Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets
Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets
Summary 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 50,538 hematopoietic stem/progenitor cells (HSPCs), 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 immunoglobulin receptor G6B as a promising JAK2-mutant clone-specific antigen warranting further development as an immunotherapy target. Our study paves the way for selective targeting of the myelofibrosis clone and more broadly illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.
Psaila Bethan、Anderson Stacie、Calicchio Monica L.、NIH Intramural Sequencing Center、Milojkovic Dragana、Thongjuea Supat、Wang Guanlin、Meira Alba Rodriguez、Li Rong、Sousos Nikolaos、Roberts Irene、Heuston Elisabeth F.、Senis Yotis、Weinberg Olga K.、Iskander Deena、Bodine David M.、Mead Adam J.、Royston Daniel、O?ˉSullivan Jennifer
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford,||MRC Molecular Haematology Unit, WIMM, University of Oxford||NIHR Biomedical Research Centre, University of Oxford||Hematopoiesis Section, National Human Genome Research Institute, National Institutes of HealthNHGRI Flow Cytometry Core, National Human Genome Research Institute, National Institutes of HealthDepartment of Pathology, Boston Children?ˉs HospitalNational Institutes of HealthCentre for Haematology, Hammersmith Hospital, Imperial College MedicineNIHR Biomedical Research Centre, University of Oxford||MRC WIMM Centre for Computational Biology, MRC WIMM, University of OxfordHaematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford,||MRC WIMM Centre for Computational Biology, MRC WIMM, University of OxfordHaematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford,||MRC Molecular Haematology Unit, WIMM, University of Oxford||NIHR Biomedical Research Centre, University of OxfordHaematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford,||MRC Molecular Haematology Unit, WIMM, University of Oxford||NIHR Biomedical Research Centre, University of OxfordHaematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford,||MRC Molecular Haematology Unit, WIMM, University of Oxford||NIHR Biomedical Research Centre, University of OxfordMRC Molecular Haematology Unit, WIMM, University of Oxford||NIHR Biomedical Research Centre, University of Oxford||Department of Paediatrics, University of OxfordHematopoiesis Section, National Human Genome Research Institute, National Institutes of HealthInstitute of Cardiovascular Sciences, College of Medical & Dental Sciences, University of BirminghamDepartment of Pathology, Boston Children?ˉs HospitalCentre for Haematology, Hammersmith Hospital, Imperial College MedicineHematopoiesis Section, National Human Genome Research Institute, National Institutes of HealthHaematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford,||MRC Molecular Haematology Unit, WIMM, University of Oxford||NIHR Biomedical Research Centre, University of OxfordDepartment of Cellular Pathology, Oxford University Hospitals NHS TrustHaematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine (WIMM), University of Oxford,||MRC Molecular Haematology Unit, WIMM, University of Oxford||NIHR Biomedical Research Centre, University of Oxford
医学研究方法基础医学肿瘤学
megakaryopoiesismyeloproliferative neoplasmplateletsTARGET-Seqimmunotherapymulti-omicsG6Bfibrosis
Psaila Bethan,Anderson Stacie,Calicchio Monica L.,NIH Intramural Sequencing Center,Milojkovic Dragana,Thongjuea Supat,Wang Guanlin,Meira Alba Rodriguez,Li Rong,Sousos Nikolaos,Roberts Irene,Heuston Elisabeth F.,Senis Yotis,Weinberg Olga K.,Iskander Deena,Bodine David M.,Mead Adam J.,Royston Daniel,O?ˉSullivan Jennifer.Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets[EB/OL].(2025-03-28)[2025-06-08].https://www.biorxiv.org/content/10.1101/642819.点此复制
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