Gene expression profiling in myeloproliferative neoplasms
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
DISEASE(S): MPN
SUBMITTER: Pascal FINETTI
PROVIDER: E-MTAB-510 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Background: Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential (CHIP) face a significantly elevated risk of cardiovascular diseases (CVDs). Endothelial cells (ECs) carrying the JAK2V617F mutation have been detected in many MPN patients. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in MPN patients. Methods: We investigated the impact of endothelial JAK2V617F mutation on CVD development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. Results and Conclusions: Our investigations revealed that JAK2V617F mutant ECs promote CVDs by impairing endothelial function and undergoing endothelial-to-mesenchymal transition (EndMT). Importantly, we discovered that inhibiting the endothelial thrombopoietin receptor MPL suppressed JAK2V617F-induced EndMT and prevented cardiovascular dysfunction caused by mutant ECs. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function, rendering it a promising therapeutic target for preventing or ameliorating cardiovascular complications in patients with MPNs.
2024-05-20 | GSE266848 | GEO
Project description:Background: Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential (CHIP) face a significantly elevated risk of cardiovascular diseases (CVDs). Endothelial cells (ECs) carrying the JAK2V617F mutation have been detected in many MPN patients. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in MPN patients. Methods: We investigated the impact of endothelial JAK2V617F mutation on CVD development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. Results and Conclusions: Our investigations revealed that JAK2V617F mutant ECs promote CVDs by impairing endothelial function and undergoing endothelial-to-mesenchymal transition (EndMT). Importantly, we discovered that inhibiting the endothelial thrombopoietin receptor MPL suppressed JAK2V617F-induced EndMT and prevented cardiovascular dysfunction caused by mutant ECs. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function, rendering it a promising therapeutic target for preventing or ameliorating cardiovascular complications in patients with MPNs.
2024-05-02 | GSE266434 | GEO
Project description:Interferons (IFNs) are cytokines with potent anti-neoplastic properties and significant clinical activity in the treatment of myeloproliferative neoplasms (MPNs). The use of pegylated IFN for the treatment of MPNs has been of particular interest, with several clinical trials establishing clinical responses. Here we demonstrate that chromatin assembly factor 1 subunit B (CHAF1B) is overexpressed in MPN patients. Targeted silencing of CHAF1B enhances transcription of IFN-stimulated genes and promotes IFN-dependent anti-neoplastic effects against MPN patient-derived cells. Our findings suggest that targeting CHAF1B in combination with IFN therapy may offer an avenue for the development of effective combination therapies for the treatment of MPNs.
2023-05-15 | PXD037376 | Pride
Project description:Janus kinases (JAKs) mediate cytokine signaling, cell growth and hematopoietic differentiation. Gain-of-function mutations activating JAK2 signaling are seen in the majority of myeloproliferative neoplasm (MPN) patients, most commonly due to the JAK2V617F driver allele. While clinically-approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic JAK inhibitor therapy in most patients. This has been postulated to be due to incomplete dependence on constitutive JAK/STAT signaling, alternative signaling pathways, and/or the presence of cooperating disease alleles; however we hypothesize this is due to the inability of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a Dre-rox/Cre-lox dual orthogonal recombinase system. Deletion of oncogenic Jak2V617F abrogates the MPN disease phenotype, induces mutant-specific cell loss including in hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition. Furthermore, reversal of Jak2V617F in MPN cells with antecedent loss of Tet2 abrogates the MPN phenotype and inhibits mutant stem cell persistence suggesting cooperating epigenetic-modifying alleles do not alter dependence on mutant JAK/STAT signaling. Our results suggest that mutant-specific inhibition of JAK2V617F represents the best therapeutic approach for JAK2V617F-mutant MPN and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.
2022-05-25 | GSE203464 | 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:Cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms. Their mechanisms are poorly understood. To investigate the role of microvesicles in these events, we performed a proteomic analysis of microvesicles derived from red blood cells from mice with a myeloproliferative neoplasms (Jak2V617F Flex/WT ;VE-cadherin-Cre) vs. littermate controls.
2020-02-17 | PXD014451 | Pride
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:Myeloproliferative neoplasms (MPN) are clonal hematopoietic diseases that include essential thrombocytosis (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) as well as BCR-ABL+ chronic myelogenous leukemia (CML). In the past several years, studies with cDNA microarrays have defined patterns of gene expression corresponding to specific molecular abnormalities, oncologic phenotypes, and clinical outcomes in hematologic malignancies. This study was aimed at the description of a gene expression signature in MPN which would eventually present a new pathogenetic approaching and also diagnostic as well as prognostic information. Using cDNA microarray analysis, involving 25,100 unique genes, we studied the gene expression profile of the pluripotent hematopoietic CD34+ stem cells and mature granulocytes obtained from peripheral blood of ET, PV, PMF and CML patients compared with healthy individuals. The average number of CD34+ cells (cells/µl) in peripheral blood was approximately 6 in PV and ET, 111 in PMF and 2880 in CML as measured by flow cytometry. A somatic point mutation JAK2V617F was detected in 93% of PV, 73% of PMF and 55% of ET patients within genetically homogenous population. The homozigosity for JAK2V617F mutation was the highest in PV (60%), less prominent in PMF (42%) and low in ET (11%) patients. The JAK2V617F mutation negative patients were also negative for exon 12 mutations. Approximately 420, 680 and 1130 genes had unique expression among CD34+ cells of ET, PV and PMF patients, respectively. In addition comparing to healthy controls, ET, PV, PMF and CML patients showed difference in 840, 1180, 1160 and 2050 expressed genes, respectively. Furthermore, we studied EPO and JAK-STAT signaling pathways related genes expression in MPN. The FOS, RAF1 and JAK2 gene expression, related to EPO signaling pathway, was elevated in ET, PV, PMF and reduced in CML comparing to healthy controls. Related to these genes, the JAK2V617F mutation homozygous and heterozygous patients generally displayed more significant differences comparing to patients with no mutation. STAT5 gene expression was decreased in all MPN patients. CSF3R, STAT1 and STAT3 gene expression, related to JAK-STAT signaling pathway, was elevated in ET, PV, PMF and reduced in CML comparing to healthy controls. CREBBP gene expression was reduced in CD34+ cells of ET, PV and PMF patients, but during maturation it enhanced expression in granulocytes. In conclusion, molecular profiling of CD34+ cells and granulocytes revealed a certain number of genes with changed expression that, beyond their recognized function in disease pathogenesis, can be related to patients’ clinical characteristics and may have an imminent prognostic relevance.
2015-03-14 | GSE55976 | GEO