Single cell RNA sequencing of MPN patients from humans in South Korea
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE254423 | GEO | 2025/01/22
REPOSITORIES: GEO
Dataset's files
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Similar Datasets
Project description:Even though mutations in epigenetic regulators frequently occur in myeloproliferative neoplasms, their effects on the epigenome have not been well studied. Furthermore, even though primary myelofibrosis (PMF) has a markedly worse prognosis compared to essential thrombocytosis (ET) or polycythemia vera (PV), the molecular distinctions between these subgroups are not well elucidated. We performed the HELP (HpaII tiny fragment enriched by LM-PCR) assay to study genome-wide methylation in PV, ET and PMF samples compared with healthy controls. We determined that PV and ET are characterized by aberrant promoter hypermethylation while PMF is an epigenetically distinct subgroup characterized by both aberrant hyper and hypomethylation. Aberrant hypomethylation in PMF was seen to occur in non CpG island loci, demonstrating further qualitative differences between the disease subgroups. The differentially methylated genes in PV and ET were involved predominantly in cell signaling pathways and were enriched for binding sites of GATA1 and other transcription factors. In contrast, aberrantly methylated genes in PMF were involved in inflammatory pathways and were enriched for NF1 (NFI), LEF1 and other transcription factors. Within the PMF subgroup, cases with ASXL1 disruptions formed an epigenetically distinct subgroup with relatively increased methylation. Cases of MPNs with TET2 mutations demonstrated decreased levels of hydroxymethylation and distinct set of hypermethylated genes. In contrast, the JAK2V617F mutation did not drive epigenetic clustering within MPNs. Finally, the significance of aberrant methylation was demonstrated by sensitivity of MPN derived cell lines to decitabine. These results demonstrate epigenetic differences between PMF and PV/ET and reveal methylomic signatures of ASXL1 and TET2 mutations. The study population consisted of 26 MPN patients (6 cases of ET, 8 cases of PV and 12 cases of PMF) 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. The purpose of this study was to assess genome wide patterns of DNA methylation across the MPN stratified by disease class.
2012-12-05 | E-GEOD-42721 | biostudies-arrayexpress
Project description:Even though mutations in epigenetic regulators frequently occur in myeloproliferative neoplasms, their effects on the epigenome have not been well studied. Furthermore, even though primary myelofibrosis (PMF) has a markedly worse prognosis compared to essential thrombocytosis (ET) or polycythemia vera (PV), the molecular distinctions between these subgroups are not well elucidated. We performed the HELP (HpaII tiny fragment enriched by LM-PCR) assay to study genome-wide methylation in PV, ET and PMF samples compared with healthy controls. We determined that PV and ET are characterized by aberrant promoter hypermethylation while PMF is an epigenetically distinct subgroup characterized by both aberrant hyper and hypomethylation. Aberrant hypomethylation in PMF was seen to occur in non CpG island loci, demonstrating further qualitative differences between the disease subgroups. The differentially methylated genes in PV and ET were involved predominantly in cell signaling pathways and were enriched for binding sites of GATA1 and other transcription factors. In contrast, aberrantly methylated genes in PMF were involved in inflammatory pathways and were enriched for NF1 (NFI), LEF1 and other transcription factors. Within the PMF subgroup, cases with ASXL1 disruptions formed an epigenetically distinct subgroup with relatively increased methylation. Cases of MPNs with TET2 mutations demonstrated decreased levels of hydroxymethylation and distinct set of hypermethylated genes. In contrast, the JAK2V617F mutation did not drive epigenetic clustering within MPNs. Finally, the significance of aberrant methylation was demonstrated by sensitivity of MPN derived cell lines to decitabine. These results demonstrate epigenetic differences between PMF and PV/ET and reveal methylomic signatures of ASXL1 and TET2 mutations.
2012-12-05 | GSE42721 | GEO
Project description:Primary myelofibrosis (PMF) together with polycythemia vera (PV) and essential thrombocythemia (ET) belongs to the classic Philadelphia-negative myeloproliferative neoplasms (MPNs). PV and ET can evolve to secondary myelofibrosis (SMF) giving rise to post-PV (PPV) and post-ET (PET) myelofibrosis (MF). PMF and SMF patients are currently managed in the same way and prediction of survival is based on the same prognostic models, even if it has been demonstrated that they can’t accurately distinguish different risk categories in SMF. In the last few years interest grew concerning the ability of gene expression profiling (GEP) to provide valuable prognostic information for clinical decision making. To construct a molecular signature that can predict survival according to gene expression we studied GEP of granulocytes from 114 MF patients, including 35 prefibrotic/early PMF (Pre-PMF), 37 overt PMF (Overt-PMF), 26 PET and 16 PPV, using microarray platform.
2021-03-09 | GSE159514 | GEO
Project description:Since most DNA methylation studies in Classic Philadelphia-negative myeloproliferative neoplasms (MPNs) M-bM-^@M-^S polycythaemia vera (PV), essential thrombocythaemia (ET), and primary myelofibrosis (PMF) - have been performed on a gene-by-gene basis, a more comprehensive methylation profiling is needed to know the real implication of this alteration. In order to investigate the DNA methylation profile in chronic and transformed phase MPNs, we performed genome-wide DNA methylation arrays in 71 chronic (24 PV, 23 ET and 24 PMF) and 13 transformed MPNs. The three types of chronic MPNs showed the same aberrant DNA methylation pattern when compared to controls. Differentially methylated genes (DMG) were enriched in a gene network centered on the NF-M-NM-:B pathway, indicating that they may be involved in the pathogenesis of these diseases. In the case of transformed MPNs we detected an increased number of DMGs with respect to chronic MPNs. Interestingly, these genes were enriched in a list of DMGs in primary AMLs and in a gene network centered around the IFN pathway. Further studies are clearly needed to elucidate the role of DMGs in MPNs, but our results suggest that this alteration plays an important role in the pathogenesis and transformation of MPNs and that modulation of these pathways would allow us to improve the quality of life of these patients. The methylation profile of 24 PBMCs samples from patients diagnosed with Policytemia Vera, 23 from Essential Thrombocythemia and 24 from primary myelofibrosis was assessed. We also included 13 secondary acute myeloid leukaemia (AML): 5 transformed PMF,4 transformed TE and 4 transformed PV. As reference,4 healthy donor PBMCs samples from whole peripheral blood and 4 PBMCs samples from bone marrow were used.
2013-11-29 | E-GEOD-42042 | biostudies-arrayexpress
Project description:Since most DNA methylation studies in Classic Philadelphia-negative myeloproliferative neoplasms (MPNs) – polycythaemia vera (PV), essential thrombocythaemia (ET), and primary myelofibrosis (PMF) - have been performed on a gene-by-gene basis, a more comprehensive methylation profiling is needed to know the real implication of this alteration. In order to investigate the DNA methylation profile in chronic and transformed phase MPNs, we performed genome-wide DNA methylation arrays in 71 chronic (24 PV, 23 ET and 24 PMF) and 13 transformed MPNs. The three types of chronic MPNs showed the same aberrant DNA methylation pattern when compared to controls. Differentially methylated genes (DMG) were enriched in a gene network centered on the NF-κB pathway, indicating that they may be involved in the pathogenesis of these diseases. In the case of transformed MPNs we detected an increased number of DMGs with respect to chronic MPNs. Interestingly, these genes were enriched in a list of DMGs in primary AMLs and in a gene network centered around the IFN pathway. Further studies are clearly needed to elucidate the role of DMGs in MPNs, but our results suggest that this alteration plays an important role in the pathogenesis and transformation of MPNs and that modulation of these pathways would allow us to improve the quality of life of these patients.
2013-11-29 | GSE42042 | GEO
Project description:Primary myelofibrosis (PMF) is a Myeloproliferative Neoplasm (MPN) characterized by megakaryocyte hyperplasia, progressive bone marrow fibrosis, extramedullary hematopoiesis and transformation to Acute Myeloid Leukemia (AML). Beginning in early 2005, a number of novel mutations involving JAK2, CALR, MPL, TET2, ASXL1, DNMT3a, CBL, IDH1 and IDH2 have been described in MPNs, depicting a really complex genomic landscape for MPNs. To shed light on the genomic lesions that can contribute to disease phenotype and/or development, we integrated gene expression and copy number signals and identified several genomic abnormalities leading to a concordant alteration in gene expression levels. In particular, copy number gain in the polyamine oxidase (PAOX) gene locus is accompanied by a coordinated transcriptional up-regulation in PMF patients. Inhibition of PAOX resulted in rapid cell death in PMF progenitor cells, but not in normal cells, suggesting that PAOX inhibition could represent a therapeutic strategy to selectively target PMF cells without affecting normal hematopoietic cells’ survival. Moreover, copy number loss in the chromatin modifier HMGXB4 gene correlates with a concomitant transcriptional down-regulation in PMF patients. Interestingly, silencing of HMGXB4 induces megakaryocyte differentiation, while inhibiting erythroid development, in human hematopoietic stem/progenitor cells. These results highlight a previously un-reported, yet potentially interesting role of HMGXB4 in the hematopoietic system suggesting that genomic and transcriptional imbalances of HMGXB4 could contribute to the aberrant expansion of the megakaryocytic lineage that characterize PMF patients. In this study, the authors take advantage of the integrative analysis of gene expression and copy number data to identify the concordant gain/up-regulation of the polyamine oxidase PAOX and the loss/down-regulation of the chromatin modifier HMGXB4. This work sheds light on the influence of genomic abnormalities on gene expression regulation in PMF CD34+ cells and on their contribution to specific features of PMF, such as a hyperplastic megakaryopoiesis.
2018-05-21 | GSE69161 | GEO
Project description:Primary mielofibrosis (PMF) is a rare chronic myeloproliferative disorder characterized by the accumulation of abnormal megakaryocytes (Mks) in the bone marrow (BM), variable degrees of BM fibrosis, osteosclerosis and angiogenesis, immature myeloid and erythroid cells, and tear-drop erythrocytes in the peripheral blood (PB), and extramedullary hematopoiesis. The identification of the JAK2V617F mutation represented a seminal discovery in the field of Philadelphia-chromosome–negative chronic myeloproliferative neoplasms (MPNs), providing clues to the pathogenesis, prompting a revision of the diagnostic criteria, and culminating in the development of clinical trials with JAK2 (and JAK1) inhibitors. The JAK2V617F mutation occurs in almost all patients with polycythemia vera (PV) and in 50%-70% of those with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Soon after the identification of the JAK2V617F mutation, mutations in JAK2 exon 12 were described in rare patients with JAK2V617F-negative PV and mutations in MPL were reported in 5%-10% of ET or PMF subjects. The complexity of the molecular pathogenesis of MPNs is reinforced by discovery of additional mutations in TET2, ASXL1, CBL, IDH1/IDH2, EZH2 and IKZF1. These mutations are detected in a minority of patients at different phases of the disorder, including leukemic transformation, and are variably associated each other and with JAK2 or MPL mutations. In order to better characterize biological differences between mutated and wild-type PMF cell populations we performed a gene expression profiling on 9 samples carrying at least one mutation in ASXL1, SRSF2 or EZH2 genes and 11 wild-type samples using the Affymetrix GeneChip technology. After data preprocessing and filtering a supervised analysis approach was used to define a gene expression signature for mutated samples. PMF samples carrying at least one mutation in ASXL1, SRSF2 or EZH2 genes exhibit a specific molecular signature as compared with WT samples. Gene expression profile (GEP) of CD34+ cells from 20 PMF patients (1 replicate for each sample). In particular, GEP was performed on 9 samples carrying at least one mutation in ASXL1, SRSF2 or EZH2 genes and 11 wild-type samples.
2013-07-23 | E-GEOD-41812 | biostudies-arrayexpress
Project description:Ph-negative myeloproliferative neoplasms (MPNs) are characterized by many somatic mutations which have already been shown useful in the prognostic assessment of MPN patients. Moreover, aberrant microRNA (miRNA) expression seems to add to the molecular complexity of MPNs, as specific miRNA signatures capable of discriminating MPN cells from those of normal donors were previously reported. In order to have a comprehensive picture of miRNA deregulation and its relationship with differential gene expression in primary myelofibrosis (PMF) cells, we obtained gene- (GEP) and miRNA expression profiles (miEP) of CD34+ cells from 31 healthy donors and 42 PMF patients using Affymetrix technology (HG-U219 and miRNA 2.0 arrays). Differentially expressed genes (DEG) and miRNAs (DEM) were sorted out by means of Partek Genomic Suite vs 6.6. Since each miRNA can target many mRNAs while a single mRNA can be targeted by multiple miRNAs, we performed Integrative Analysis (IA) by means of Ingenuity Pathway Analysis (IPA) to untangle this combinatorial complexity. In particular, IPA points out DEM-DEG pairs among experimentally validated interactions from TarBase, miRecords and Ingenuity Expert Findings as well as predicted microRNA-mRNA interactions from TargetScan. IPA microRNA Target Filter was then employed to select only the DEM-DEG pairs showing an anti-correlated expression pattern and to build regulatory networks. Finally, 3'UTR luciferase reporter assays were performed to validate IPA predicted miRNA-mRNA interactions. This study allowed the identification of different networks possibly involved in PMF onset and progression, highlighting an aberrant cross-regulation in miRNA-targets involved in malignant hematopoiesis. Furthermore, Integrative analysis was proved a powerful tool to unravel miRNA-mRNA interactions in functional networks, shedding light on the potential contribution of miRNAs to PMF pathogenesis. Gene expression profile (GEP) and miRNA expression profile (miEP) were performed starting from the same totalRNA of CD34+ cells from 42 PMF patients and 31 healthy donors (n=16 PB CD34+, n=15 BM CD34+) (1 replicate for each sample). In particular, GEP and miEP were performed on 23 PMF patients carrying the mutation JAK2V617F and 19 wild-type samples.
2014-10-01 | E-GEOD-53482 | biostudies-arrayexpress
Project description:An increased number of circulating CD34+ hematopoietic progenitors (HP) and a prominent amplification of dystrophic megakaryocytes (MK) are observed in PMF patients. As transcriptome data from CD34+ hematopoietic progenitors showed modulations of FLT3 and MAP kinase expression independently of the JAK2V617F mutation status Transcriptome analysis was performed on circulating CD34+ cells from PMF patients using Agilent 22K microarray and compared to CD34+ cells from blood and bone marrow from un-mobilized healthy donors. Indirect map: each tested sample was hybridzed with reference probe
2008-07-29 | E-GEOD-12234 | biostudies-arrayexpress
Project description:An increased number of circulating CD34+ hematopoietic progenitors (HP) and a prominent amplification of dystrophic megakaryocytes (MK) are observed in PMF patients. As transcriptome data from CD34+ hematopoietic progenitors showed modulations of FLT3 and MAP kinase expression independently of the JAK2V617F mutation status
2008-07-29 | GSE12234 | GEO