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:Myeloproliferative neoplasms (MPNs) arise via the acquisition of a driver mutation in a single hematopoietic stem cell (HSC), often decades prior to the development of a clinical phenotype. The most common MPN driver mutation, JAK2V617F, activates aberrant JAK/STAT signaling via cytokine receptors critical for myelopoiesis. Over time, this MPN HSC clone outcompetes its normal counterparts, leading to excessive myeloid cell production and contributes to lymphopenia in patients with MPNs and leades to elevated neutrophil-to-lymphocyte ratio (NLR), which is predictive of disease-related complications including thrombosis and mortality. We conducted this study to learn how hematopoiesis from the JAK2V617F clone affects lymphopoiesis in patients with MPNs. Although myeloid proliferation via aberrant JAK2 signaling is the most apparent mechanistic link between JAK2V617F and MPN phenotypes, our findings demonstrate that impaired lymphoid differentiation is an additional feature of JAK2V617F hematopoiesis, leading to the rarity of JAK2V617F lymphocytes despite the dominance of JAK2V617F HSCs in patients with MPNs. The combination of prolific myelopoiesis and defective lymphopoiesis from the JAK2V617F clone is a potential connection between MPN pathology and the surrogate markers, including NLR and lymphopenia, which hold prognostic significance. Based on our data, we speculate that, defective JAK2V617F lymphopoiesis and the consequent increased burden of lymphopoiesis from residual normal HSC clones drives the appearance of abnormal lymphocyte subsets, lymphoproliferative disease or T cell exhaustion in MPNs. Further study of MPN lymphopoiesis provides an opportunity to define the immune deficits underlying the myriad complications that affect patients with MPNs.
2024-09-01 | GSE269568 | 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: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: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: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: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:Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal disorders characterized by aberrant hematopoietic proliferation and an intrinsic risk of progression to blast phase. The WHO classification 2022 identifies chronic myeloid leukemia and the BCR::ABL1 negative MPNs polycythemia vera, primary myelofibrosis and essential thrombocythemia as individual entities. However, overlaps, borderline findings or transitions between MPN subtypes occur and incomplete clinical data often complicates diagnosis. By conducting a thorough genetic analysis, we've developed a model that relies on 12 genetic markers to accurately stratify MPN patients. The model can be simplified into a decision tree for routine use. Comparing samples at chronic and blast phase revealed, that one third of patients lost their MPN driver-gene mutation, while mutations in splicing and chromatin modifying genes were stable, indicating a shared founder clone of chronic and blast phase with different driver mutations and therefore different progressing capacities. This was further supported by gain of typical de novo AML gene mutations, accompanied by gain of complex karyotypes and RAS pathway gene mutations. Our data suggest to perform a broader genetic screening at diagnosis and also at clinical progression, as driver mutations may change and the MPN driver mutations present at diagnosis may disappear.
2024-09-20 | GSE277354 | 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.
2012-12-05 | GSE42721 | GEO