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Nintedanib targets KIT D816V neoplastic cells derived from induced pluripotent stem cells of systemic mastocytosis

The KIT D816V mutation is found in >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 in...

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Main Authors: Toledo, Marcelo A. S. de (Author) , Gatz, Malrun (Author) , Sontag, Stephanie (Author) , Gleixner, Karoline V. (Author) , Eisenwort, Gregor (Author) , Feldberg, Kristina (Author) , Hamouda, Ahmed E. I. (Author) , Kluge, Frederick (Author) , Guareschi, Riccardo (Author) , Rossetti, Giulia (Author) , Sechi, Antonio S. (Author) , Dufva, Olli M. J. (Author) , Mustjoki, Satu M. (Author) , Maurer, Angela (Author) , Schüler, Herdit M. (Author) , Goetzke, Roman (Author) , Braunschweig, Till (Author) , Kaiser, Anne (Author) , Panse, Jens (Author) , Jawhar, Mohamad (Author) , Reiter, Andreas (Author) , Hilberg, Frank (Author) , Ettmayer, Peter (Author) , Wagner, Wolfgang (Author) , Koschmieder, Steffen (Author) , Brümmendorf, Tim H. (Author) , Valent, Peter (Author) , Chatain, Nicolas (Author) , Zenke, Martin (Author)
Format: Article (Journal)
Language:English
Published: April 15, 2021
In: Blood
Year: 2021, Volume: 137, Issue: 15, Pages: 2070-2084
ISSN:1528-0020
DOI:10.1182/blood.2019004509
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood.2019004509
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Author Notes:Marcelo A.S. Toledo, Malrun Gatz, Stephanie Sontag, Karoline V. Gleixner, Gregor Eisenwort, Kristina Feldberg, Ahmed E.I. Hamouda, Frederick Kluge, Riccardo Guareschi, Giulia Rossetti, Antonio S. Sechi, Olli M.J. Dufva, Satu M. Mustjoki, Angela Maurer, Herdit M. Schüler, Roman Goetzke, Till Braunschweig, Anne Kaiser, Jens Panse, Mohamad Jawhar, Andreas Reiter, Frank Hilberg, Peter Ettmayer, Wolfgang Wagner, Steffen Koschmieder, Tim H. Brümmendorf, Peter Valent, Nicolas Chatain, Martin Zenke
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Summary:The KIT D816V mutation is found in >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-approved 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-targeted therapy of advanced SM.
Item Description:Gesehen am 10.08.2021
Physical Description:Online Resource
ISSN:1528-0020
DOI:10.1182/blood.2019004509

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