Melatonin nanoparticles inhibit mutant hematopoiesis & restore bone marrow architecture in myeloproliferative neoplasms
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Myeloproliferative neoplasms (MPN) are chronic hematologic malignancies characterized by clonal myeloid expansion, inflammation, oxidative stress, and progressive bone marrow (BM) remodeling that may culminate in fibrosis and secondary acute leukemia. Here, we evaluated the therapeutic efficacy and the underlying mechanisms of melatonin (MT) and liposomal melatonin (nano-MT) in preclinical MPN models. MT selectively inhibited clonogenic growth of patient-derived peripheral blood mononuclear cells and induced pluripotent stem cell-derived CD34⁺ hematopoietic stem and progenitor cells in comparison to healthy controls. This effect was associated with increased apoptosis, reduced reactive oxygen species (ROS), and decreased glucose uptake, independently of MT receptor signaling. Transcriptomic profiling of primary MPN CD34⁺ cells revealed suppression of MYC targets, G 2 M checkpoint signaling, ROS, and glycolysis pathways. In co-culture models, MT reduced stromal α-smooth muscle actin and phosphorylated SMAD2/3, indicating inhibition of TGF-β-driven mesenchymal stromal cell-to-myofibroblast formation. In tamoxifen-inducible SclCreER;JAK2 V617F mice, nano-MT achieved efficient spleen and BM targeting. Therapeutically, nano-MT reduced erythrocytosis, myeloid progenitor expansion, and BM IL-1β levels. Longitudinal micro-computed tomography and histological analyses demonstrated normalization of BM architecture, reduced osteosclerotic remodeling and splenomegaly, decreased reticulin deposition and megakaryocyte numbers. In a dose-escalation study, nano-MT restored erythrocyte, hematocrit, and platelet counts and normalized megakaryocyte-erythroid progenitors. Combination treatment with ruxolitinib further reduced leukocytosis, neutrophilia, and monocytosis. Collectively, these findings demonstrate that (nano-)MT attenuates MPN and BM remodeling by targeting metabolic, inflammatory, and fibrotic pathways. This study provides the first evidence for a therapeutic benefit of nano-MT in MPN and establishes a rationale for further translational evaluation. Key points Melatonin impairs MPN progenitors and blunts TGF-β-driven stromal activation in vitro . Liposomal melatonin normalizes blood counts, megakaryocyte burden, and bone marrow fibrosis in MPN mice.
Authors 27
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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Medizinische Hochschule Hannover · Kantonsspital St. Gallen
Affiliation as printed
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Hannover, Germany
Laboratory of Stem Cells and Cancer Biology, Division Medical Oncology and Hematology, Health Ostschweiz (HOCH), Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
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Emiel P. C. van der Vorst Aachen Department of Internal Medicine I (Cardiology) Institute of Molecular Cardiovascular Research
RWTH Aachen University · Universitätsklinikum Aachen · Ludwig-Maximilians-Universität München · Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten
Affiliation as printed
Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University Hospital, Aachen, Germany
Department of Internal Medicine I, RWTH Aachen University Hospital, Aachen, Germany
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Molecular Cardiovascular Research (IMCAR), RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen · Radboud University Medical Center · Radboud University Nijmegen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Medical Biosciences, Radboud University Medical Center, Nijmegen, Netherlands
Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
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RWTH Aachen University · Universitätsklinikum Aachen
Affiliation as printed
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIOABCD), RWTH Aachen University Hospital, Aachen, Germany
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany
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