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  Synergistic killing of FLT3ITD-positive AML cells by combined inhibition of tyrosine-kinase activity and N-glycosylation

Tsitsipatis, D., Jayavelu, A. K., Mueller, J. P., Bauer, R., Schmidt-Arras, D., Mahboobi, S., et al. (2017). Synergistic killing of FLT3ITD-positive AML cells by combined inhibition of tyrosine-kinase activity and N-glycosylation. Oncotarget, 8(16), 26613-26624. doi:10.18632/oncotarget.15772.

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Tsitsipatis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Tsitsipatis, Dimitrios1, Author
Jayavelu, Ashok Kumar2, Author              
Mueller, Joerg P.1, Author
Bauer, Reinhard1, Author
Schmidt-Arras, Dirk1, Author
Mahboobi, Siavosh1, Author
Schnoeder, Tina M.1, Author
Heidel, Florian1, Author
Boehmer, Frank-D.1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: ACUTE MYELOID-LEUKEMIA; ENDOPLASMIC-RETICULUM STRESS; INTERNAL TANDEM DUPLICATION; LINKED GLYCOSYLATION; ITD MUTATIONS; FLT3 ITD; CANCER; TUNICAMYCIN; TRANSFORMATION; INACTIVATIONOncology; Cell Biology; acute myeloid leukemia; FLT3ITD; tunicamycin; selective cytotoxicity;
 Abstract: 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 antiproliferative 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.

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Language(s): eng - English
 Dates: 2017-02-282017
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000399819700067
DOI: 10.18632/oncotarget.15772
 Degree: -

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Title: Oncotarget
Source Genre: Journal
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Pages: - Volume / Issue: 8 (16) Sequence Number: - Start / End Page: 26613 - 26624 Identifier: ISSN: 1949-2553
CoNE: https://pure.mpg.de/cone/journals/resource/1949-2553