Oncodevelopmental plasticity of the skeleton in myeloid neoplasms
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Myelofibrosis in patients with myeloproliferative neoplasms (MPNs) is traditionally characterized by bone marrow fibrosis and osteosclerosis, with de novo bone formation commonly attributed to impaired osteoclast-mediated resorption. Here, we challenge this paradigm by demonstrating that a solitary clonal driver mutation simultaneously induces pathological bone formation and resorption, with osteosclerosis acting to conceal localized and active bone destruction rather than inhibiting it. Through population analysis; clinical imaging; patient-derived multi-tissue sequencing; murine models and organ-on-a-chip systems, we demonstrate that spatial and ontogeny-dependent remodeling in mesoderm- and neural crest–derived bones is mechanistically interconnected via a previously unidentified osteochondral stromal injury program. Neural crest–derived stromal cells suppress osteogenic programs and undergo injury-induced lineage plasticity with ectopic chondrogenesis, mirroring pathological remodeling in mesoderm-derived growth plate regions. This shared injury response promotes osteoclastogenesis and is mediated by a conserved Thrombospondin 1+ (THBS1+) stromal population that links fibrotic remodeling to bone loss. Combined pharmacological inhibition of THBS1 and JAK signaling reduces myeloproliferation, halts fibrosis progression, and restores two developmentally distinct bones, establishing THBS1 as a unifying therapeutic target in myelofibrosis.
Authors 41
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Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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German Cancer Research Center · Heidelberg University · Heidelberg Institute for Stem Cell Technology and Experimental Medicine
Affiliation as printed
Faculty of Biosciences, University of Heidelberg
German Cancer Research Center (DKFZ), Division of Experimental Hematology, Heidelberg, Germany
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Developmental Biology, Erasmus Medical Center, Rotterdam, The Netherlands
Oncode Institute, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands
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Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Orthodontics, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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German Cancer Research Center · Heidelberg University · Heidelberg Institute for Stem Cell Technology and Experimental Medicine
Affiliation as printed
Faculty of Biosciences, University of Heidelberg
German Cancer Research Center (DKFZ), Division of Experimental Hematology, Heidelberg, Germany
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany
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German Cancer Research Center · Heidelberg Institute for Stem Cell Technology and Experimental Medicine
Affiliation as printed
German Cancer Research Center (DKFZ), Division of Experimental Hematology, Heidelberg, Germany
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany
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Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Aleksandar V. Kargaliev Aachen Department of Diagnostic and Interventional Radiology Faculty of Medicine
Affiliation as printed
Department of Diagnostic and Interventional Radiology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Maastricht University Medical Centre · RWTH Aachen University
Affiliation as printed
Department of Nuclear Medicine, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
Department of Radiology and Nuclear Medicine, Academic Hospital Maastricht, Maastricht, The Netherlands
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Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Orthodontics, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
Institute of Pathology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Laboratory of Stem Cells and Cancer Biology, Division Oncology and Hematology, HOCH Health Ostschweiz, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
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Affiliation as printed
Laboratory of Stem Cells and Cancer Biology, Division Oncology and Hematology, HOCH Health Ostschweiz, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
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Affiliation as printed
Department of Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Jitske Jansen Aachen Department of Nephrology, Rheumatology Clinical Immunology and Hypertension) Faculty of Medicine Institute for Experimental Internal Medicine and Systems Biology
Affiliation as printed
Department of Nephrology, Rheumatology, Clinical Immunology and Hypertension, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
Institute for Experimental Internal Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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University Medical Center Hamburg-Eppendorf · Essen University Hospital · Stiftung Universitätsmedizin Essen
Affiliation as printed
Department for Hematology and Stem Cell Transplantation, University Medical Center Essen, Essen, Germany
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Maastricht University Medical Centre · RWTH Aachen University
Affiliation as printed
Department of Nuclear Medicine, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
Department of Radiology and Nuclear Medicine, Academic Hospital Maastricht, Maastricht, The Netherlands
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Affiliation as printed
Department of Diagnostic and Interventional Radiology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Erasmus MC · Erasmus MC Cancer Institute · RWTH Aachen University
Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
Department of Developmental Biology, Erasmus Medical Center, Rotterdam, The Netherlands
Oncode Institute, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands
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Affiliation as printed
Laboratory of Stem Cells and Cancer Biology, Division Oncology and Hematology, HOCH Health Ostschweiz, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
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Affiliation as printed
Department of Orthodontics, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Carolin Victoria Schneider Aachen Department of Gastroenterology, Metabolic Diseases and Intensive Care Faculty of Medicine
Affiliation as printed
Department of Gastroenterology, Metabolic Diseases and Intensive Care, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Rafael Kramann Aachen Department of Nephrology, Rheumatology Clinical Immunology and Hypertension) Faculty of Medicine Institute for Experimental Internal Medicine and Systems Biology
Affiliation as printed
Department of Nephrology, Rheumatology, Clinical Immunology and Hypertension, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
Institute for Experimental Internal Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Oral and Maxillofacial Surgery, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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German Cancer Research Center · Heidelberg Institute for Stem Cell Technology and Experimental Medicine
Affiliation as printed
German Cancer Research Center (DKFZ), Division of Experimental Hematology, Heidelberg, Germany
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany
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Erasmus MC · Erasmus MC Cancer Institute · RWTH Aachen University
Affiliation as printed
Department of Cell and Tumor Biology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
Department of Developmental Biology, Erasmus Medical Center, Rotterdam, The Netherlands
Oncode Institute, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands
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