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Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets.
Psaila, Bethan; Wang, Guanlin; Rodriguez-Meira, Alba; Li, Rong; Heuston, Elisabeth F; Murphy, Lauren; Yee, Daniel; Hitchcock, Ian S; Sousos, Nikolaos; O'Sullivan, Jennifer; Anderson, Stacie; Senis, Yotis A; Weinberg, Olga K; Calicchio, Monica L; Iskander, Deena; Royston, Daniel; Milojkovic, Dragana; Roberts, Irene; Bodine, David M; Thongjuea, Supat; Mead, Adam J.
Affiliation
  • Psaila B; Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; NIHR Biomedical Research Centre, University of
  • Wang G; Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; NIHR Biomedical Research Centre, University of
  • Rodriguez-Meira A; Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; NIHR Biomedical Research Centre, University of
  • Li R; Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; NIHR Biomedical Research Centre, University of
  • Heuston EF; Hematopoiesis Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4442, USA.
  • Murphy L; Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; NIHR Biomedical Research Centre, University of
  • Yee D; York Biomedical Research Institute and Department of Biology, University of York, Heslington, York YO10 5DD, UK.
  • Hitchcock IS; York Biomedical Research Institute and Department of Biology, University of York, Heslington, York YO10 5DD, UK.
  • Sousos N; Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; NIHR Biomedical Research Centre, University of
  • O'Sullivan J; Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; NIHR Biomedical Research Centre, University of
  • Anderson S; NHGRI Flow Cytometry Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4442, USA.
  • Senis YA; Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S 1255, Etablissement Français du Sang Grand Est, Strasbourg 67065, France.
  • Weinberg OK; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
  • Calicchio ML; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
  • Iskander D; Centre for Haematology, Hammersmith Hospital, Imperial College of Medicine, London W12 OHS, UK.
  • Royston D; Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • Milojkovic D; Centre for Haematology, Hammersmith Hospital, Imperial College of Medicine, London W12 OHS, UK.
  • Roberts I; MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; NIHR Biomedical Research Centre, University of Oxford, Oxford OX4 2PG, UK; Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK.
  • Bodine DM; Hematopoiesis Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4442, USA.
  • Thongjuea S; NIHR Biomedical Research Centre, University of Oxford, Oxford OX4 2PG, UK; MRC WIMM Centre for Computational Biology, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK. Electronic address: supat.thongjuea@imm.ox.ac.uk.
  • Mead AJ; Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; NIHR Biomedical Research Centre, University of
Mol Cell ; 78(3): 477-492.e8, 2020 05 07.
Article in En | MEDLINE | ID: mdl-32386542
ABSTRACT
Myelofibrosis is a severe myeloproliferative neoplasm characterized 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 and progenitor cells (HSPCs), single-cell proteomics, genomics, and functional assays. We identified a bias toward megakaryocyte differentiation apparent from early multipotent stem cells in myelofibrosis and associated aberrant molecular signatures. A sub-fraction of myelofibrosis megakaryocyte progenitors (MkPs) are transcriptionally similar to healthy-donor MkPs, but the majority are disease specific, with distinct populations expressing fibrosis- and proliferation-associated genes. Mutant-clone HSPCs have 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Megakaryocytes / Primary Myelofibrosis / Hematopoiesis Limits: Aged / Aged80 / Female / Humans / Male / Middle aged Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2020 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Megakaryocytes / Primary Myelofibrosis / Hematopoiesis Limits: Aged / Aged80 / Female / Humans / Male / Middle aged Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2020 Document type: Article