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Autophagy activation mediates resistance to FLT3 inhibitors in acute myeloid leukemia with FLT3-ITD mutation

BACKGROUND: Autophagy plays a critical role in drug resistance in acute myeloid leukemia (AML), including the subtype with FLT3-ITD mutation. Yet how autophagy is activated and mediates resistance to FLT3 inhibitors in FLT3-ITD-positive AML remains unsure. METHODS: We detected the expression of auto...

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Autores principales: Xu, Dan, Chen, Yishan, Yang, Ying, Yin, Zhao, Huang, Changfen, Wang, Qiang, Jiang, Ling, Jiang, Xuejie, Yin, Changxin, Liu, Qifa, Yu, Guopan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258138/
https://www.ncbi.nlm.nih.gov/pubmed/35794565
http://dx.doi.org/10.1186/s12967-022-03498-1
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author Xu, Dan
Chen, Yishan
Yang, Ying
Yin, Zhao
Huang, Changfen
Wang, Qiang
Jiang, Ling
Jiang, Xuejie
Yin, Changxin
Liu, Qifa
Yu, Guopan
author_facet Xu, Dan
Chen, Yishan
Yang, Ying
Yin, Zhao
Huang, Changfen
Wang, Qiang
Jiang, Ling
Jiang, Xuejie
Yin, Changxin
Liu, Qifa
Yu, Guopan
author_sort Xu, Dan
collection PubMed
description BACKGROUND: Autophagy plays a critical role in drug resistance in acute myeloid leukemia (AML), including the subtype with FLT3-ITD mutation. Yet how autophagy is activated and mediates resistance to FLT3 inhibitors in FLT3-ITD-positive AML remains unsure. METHODS: We detected the expression of autophagy markers in FLT3-ITD-positive leukemic cells after vs. before acquired resistance to FLT3 inhibitors; tested the stimulative effect of acquired D835Y mutation and bone marrow micro-environment (BME) on autophagy; explored the mechanism of autophagy mediating FLT3 inhibitor resistance. RESULTS: Sorafenib-resistant cells markedly overpresented autophagy markers in comparison with sorafenib-sensitive cells or the cells before sorafenib treatment. Both acquired D835Y mutation and BME activated cytoprotective autophagy to mediate FLT3 inhibitor resistance. Autophagy activation decreased the suppression efficacy of FLT3 inhibitors on FLT3 downstream signaling and then weakened their anti-leukemia effect. Inhibition of autophagy with CQ significantly enhanced the suppressive effect of FLT3 inhibitor on FLT3 downstream signaling, in the end overcame resistance to FLT3 inhibitors. CONCLUSIONS: Autophagy might be stimulated by acquired mutation or BME, and bypass activate FLT3 downstream signaling to mediate FLT3 inhibitor resistance in FLT3-ITD-positive AML. Targeting autophagy could be a promising strategy to overcome resistance.
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spelling pubmed-92581382022-07-07 Autophagy activation mediates resistance to FLT3 inhibitors in acute myeloid leukemia with FLT3-ITD mutation Xu, Dan Chen, Yishan Yang, Ying Yin, Zhao Huang, Changfen Wang, Qiang Jiang, Ling Jiang, Xuejie Yin, Changxin Liu, Qifa Yu, Guopan J Transl Med Research BACKGROUND: Autophagy plays a critical role in drug resistance in acute myeloid leukemia (AML), including the subtype with FLT3-ITD mutation. Yet how autophagy is activated and mediates resistance to FLT3 inhibitors in FLT3-ITD-positive AML remains unsure. METHODS: We detected the expression of autophagy markers in FLT3-ITD-positive leukemic cells after vs. before acquired resistance to FLT3 inhibitors; tested the stimulative effect of acquired D835Y mutation and bone marrow micro-environment (BME) on autophagy; explored the mechanism of autophagy mediating FLT3 inhibitor resistance. RESULTS: Sorafenib-resistant cells markedly overpresented autophagy markers in comparison with sorafenib-sensitive cells or the cells before sorafenib treatment. Both acquired D835Y mutation and BME activated cytoprotective autophagy to mediate FLT3 inhibitor resistance. Autophagy activation decreased the suppression efficacy of FLT3 inhibitors on FLT3 downstream signaling and then weakened their anti-leukemia effect. Inhibition of autophagy with CQ significantly enhanced the suppressive effect of FLT3 inhibitor on FLT3 downstream signaling, in the end overcame resistance to FLT3 inhibitors. CONCLUSIONS: Autophagy might be stimulated by acquired mutation or BME, and bypass activate FLT3 downstream signaling to mediate FLT3 inhibitor resistance in FLT3-ITD-positive AML. Targeting autophagy could be a promising strategy to overcome resistance. BioMed Central 2022-07-06 /pmc/articles/PMC9258138/ /pubmed/35794565 http://dx.doi.org/10.1186/s12967-022-03498-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Xu, Dan
Chen, Yishan
Yang, Ying
Yin, Zhao
Huang, Changfen
Wang, Qiang
Jiang, Ling
Jiang, Xuejie
Yin, Changxin
Liu, Qifa
Yu, Guopan
Autophagy activation mediates resistance to FLT3 inhibitors in acute myeloid leukemia with FLT3-ITD mutation
title Autophagy activation mediates resistance to FLT3 inhibitors in acute myeloid leukemia with FLT3-ITD mutation
title_full Autophagy activation mediates resistance to FLT3 inhibitors in acute myeloid leukemia with FLT3-ITD mutation
title_fullStr Autophagy activation mediates resistance to FLT3 inhibitors in acute myeloid leukemia with FLT3-ITD mutation
title_full_unstemmed Autophagy activation mediates resistance to FLT3 inhibitors in acute myeloid leukemia with FLT3-ITD mutation
title_short Autophagy activation mediates resistance to FLT3 inhibitors in acute myeloid leukemia with FLT3-ITD mutation
title_sort autophagy activation mediates resistance to flt3 inhibitors in acute myeloid leukemia with flt3-itd mutation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258138/
https://www.ncbi.nlm.nih.gov/pubmed/35794565
http://dx.doi.org/10.1186/s12967-022-03498-1
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