Year: 2026
Type: preprint
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: Salim Atakhanov, Ian Ghezzi, Hector Tejeda Mora, Lucas Greven, Marta Rizk, Lina Schmidt, Katrin Götz, Lina Merg, Valeria Solozobova, Adam Benabid, Pia Wanner, Niklas Lutterbach, Aleksandar V. Kargaliev, Mathias Schäfersküpper, Alexandru Florea, Juliette E. Pearce, Susanne Schmitz, Carmen Schalla, Paul Wanek, Rogerio B. Craveiro, Chloé Radermacher, Chiara Stüdle, Thomas Lehmann, Marek Weiler, Marcelo A.S. de Toledo, Steffen Koschmieder, Jitske Jansen, Francis Ayuk, Nicolaus Kröger, Felix M. Mottaghy, Daniel Truhn, Fabian Kiessling, Helene F.E. Gleitz, Tata Nageswara Rao, Michael Wolf, Carolin V. Schneider, Rafael Kramann, Anna Bock, Martina Crysandt, Michael Milsom, Rebekka K. Schneider
Institutions: RWTH Aachen University, German Cancer Research Center, Heidelberg University, Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Erasmus MC, Erasmus MC Cancer Institute, University Medical Center Hamburg-Eppendorf, Maastricht University Medical Centre, Kantonsspital St. Gallen, Essen University Hospital, Stiftung Universitätsmedizin Essen
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, MPN Research Foundation, Wilhelm Sander-Stiftung, Deutsche Forschungsgemeinschaft, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, ZonMw, Bundesministerium für Bildung und Forschung, RWTH Aachen University, Swiss Cancer Research Foundation
Awards: G1040688976, Kartierung der Transkriptions und Mutationslandschaft des malignen hämatopoetischen Klons in Wechselwirkung mit Fibrosetreibenden Stromazellen in myeloproliferativen Neoplasien, G3685652688, KFO 344: Mechanismen und molekulare Zielstrukturen der Myelofibrose in Myeloproliferativen Neoplasien (MPN), Wechselseitige Interaktion zwischen parodontaler Entzündung und Vorstufen der Leukämie, SFB 1382: Die DarmLeber Achse – Funktionelle Zusammenhänge und therapeutische Strategien, G8029302973, GRK 2375: TumorTargeted Drug Delivery, G880118091
OpenAlex ID: W7140056087