{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:40:08Z","timestamp":1790746808309,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["HemaSphere"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Inflammation from the hematopoietic compartment is a critical driver of fibrosis and cytopenias in myeloproliferative neoplasms (MPNs). We previously demonstrated that tasquinimod ameliorates the MPN phenotype, reducing splenomegaly and normalizing fibrosis in a JAK2V617F\u2010driven preclinical model. Using bulk RNA sequencing, we now show that tasquinimod primarily targets the malignant JAK2V617F hematopoietic clone, particularly affecting megakaryocytes and monocytes. Tasquinimod downregulates pro\u2010proliferative pathways, MYC targets, and mTORC signaling, while increasing apoptosis in particularly in JAK2V617F mutant cells. Our data reveal that tasquinimod reverses TGF\u03b2\u2010driven fibrotic reprogramming of megakaryocytes and monocytes. This reversal is crucial for mitigating the pro\u2010fibrotic interactions and signaling in the BM, thereby decreasing the activation of stromal cells. Coculture experiments confirm that direct interaction between JAK2V617F hematopoietic cells and mesenchymal stromal cells upregulates S100A8 in stromal cells, independent of TGF\u03b2 alone. In line, genetic ablation of S100A9 in the hematopoietic but not stromal compartment significantly improves the MPN phenotype and normalizes BM fibrosis. Our data highlight the hematopoietic origin of the inflammatory signals driving fibrosis. These insights pave the way for potential therapeutic strategies targeting inflammatory signaling pathways in MPN to mitigate fibrosis and improve patient outcomes.<\/jats:p>","DOI":"10.1002\/hem3.70179","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T07:46:53Z","timestamp":1755157613000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Inhibiting the alarmin\u2010driven hematopoiesis\u2010stromal cell crosstalk in primary myelofibrosis ameliorates bone marrow fibrosis"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6138-8916","authenticated-orcid":false,"given":"H\u00e9l\u00e8ne F. E.","family":"Gleitz","sequence":"first","affiliation":[{"name":"Department of Developmental Biology Erasmus Medical Center Rotterdam The Netherlands"},{"name":"Oncode Institute Erasmus Medical Center Cancer Institute Rotterdam The Netherlands"},{"name":"Department of Cell and Tumor Biology, Faculty of Medicine University Hospital RWTH Aachen Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stijn N. R.","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology Erasmus Medical Center Rotterdam The Netherlands"},{"name":"Oncode Institute Erasmus Medical Center Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge A. M.","family":"Snoeren","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology Erasmus Medical Center Rotterdam The Netherlands"},{"name":"Oncode Institute Erasmus Medical Center Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Boys","sequence":"additional","affiliation":[{"name":"Institute for Computational Biomedicine, Faculty of Medicine, and Heidelberg University Hospital Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Nagai","sequence":"additional","affiliation":[{"name":"Institute for Computational Genomics, Faculty of Medicine RWTH Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hector","family":"Tejeda\u2010Mora","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology Erasmus Medical Center Rotterdam The Netherlands"},{"name":"Oncode Institute Erasmus Medical Center Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Kl\u00f6ker","sequence":"additional","affiliation":[{"name":"Institute for Computational Genomics, Faculty of Medicine RWTH Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica E.","family":"Pritchard","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology Erasmus Medical Center Rotterdam The Netherlands"},{"name":"Oncode Institute Erasmus Medical Center Cancer Institute Rotterdam The Netherlands"},{"name":"Department of Cell and Tumor Biology, Faculty of Medicine University Hospital RWTH Aachen Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris J.","family":"Bakker","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology Erasmus Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Gargallo Garasa","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology Erasmus Medical Center Rotterdam The Netherlands"},{"name":"Oncode Institute Erasmus Medical Center Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Bindels","sequence":"additional","affiliation":[{"name":"Department of Hematology Erasmus Medical Center Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Saez\u2010Rodriguez","sequence":"additional","affiliation":[{"name":"Institute for Computational Biomedicine, Faculty of Medicine, and Heidelberg University Hospital Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Vogl","sequence":"additional","affiliation":[{"name":"Institute of Immunology University of M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Kramann","sequence":"additional","affiliation":[{"name":"Institute of Experimental Medicine and Systems Biology, Medical Faculty RWTH Aachen University Aachen Germany"},{"name":"Division of Nephrology and Clinical Immunology, Medical Faculty RWTH Aachen University Aachen Germany"},{"name":"Department of Internal Medicine, Nephrology and Transplantation Erasmus Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lien","family":"Dugourd","sequence":"additional","affiliation":[{"name":"Institute for Computational Biomedicine, Faculty of Medicine, and Heidelberg University Hospital Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan G.","family":"Costa","sequence":"additional","affiliation":[{"name":"Institute for Computational Genomics, Faculty of Medicine RWTH Aachen University Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0749-1565","authenticated-orcid":false,"given":"Rebekka K.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology Erasmus Medical Center Rotterdam The Netherlands"},{"name":"Oncode Institute Erasmus Medical Center Cancer Institute Rotterdam The Netherlands"},{"name":"Department of Cell and Tumor Biology, Faculty of Medicine University Hospital RWTH Aachen Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.11.004"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019004095"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2017.03.008"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3530"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13383"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02391-6"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btab370"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.104"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.240663.118"},{"issue":"1","key":"e_1_2_10_12_1","article-title":"decoupleR: ensemble of computational methods to infer biological activities from omics data","volume":"2","author":"Badia\u2010i\u2010Mompel P","year":"2022","journal-title":"Bioinf Adv"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41540-019-0118-z"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4077"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-00934-y"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/606819"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8080854"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-023-00962-z"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/2643-3230.BCD-23-0210"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01480-1"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI154092"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.3.1034-1043.2003"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080132"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/18.suppl_1.S96"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_2_10_26_1","doi-asserted-by":"crossref","unstructured":"KorotkevichG SukhovV BudinN ShpakB ArtyomovMN SergushichevA. Fast gene set enrichment analysis.bioRxiv. Published online February 1 2021.doi:10.1101\/060012","DOI":"10.1101\/060012"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2019.194431"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3593"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4IB00294F"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giaa151"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2019.03.003"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0605-1"}],"container-title":["HemaSphere"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hem3.70179","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T16:25:32Z","timestamp":1764433532000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/hem3.70179"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":32,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1002\/hem3.70179"],"URL":"https:\/\/doi.org\/10.1002\/hem3.70179","archive":["Portico"],"relation":{},"ISSN":["2572-9241","2572-9241"],"issn-type":[{"value":"2572-9241","type":"print"},{"value":"2572-9241","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8]]},"assertion":[{"value":"2024-09-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70179"}}