marrow microenvironment contributes to the pathogenesis of ineffective hematopoiesis in Myelodysplastic Syndromes (MDS). Since mutations and cytogenetic alterations are generally not present in marrow stromal cells, we hypothesized that epigenetic alterations may be responsible for altered stroma functionin MDS. Global DNA methylation of MDS marrow-derived stroma was analyzed by HELP assay and compared to healthy controls. MDS stroma showed aberrant hypermethylation that preferentially occurred outside of CpG islands and involved important signaling pathways.Comparison with stroma derived from 5-Azacytidine (5-Aza) treated MDS patients revealed abrogation of aberrant methylation in treated samples. Integrative expression analysis revealed that the WNT pathway was epigenetically dysregulated in MDS stroma, and the WNT antagonists FRZB and SFRP1 were aberrantly hypermethylated and underexpressed. These epigenetic changes were validated ina co-culture model of stroma and leukemic cells and in an independent set of MDS samples. Importantly, 5-Aza treatment of MDS stroma enhanced hematopoietic activity and erythroid differentiationfrom co-cultured healthy CD34+ cells. These results reveal widespread aberrant epigenetic changes in the MDS marrow microenvironment and demonstrate that DNA methyl transferase inhibitors alter the epigenomic profiles of stromal cells, potentiallycontributing to theirtherapeutic efficacy. The study population consisted of 6 MDS patients and 3 healthy controls. Individual HpaII restriction digest profiles were compared to an internal MspI digest control, to yield differentially methylated fragments for every sample.
2015-05-20 | E-GEOD-60233 | biostudies-arrayexpress
Project description:In order to gain insight into the molecular pathogenesis of the myelodysplastic syndromes (MDS), we performed global gene expression profiling and pathway analysis on the hematopoietic stem cells (HSC) of 183 MDS patients as compared with the HSC of 17 healthy controls. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathway. Among the most significantly deregulated gene pathways in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of DNA damage response and checkpoint pathways. We have identified distinct gene expression profiles and deregulated gene pathways in patients with del(5q), trisomy 8 or â??7/del(7q). Patients with trisomy 8 are characterized by deregulation of pathways involved in the immune response, patients with â??7/del(7q) by pathways involved in cell survival, whilst patients with del(5q) show deregulation of integrin signaling and cell cycle regulation pathways. This is the first study to determine deregulated gene pathways and ontology groups in the HSC of a large group of MDS patients. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype and give new insights into the molecular pathogenesis of this disorder thereby providing new targets for therapeutic intervention. 183 patients with MDS patients and 17 healthy controls were included in the study. Bone marrow samples were obtained and CD34+ cells isolated from MDS patients and healthy controls. Samples were hybridized to Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays
2010-03-24 | E-GEOD-19429 | biostudies-arrayexpress
Project description:In recent years fatty acid metabolism has gained greater attention in haematological cancers, such as myeloid dysplastic syndrome (MDS) and secondary acute myeloid leukaemia (sAML), and has been implicated in increased proliferation and drug resistance. We have characterised two populations of FACS-sorted MDS/sAML cells - SKK-1LOW and SKK-1HIGH - that retain distinct fatty acid uptake phenotypes that are stable over time. Transcriptomic analysis of SKK-1LOW and SKK-1HIGH confirmed differentially expressed genes. Gene ontology analysis revealed gene expression differences principally in fatty acid transport genes and receptor tyrosine kinases, of which KIT was associated with low fatty acid uptake. SKK-1LOW resembled a leukaemic stem cell sub-population on the level of its immunophenotype and exhibited greater resistance to the hypomethylating agent, azacitadine. Overall, this study sheds new light on the relatively under-characterised SKK-1 cell line, which may be useful for the study of MDS-to-sAML transformation.
2021-06-13 | GSE152161 | GEO
Project description:Poor clinical outcome of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) has been attributed to failure of current chemotherapeutic regimens to target leukemic stem cells. We recently identified p21-activated kinase (PAK1) as a downstream effector molecule of H2.0-like homeobox (HLX), a gene functionally relevant for AML pathogenesis. In this study, we find that inhibition of PAK1 activity by small molecule inhibitors or by RNA interference leads to profound leukemia-inhibitory effects both in vitro and in vivo. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of MYC oncogene and a core network of MYC target genes. Moreover, we find that PAK1 up-regulation occurs during disease progression and is relevant for patient survival in MDS. Importantly, we find that inhibition of PAK1 inhibits primary human leukemic cells including immature leukemic stem cell-enriched populations. Our studies highlight PAK1 as a novel target in AML and MDS, and support the use of PAK1 inhibitors as a therapeutic strategy in these diseases. To obtain insight into the molecular mechanism for the induction of apoptosis and differentiation resulting from PAK1 inhibition in AML, we performed gene expression microarrays following treatment with either IPA-3 or FRAX-597. RNA was isolated from THP-1 cells after 5 hours of treatment with IPA-3 (6 ug/mL), FRAX-597 (2 ug/mL) or an equal volume of DMSO using Trizol Reagent (Invitrogen).
2015-07-11 | E-GEOD-70791 | biostudies-arrayexpress