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

文献类型：期刊论文

作者Wang, Hanlin2,3,4; Luo, Guanghao2,4,5; Hu, Xiaobei2,6; Xu, Gaoya2,7; Wang, Tao8; Liu, Minmin2,9; Qiu, Xiaohui2,6; Li, Jianan2,7; Fu, Jingfeng2,4; Feng, Bo1,2
刊名NATURE COMMUNICATIONS
出版日期2023-04-05
卷号14期号:1页码:18
DOI10.1038/s41467-023-37381-4
通讯作者Zhou, Yubo(ybzhou@simm.ac.cn) ; Yang, Jianmin(chyangjianmin@163.com) ; Li, Jia(jli@simm.ac.cn)
英文摘要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/EBP alpha activation as a top PR feature by analyzing data from primary AML patient samples in Vizome. C/EBP alpha 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/EBP alpha inactivation. Furthermore, guanfacine exerts a synergistic effect with FLT3i in vitro and in vivo. Finally, we ascertain the role of C/EBP alpha activation in PR in an independent cohort of FLT3-ITD patients. These findings highlight C/EBP alpha 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. Resistance of FLT3-ITD acute myeloid leukaemia (AML) patients to FLT3 inhibitors (FLT3i) remains an urgent clinical challenge. Here, the authors identify C/EBP alpha activation as a mechanism of FLT3i resistance and therapeutically target C/EBP alpha activation in combination with FLT3i in preclinical models FLT3-ITD AML.
WOS关键词PROGNOSTIC RELEVANCE ; CONNECTIVITY MAP ; MUTATIONS ; EXPRESSION ; AML ; CEBPA ; DIFFERENTIATION ; PHOSPHORYLATION ; GILTERITINIB ; SUPPRESSES
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000964899900016
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/306563]  
专题新药研究国家重点实验室
通讯作者Zhou, Yubo; Yang, Jianmin; Li, Jia
作者单位1.Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, 103 Wenhua Rd, Shenyang, Liaoning, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State key Lab Drug Res, Shanghai 201203, Peoples R China
3.Fudan Univ, Coll Pharm, Shanghai 210023, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310000, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Guangzhou 528400, Guangdong, Peoples R China
7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
8.Naval Med Univ, Changhai Hosp, Dept Hematol, Shanghai 200433, Peoples R China
9.Jiangnan Univ, Sch Pharmaceut Sci, Wuxi 214122, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Hanlin,Luo, Guanghao,Hu, Xiaobei,et al. Targeting C/EBP alpha overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia[J]. NATURE COMMUNICATIONS,2023,14(1):18.
APA Wang, Hanlin.,Luo, Guanghao.,Hu, Xiaobei.,Xu, Gaoya.,Wang, Tao.,...&Li, Jia.(2023).Targeting C/EBP alpha overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia.NATURE COMMUNICATIONS,14(1),18.
MLA Wang, Hanlin,et al."Targeting C/EBP alpha overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia".NATURE COMMUNICATIONS 14.1(2023):18.

入库方式： OAI收割

来源：上海药物研究所

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