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@ARTICLE{Toledo:885554,
      author       = {Toledo, Marcelo A. S. and Gatz, Malrun and Sontag,
                      Stephanie and Gleixner, Karoline V. and Eisenwort, Gregor
                      and Feldberg, Kristina and Kluge, Frederick and Guareschi,
                      Riccardo and Rossetti, Giulia and Sechi, Antonio S. and
                      Dufva, Olli M. J. and Mustjoki, Satu M. and Maurer, Angela
                      and Schüler, Herdit M. and Goetzke, Roman and Braunschweig,
                      Till and Simonowski, Anne and Panse, Jens and Jawhar,
                      Mohamad and Reiter, Andreas and Hilberg, Frank and Ettmayer,
                      Peter and Wagner, Wolfgang and Koschmieder, Steffen and
                      Brümmendorf, Tim H. and Valent, Peter and Chatain, Nicolas
                      and Zenke, Martin},
      title        = {{N}intedanib {T}argets {KIT} {D}816{V} {N}eoplastic {C}ells
                      {D}erived from {I}nduced {P}luripotent {S}tem cells of
                      {S}ystemic {M}astocytosis},
      reportid     = {FZJ-2020-03925},
      year         = {2020},
      abstract     = {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.},
      cin          = {IAS-5 / JSC / INM-9},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)JSC-20090406 /
                      I:(DE-Juel1)INM-9-20140121},
      pnm          = {573 - Neuroimaging (POF3-573) / 511 - Computational Science
                      and Mathematical Methods (POF3-511)},
      pid          = {G:(DE-HGF)POF3-573 / G:(DE-HGF)POF3-511},
      typ          = {PUB:(DE-HGF)25},
      doi          = {10.1101/2020.05.06.080150},
      url          = {https://juser.fz-juelich.de/record/885554},
}