{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T21:16:17Z","timestamp":1792444577277,"version":"4.5.0"},"reference-count":51,"publisher":"American Society of Hematology","issue":"15","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The KIT D816V mutation is found in &amp;gt;80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs. Therefore, KIT D816V represents a prime therapeutic target for SM. Here, we generated a panel of patient-specific KIT D816V induced pluripotent stem cells (iPSCs) from patients with aggressive SM and mast cell leukemia to develop a patient-specific SM disease model for mechanistic and drug-discovery studies. KIT D816V iPSCs differentiated into neoplastic hematopoietic progenitor cells and MCs with patient-specific phenotypic features, thereby reflecting the heterogeneity of the disease. CRISPR\/Cas9n-engineered KIT D816V human embryonic stem cells (ESCs), when differentiated into hematopoietic cells, recapitulated the phenotype observed for KIT D816V iPSC hematopoiesis. KIT D816V causes constitutive activation of the KIT tyrosine kinase receptor, and we exploited our iPSCs and ESCs to investigate new tyrosine kinase inhibitors targeting KIT D816V. Our study identified nintedanib, a US Food and Drug Administration\u2013approved angiokinase inhibitor that targets vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, as a novel KIT D816V inhibitor. Nintedanib selectively reduced the viability of iPSC-derived KIT D816V hematopoietic progenitor cells and MCs in the nanomolar range. Nintedanib was also active on primary samples of KIT D816V SM patients. Molecular docking studies show that nintedanib binds to the adenosine triphosphate binding pocket of inactive KIT D816V. Our results suggest nintedanib as a new drug candidate for KIT D816V\u2013targeted therapy of advanced SM.<\/jats:p>","DOI":"10.1182\/blood.2019004509","type":"journal-article","created":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T19:52:39Z","timestamp":1608753159000},"page":"2070-2084","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":28,"title":["Nintedanib targets KIT D816V neoplastic cells derived from induced pluripotent stem cells of systemic mastocytosis"],"prefix":"10.1182","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4318-7381","authenticated-orcid":false,"given":"Marcelo A. S.","family":"Toledo","sequence":"first","affiliation":[{"name":"Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany;"},{"name":"Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany;"},{"name":"Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Medical School, Aachen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malrun","family":"Gatz","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany;"},{"name":"Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Sontag","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany;"},{"name":"Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karoline V.","family":"Gleixner","sequence":"additional","affiliation":[{"name":"Division of Hematology and Hemostaseology, Department of Internal Medicine I, and"},{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2735-4645","authenticated-orcid":false,"given":"Gregor","family":"Eisenwort","sequence":"additional","affiliation":[{"name":"Division of Hematology and Hemostaseology, Department of Internal Medicine I, and"},{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Feldberg","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Medical School, Aachen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6532-9585","authenticated-orcid":false,"given":"Ahmed E. I.","family":"Hamouda","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany;"},{"name":"Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick","family":"Kluge","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany;"},{"name":"Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Guareschi","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience and Medicine, Institute for Advanced Simulation, J\u00fclich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2032-4630","authenticated-orcid":false,"given":"Giulia","family":"Rossetti","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Medical School, Aachen, Germany;"},{"name":"Institute of Neuroscience and Medicine, Institute for Advanced Simulation, J\u00fclich, Germany;"},{"name":"J\u00fclich Supercomputing Centre, Research Centre J\u00fclich, J\u00fclich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1374-1794","authenticated-orcid":false,"given":"Antonio S.","family":"Sechi","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany;"},{"name":"Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8084-0282","authenticated-orcid":false,"given":"Olli M. 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