Longitudinal inflammatory gene expression associated with advanced myelofibrosis
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ABSTRACT:
PROVIDER: PRJNA852160 | ENA |
REPOSITORIES: ENA
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Project description:Inflammatory gene expression associated with advanced myelofibrosis
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Project description:Myelofibrosis (MF) is a progressive, bone marrow (BM) malignancy associated with monocytosis, and is believed to promote the pathological remodelling of the extracellular matrix. Here, we show that the pathologic grading of MF was associated with inflammatory gene expression in primary patient samples.
2022-07-11 | GSE206770 | GEO
Project description:Myelofibrosis (MF) is a progressive, bone marrow (BM) malignancy associated with monocytosis, and is believed to promote the pathological remodelling of the extracellular matrix. Here, we show that the pathologic grading of MF was associated with inflammatory gene expression in primary patient samples.
2022-07-11 | GSE206768 | GEO
Project description:Myelofibrosis (MF) is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. MF patients frequently carry driver mutations in JAK2 and Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across MF patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three therapeutic vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high MAPK-Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high ER stress, responding to ER stressors and UPR inhibition. Overall, our integrated analyses provide a molecularly-motivated roadmap for individualized MF patient treatment.
2023-10-12 | PXD036075 | Pride
Project description:Myelofibrosis is a severe myeloproliferative neoplasm characterised by increased numbers of abnormal bone marrow megakaryocytes that induce fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed single-cell transcriptome profiling of 135,929 CD34+Lineage- hematopoietic stem/progenitor cells (HSPCs), single-cell proteomics, genomics and functional assays. We identified a bias towards megakaryocyte differentiation apparent from early multipotent stem cells in myelofibrosis and associated aberrant molecular signatures. A sub-fraction of myelofibrosis megakaryocyte progenitors (MkP) were transcriptionally similar to healthy-donor MkP but the majority were disease-specific, with distinct populations expressing fibrosis- and proliferation-associated genes. Mutant-clone HSPCs showed increased expression of megakaryocyte-associated genes compared to wild-type HSPCs, and we provide early validation of G6B as a potential immunotherapy target. Our study paves the way for selective targeting of the myelofibrosis clone and illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.
2020-05-07 | GSE144568 | GEO
Project description:Longitudinal Multi’omics of the Human Microbiome in Inflammatory Bowel Disease
| PRJNA438663 | ENA
Project description:Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm whose severity and treatment complexity is attributed to the presence of bone marrow (BM) fibrosis and alterations of stroma impairing the production of normal blood cells. Despite the recently discovered mutations including the JAK2V617F mutation in about half of patients, the primitive event responsible for the clonal proliferation is still unknown. In the highly inflammatory context of PMF, the presence of fibrosis associated with a neoangiogenesis and an osteosclerosis concomitant to the myeloproliferation and to the increase number of circulating hematopoietic progenitors suggests that the crosstalk between hematopoietic and stromal cells is deregulated in the PMF BM microenvironment. Within these niches, Mesenchymal Stromal Cells (BM-MSC) play a supportive role in the production of growth factors and extracellular matrix which regulate the proliferation, differentiation, adhesion and migration of hematopoietic progenitors. A transcriptome analysis of BM-MSC in PMF patients will help to characterize their molecular alterations and to understand their involvement in the hematopoietic progenitor deregulation that features PMF. Primary Myelofibrosis, mesenchymal stroma cells, bone marrow, myeloproliferative disorders Transcriptome analysis was performed on BM-MSC amplified in vitro after 3 to 5 passages. Agilent Whole Human Genome Oligo Microarrays were used to compare expression profiling of BM-MSC from PMF patients and healthy donors.
2015-01-10 | E-GEOD-44426 | biostudies-arrayexpress
Project description:Cannabis smoking is associated with advanced epigenetic age
| PRJNA1077260 | ENA
Project description:Myelofibrosis is a severe myeloproliferative neoplasm characterised by increased numbers of abnormal bone marrow megakaryocytes that induce progressive fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed high-throughput single-cell transcriptome profiling of 50,702 hematopoietic stem/progenitor cells (HSPCs), and single-cell proteomics, genomics and functional assays. We identified an aberrant pathway for direct megakaryocyte differentiation from the earliest stages of hematopoiesis in myelofibrosis and associated aberrant molecular signatures, including surface antigens selectively expressed by JAK2-mutant HSPCs. Myelofibrosis megakaryocyte progenitors were heterogeneous, with distinct expression of fibrosis and proliferation-associated genes and putative therapy targets. We validated the integrin G6B as a promising JAK2-mutant clone-specific surface antigen, warranting further development as an immunotherapeutic target. Our study paves the way for selective immunotherapeutic targeting in myelofibrosis and more broadly illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.
2020-06-30 | GSE131593 | GEO
Project description:Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm whose severity and treatment complexity is attributed to the presence of bone marrow (BM) fibrosis and alterations of stroma impairing the production of normal blood cells. Despite the recently discovered mutations including the JAK2V617F mutation in about half of patients, the primitive event responsible for the clonal proliferation is still unknown. In the highly inflammatory context of PMF, the presence of fibrosis associated with a neo-osteogenesis and an osteosclerosis concomitant to the myeloproliferation and to the increase number of circulating hematopoietic progenitors suggests that the crosstalk between hematopoietic cells and the osteoblastic niche is deregulated in the PMF BM microenvironment. Osteoblastic niche is well known to be an important support to regulate hematopoietic stem cell functions in bone marrow. A transcriptome analysis of bone marrow mesenchymal stem cells (BM-MSC) induced in vitro to differentiate in osteoblasts will help to understand the role of these cells in pathophysiology of PMF. Transcriptome analysis was performed on BM-MSC at J0 and J21 of in vitro osteoblastic differentiation. Agilent Whole Human Genome Oligo Microarrays were used to compare expression profiling of BM-MSCs from PMF patients and healthy donors before and after osteoblastic differentiation. Primary Myelofibrosis, mesenchymal stroma cells, bone marrow, myeloproliferative disorders
2015-01-10 | E-GEOD-46021 | biostudies-arrayexpress