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Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia

The outcomes of FLT3-ITD acute myeloid leukaemia (AML) have been improved since the approval of FLT3 inhibitors (FLT3i). However, approximately 30-50% of patients exhibit primary resistance (PR) to FLT3i with poorly defined mechanisms, posing a pressing clinical unmet need. Here, we identify C/EBPα...

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Autores principales: Wang, Hanlin, Luo, Guanghao, Hu, Xiaobei, Xu, Gaoya, Wang, Tao, Liu, Minmin, Qiu, Xiaohui, Li, Jianan, Fu, Jingfeng, Feng, Bo, Tu, Yutong, Kan, Weijuan, Wang, Chang, Xu, Ran, Zhou, Yubo, Yang, Jianmin, Li, Jia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10076519/
https://www.ncbi.nlm.nih.gov/pubmed/37019911
http://dx.doi.org/10.1038/s41467-023-37381-4
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author Wang, Hanlin
Luo, Guanghao
Hu, Xiaobei
Xu, Gaoya
Wang, Tao
Liu, Minmin
Qiu, Xiaohui
Li, Jianan
Fu, Jingfeng
Feng, Bo
Tu, Yutong
Kan, Weijuan
Wang, Chang
Xu, Ran
Zhou, Yubo
Yang, Jianmin
Li, Jia
author_facet Wang, Hanlin
Luo, Guanghao
Hu, Xiaobei
Xu, Gaoya
Wang, Tao
Liu, Minmin
Qiu, Xiaohui
Li, Jianan
Fu, Jingfeng
Feng, Bo
Tu, Yutong
Kan, Weijuan
Wang, Chang
Xu, Ran
Zhou, Yubo
Yang, Jianmin
Li, Jia
author_sort Wang, Hanlin
collection PubMed
description The outcomes of FLT3-ITD acute myeloid leukaemia (AML) have been improved since the approval of FLT3 inhibitors (FLT3i). However, approximately 30-50% of patients exhibit primary resistance (PR) to FLT3i with poorly defined mechanisms, posing a pressing clinical unmet need. Here, we identify C/EBPα activation as a top PR feature by analyzing data from primary AML patient samples in Vizome. C/EBPα activation limit FLT3i efficacy, while its inactivation synergistically enhances FLT3i action in cellular and female animal models. We then perform an in silico screen and identify that guanfacine, an antihypertensive medication, mimics C/EBPα inactivation. Furthermore, guanfacine exerts a synergistic effect with FLT3i in vitro and in vivo. Finally, we ascertain the role of C/EBPα activation in PR in an independent cohort of FLT3-ITD patients. These findings highlight C/EBPα activation as a targetable PR mechanism and support clinical studies aimed at testing the combination of guanfacine with FLT3i in overcoming PR and enhancing the efficacy of FLT3i therapy.
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spelling pubmed-100765192023-04-07 Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia Wang, Hanlin Luo, Guanghao Hu, Xiaobei Xu, Gaoya Wang, Tao Liu, Minmin Qiu, Xiaohui Li, Jianan Fu, Jingfeng Feng, Bo Tu, Yutong Kan, Weijuan Wang, Chang Xu, Ran Zhou, Yubo Yang, Jianmin Li, Jia Nat Commun Article The outcomes of FLT3-ITD acute myeloid leukaemia (AML) have been improved since the approval of FLT3 inhibitors (FLT3i). However, approximately 30-50% of patients exhibit primary resistance (PR) to FLT3i with poorly defined mechanisms, posing a pressing clinical unmet need. Here, we identify C/EBPα activation as a top PR feature by analyzing data from primary AML patient samples in Vizome. C/EBPα activation limit FLT3i efficacy, while its inactivation synergistically enhances FLT3i action in cellular and female animal models. We then perform an in silico screen and identify that guanfacine, an antihypertensive medication, mimics C/EBPα inactivation. Furthermore, guanfacine exerts a synergistic effect with FLT3i in vitro and in vivo. Finally, we ascertain the role of C/EBPα activation in PR in an independent cohort of FLT3-ITD patients. These findings highlight C/EBPα activation as a targetable PR mechanism and support clinical studies aimed at testing the combination of guanfacine with FLT3i in overcoming PR and enhancing the efficacy of FLT3i therapy. Nature Publishing Group UK 2023-04-05 /pmc/articles/PMC10076519/ /pubmed/37019911 http://dx.doi.org/10.1038/s41467-023-37381-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wang, Hanlin
Luo, Guanghao
Hu, Xiaobei
Xu, Gaoya
Wang, Tao
Liu, Minmin
Qiu, Xiaohui
Li, Jianan
Fu, Jingfeng
Feng, Bo
Tu, Yutong
Kan, Weijuan
Wang, Chang
Xu, Ran
Zhou, Yubo
Yang, Jianmin
Li, Jia
Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
title Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
title_full Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
title_fullStr Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
title_full_unstemmed Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
title_short Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
title_sort targeting c/ebpα overcomes primary resistance and improves the efficacy of flt3 inhibitors in acute myeloid leukaemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10076519/
https://www.ncbi.nlm.nih.gov/pubmed/37019911
http://dx.doi.org/10.1038/s41467-023-37381-4
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