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Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets

ABSTRACT: Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets

PROVIDER: PRJNA544104 | ENA |

REPOSITORIES: ENA

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Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets

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

Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets

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

Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets

Project description:Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets

| PRJNA604963 | ENA

Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets.

Project description: Not available

| S-EPMC7217381 | biostudies-literature

A Critical Role of RUNX1 in Governing Megakaryocyte-Primed Hematopoietic Stem Cell Differentiation [10x scRNAseq]

2023-01-20 | GSE211861 | GEO

A Critical Role of RUNX1 in Governing Megakaryocyte-Primed Hematopoietic Stem Cell Differentiation [Single MK RNAseq]

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Osteomacs promote maintenance of murine hematopoiesis through megakaryocyte-induced upregulation of Embigin and CD166

Project description:Maintenance of hematopoietic stem cell (HSC) function in the niche is an orchestrated event. Osteomacs (OM), are key cellular components of the niche. Previously, we documented that osteoblasts, OM, and megakaryocytes interact to promote hematopoiesis. Here, we further characterize OM and identify megakaryocyte-induced mediators that augment the role of OM in the niche. Single cell mRNAseq, mass spectrometry, and CyTOF examination of megakaryocyte-stimulated OM suggested that upregulation of CD166 and Embigin on OM augment their hematopoiesis maintenance function. CD166 knockout OM or shRNA-Embigin knockdown OM, confirmed that loss of these molecules significantly reduced OM ability to augment the osteoblast-mediated hematopoietic enhancing activity. Recombinant CD166 and Embigin partially substituted for OM function, characterizing both proteins as critical mediators of OM hematopoietic function. Our data identify Embigin and CD166 as OM-regulated critical components of HSC function in the niche and potential participants in various in vitro manipulations of stem cells.

2024-01-11 | MSV000093840 | MassIVE

Osteomacs promote maintenance of murine hematopoiesis through megakaryocyte-induced upregulation of Embigin and CD166

2024-02-08 | GSE254995 | GEO

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Project description:RUNX1 is crucial for multiple stages of hematopoiesis and its mutation can cause familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML). We aim to study the role of RUNX1 in megakaryocyte-biased HSCs differentiation to megakaryocytes. Here, by using Runx1F/FMx1-Cre mouse model, we sorted CD41pos HSCs and CD41neg HSCs in both RUNX1 WT and KO, and compared their gene expression profiles.

2023-01-20 | GSE211935 | GEO

A Critical Role of RUNX1 in Governing Megakaryocyte-Primed Hematopoietic Stem Cell Differentiation [CUT&RUN Chip-seq]

Project description:RUNX1 is crucial for multiple stages of hematopoiesis and its mutation can cause familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML). We aim to study the role of RUNX1 in megakaryocyte-biased HSCs differentiation to megakaryocytes. Here, by using Runx1F/FMx1-Cre mouse model ,we sorted CD41pos HSCs and CD41neg HSCs in both RUNX1 WT and KO, and tested the RUNX1 direct binding targets in these cells genome.

2023-01-20 | GSE212001 | GEO

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