guest ::
| Home > Publications database > Nintedanib Targets KIT D816V Neoplastic Cells Derived from Induced Pluripotent Stem cells of Systemic Mastocytosis > print |
| Home > Publications database > Nintedanib Targets KIT D816V Neoplastic Cells Derived from Induced Pluripotent Stem cells of Systemic Mastocytosis > print |
| 001 | 885554 | ||
| 005 | 20240625095122.0 | ||
| 024 | 7 | _ | |a 10.1101/2020.05.06.080150 |2 doi |
| 024 | 7 | _ | |a 2128/25859 |2 Handle |
| 024 | 7 | _ | |a altmetric:81635887 |2 altmetric |
| 037 | _ | _ | |a FZJ-2020-03925 |
| 100 | 1 | _ | |a Toledo, Marcelo A. S. |0 P:(DE-HGF)0 |b 0 |
| 245 | _ | _ | |a Nintedanib Targets KIT D816V Neoplastic Cells Derived from Induced Pluripotent Stem cells of Systemic Mastocytosis |
| 260 | _ | _ | |c 2020 |
| 336 | 7 | _ | |a Preprint |b preprint |m preprint |0 PUB:(DE-HGF)25 |s 1602242905_12680 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a WORKING_PAPER |2 ORCID |
| 336 | 7 | _ | |a Electronic Article |0 28 |2 EndNote |
| 336 | 7 | _ | |a preprint |2 DRIVER |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a Output Types/Working Paper |2 DataCite |
| 520 | _ | _ | |a The KIT D816V mutation is found in more than 80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs. KIT D816V therefore 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 (ASM) and mast cell leukemia (MCL) 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 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 ATP binding pocket of inactive KIT D816V. Our results suggest nintedanib as a new drug candidate for KIT D816V targeted therapy of advanced SM. |
| 536 | _ | _ | |a 573 - Neuroimaging (POF3-573) |0 G:(DE-HGF)POF3-573 |c POF3-573 |f POF III |x 0 |
| 536 | _ | _ | |a 511 - Computational Science and Mathematical Methods (POF3-511) |0 G:(DE-HGF)POF3-511 |c POF3-511 |f POF III |x 1 |
| 588 | _ | _ | |a Dataset connected to CrossRef |
| 700 | 1 | _ | |a Gatz, Malrun |0 P:(DE-HGF)0 |b 1 |
| 700 | 1 | _ | |a Sontag, Stephanie |0 P:(DE-HGF)0 |b 2 |
| 700 | 1 | _ | |a Gleixner, Karoline V. |0 P:(DE-HGF)0 |b 3 |
| 700 | 1 | _ | |a Eisenwort, Gregor |0 P:(DE-HGF)0 |b 4 |
| 700 | 1 | _ | |a Feldberg, Kristina |0 P:(DE-HGF)0 |b 5 |
| 700 | 1 | _ | |a Kluge, Frederick |0 P:(DE-HGF)0 |b 6 |
| 700 | 1 | _ | |a Guareschi, Riccardo |0 P:(DE-Juel1)172064 |b 7 |
| 700 | 1 | _ | |a Rossetti, Giulia |0 P:(DE-Juel1)145921 |b 8 |u fzj |
| 700 | 1 | _ | |a Sechi, Antonio S. |0 P:(DE-HGF)0 |b 9 |
| 700 | 1 | _ | |a Dufva, Olli M. J. |0 P:(DE-HGF)0 |b 10 |
| 700 | 1 | _ | |a Mustjoki, Satu M. |0 P:(DE-HGF)0 |b 11 |
| 700 | 1 | _ | |a Maurer, Angela |0 P:(DE-HGF)0 |b 12 |
| 700 | 1 | _ | |a Schüler, Herdit M. |0 P:(DE-HGF)0 |b 13 |
| 700 | 1 | _ | |a Goetzke, Roman |0 P:(DE-HGF)0 |b 14 |
| 700 | 1 | _ | |a Braunschweig, Till |0 P:(DE-HGF)0 |b 15 |
| 700 | 1 | _ | |a Simonowski, Anne |0 P:(DE-HGF)0 |b 16 |
| 700 | 1 | _ | |a Panse, Jens |0 P:(DE-HGF)0 |b 17 |
| 700 | 1 | _ | |a Jawhar, Mohamad |0 P:(DE-HGF)0 |b 18 |
| 700 | 1 | _ | |a Reiter, Andreas |0 P:(DE-HGF)0 |b 19 |
| 700 | 1 | _ | |a Hilberg, Frank |0 P:(DE-HGF)0 |b 20 |
| 700 | 1 | _ | |a Ettmayer, Peter |0 P:(DE-HGF)0 |b 21 |
| 700 | 1 | _ | |a Wagner, Wolfgang |0 0000-0002-1971-3217 |b 22 |
| 700 | 1 | _ | |a Koschmieder, Steffen |0 P:(DE-HGF)0 |b 23 |
| 700 | 1 | _ | |a Brümmendorf, Tim H. |0 P:(DE-HGF)0 |b 24 |
| 700 | 1 | _ | |a Valent, Peter |0 P:(DE-HGF)0 |b 25 |
| 700 | 1 | _ | |a Chatain, Nicolas |0 P:(DE-HGF)0 |b 26 |
| 700 | 1 | _ | |a Zenke, Martin |0 0000-0002-1107-3251 |b 27 |e Corresponding author |
| 773 | _ | _ | |a 10.1101/2020.05.06.080150 |
| 856 | 4 | _ | |u https://www.biorxiv.org/content/10.1101/2020.05.06.080150v1.full.pdf |
| 856 | 4 | _ | |u https://juser.fz-juelich.de/record/885554/files/2020.05.06.080150v1.full.pdf |y OpenAccess |
| 856 | 4 | _ | |u https://juser.fz-juelich.de/record/885554/files/2020.05.06.080150v1.full.pdf?subformat=pdfa |x pdfa |y OpenAccess |
| 909 | C | O | |o oai:juser.fz-juelich.de:885554 |p openaire |p open_access |p VDB |p driver |p dnbdelivery |
| 910 | 1 | _ | |a Forschungszentrum Jülich |0 I:(DE-588b)5008462-8 |k FZJ |b 7 |6 P:(DE-Juel1)172064 |
| 910 | 1 | _ | |a Forschungszentrum Jülich |0 I:(DE-588b)5008462-8 |k FZJ |b 8 |6 P:(DE-Juel1)145921 |
| 913 | 1 | _ | |a DE-HGF |b Key Technologies |l Decoding the Human Brain |1 G:(DE-HGF)POF3-570 |0 G:(DE-HGF)POF3-573 |2 G:(DE-HGF)POF3-500 |v Neuroimaging |x 0 |4 G:(DE-HGF)POF |3 G:(DE-HGF)POF3 |
| 913 | 1 | _ | |a DE-HGF |b Key Technologies |1 G:(DE-HGF)POF3-510 |0 G:(DE-HGF)POF3-511 |2 G:(DE-HGF)POF3-500 |v Computational Science and Mathematical Methods |x 1 |4 G:(DE-HGF)POF |3 G:(DE-HGF)POF3 |l Supercomputing & Big Data |
| 914 | 1 | _ | |y 2020 |
| 915 | _ | _ | |a OpenAccess |0 StatID:(DE-HGF)0510 |2 StatID |
| 915 | _ | _ | |a Creative Commons Attribution-NonCommercial-NoDerivs CC BY-NC-ND 4.0 |0 LIC:(DE-HGF)CCBYNCND4 |2 HGFVOC |
| 920 | 1 | _ | |0 I:(DE-Juel1)IAS-5-20120330 |k IAS-5 |l Computational Biomedicine |x 0 |
| 920 | 1 | _ | |0 I:(DE-Juel1)JSC-20090406 |k JSC |l Jülich Supercomputing Center |x 1 |
| 920 | 1 | _ | |0 I:(DE-Juel1)INM-9-20140121 |k INM-9 |l Computational Biomedicine |x 2 |
| 980 | _ | _ | |a preprint |
| 980 | _ | _ | |a VDB |
| 980 | _ | _ | |a UNRESTRICTED |
| 980 | _ | _ | |a I:(DE-Juel1)IAS-5-20120330 |
| 980 | _ | _ | |a I:(DE-Juel1)JSC-20090406 |
| 980 | _ | _ | |a I:(DE-Juel1)INM-9-20140121 |
| 980 | 1 | _ | |a FullTexts |
| Library | Collection | CLSMajor | CLSMinor | Language | Author |
|---|