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1000 Titel
  • Synergistic killing of FLT3ITD-positive AML cells by combined inhibition of tyrosine-kinase activity and N-glycosylation
1000 Autor/in
  1. Tsitsipatis, Dimitrios |
  2. Kumar Jayavelu, Ashok |
  3. Müller, Jörg P. |
  4. Bauer, Reinhard |
  5. Schmidt-Arras, Dirk |
  6. Mahboobi, Siavosh |
  7. Schnöder, Tina M. |
  8. Heidel, Florian |
  9. Böhmer, Frank-D. |
1000 Erscheinungsjahr 2017
1000 LeibnizOpen
1000 Art der Datei
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2017-02-28
1000 Erschienen in
1000 Quellenangabe
  • 8(16):26613-26624
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2017
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.18632/oncotarget.15772 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28460451/ |
1000 Ergänzendes Material
  • http://www.oncotarget.com/index.php?journal=oncotarget&page=rt&op=suppFiles&path%5B%5D=15772&path%5B%5D=0 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Fms-like tyrosine kinase 3 (FLT3) with internal tandem duplications (ITD) is a major oncoprotein in acute myeloid leukemia (AML), and confers an unfavorable prognosis. Interference with FLT3ITD signaling is therefore pursued as a promising therapeutic strategy. In this study we show that abrogation of FLT3ITD glycoprotein maturation using low doses of the N-glycosylation inhibitor tunicamycin has anti-proliferative and pro-apoptotic effects on FLT3ITD-expressing human and murine cell lines. This effect is mediated in part by arresting FLT3ITD in an underglycosylated state and thereby attenuating FLT3ITD-driven AKT and ERK signaling. In addition, tunicamycin caused pronounced endoplasmatic reticulum stress and apoptosis through activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activation of the gene encoding CCAAT-enhancer-binding protein homologous protein (CHOP). PERK inhibition with a small molecule attenuated CHOP induction and partially rescued cells from apoptosis. Combination of tunicamycin with potent FLT3ITD kinase inhibitors caused synergistic cell killing, which was highly selective for cell lines and primary AML cells expressing FLT3ITD. Although tunicamycin is currently not a clinically applicable drug, we propose that mild inhibition of N-glycosylation may have therapeutic potential in combination with FLT3 kinase inhibitors for FLT3ITD-positive AML.
1000 Sacherschließung
lokal selective cytotoxicity
lokal acute myeloid leukemia
lokal FLT3ITD
lokal tunicamycin
1000 Fachgruppe
  1. Medizin |
  2. Biologie |
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/creator/VHNpdHNpcGF0aXMsIERpbWl0cmlvcw==|https://frl.publisso.de/adhoc/creator/S3VtYXIgSmF5YXZlbHUsIEFzaG9r|https://frl.publisso.de/adhoc/creator/TcO8bGxlciwgSsO2cmcgUC4=|https://frl.publisso.de/adhoc/creator/QmF1ZXIsIFJlaW5oYXJk|https://frl.publisso.de/adhoc/creator/U2NobWlkdC1BcnJhcywgRGlyaw==|https://frl.publisso.de/adhoc/creator/TWFoYm9vYmksIFNpYXZvc2g=|https://frl.publisso.de/adhoc/creator/U2NobsO2ZGVyLCBUaW5hIE0u|https://orcid.org/0000-0002-9559-7297|https://frl.publisso.de/adhoc/creator/QsO2aG1lciwgRnJhbmstRC4=
1000 Label
1000 Förderer
  1. German Academic Exchange Service (DAAD) |
  2. Deutsche Forschungsgemeinschaft (DFG) |
1000 Fördernummer
  1. -
  2. BO 1043/10-1
1000 Förderprogramm
  1. -
  2. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer German Academic Exchange Service (DAAD) |
    1000 Förderprogramm -
    1000 Fördernummer -
  2. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft (DFG) |
    1000 Förderprogramm -
    1000 Fördernummer BO 1043/10-1
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6413794.rdf
1000 Erstellt am 2019-04-04T12:52:43.019+0200
1000 Erstellt von 285
1000 beschreibt frl:6413794
1000 Bearbeitet von 25
1000 Zuletzt bearbeitet Fri Jan 31 00:56:03 CET 2020
1000 Objekt bearb. Mon Apr 08 13:45:09 CEST 2019
1000 Vgl. frl:6413794
1000 Oai Id
  1. oai:frl.publisso.de:frl:6413794 |
1000 Sichtbarkeit Metadaten public
1000 Sichtbarkeit Daten public
1000 Gegenstand von

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