Gaoya Xu

Shanghai Institute of Materia Medica

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Hanlin Wang

Shandong University

Jun‐Yu Xu

Chinese Academy of Sciences

Jing-feng Fu

Chinese Academy of Sciences

Linhui Zhai

Shanghai Institute of Materia Medica

Jia Li

Army Medical University

Yutong Tu

Chinese Academy of Sciences

Y Ye

Shanghai Institute of Materia Medica

Tao Wang

Medical College of Wisconsin

Jia Li

Chinese Academy of Sciences

Jianmin Yang

Shanghai Maritime University

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Shanghai Institute of Materia Medica

Chinese Academy of Sciences

University of Chinese Academy of Sciences

Nanjing University of Chinese Medicine

National Center for Drug Screening

Changhai Hospital

Second Military Medical University

Central South University

Southern Medical University

Peking University

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

Nature Communications (2023)

Hanlin Wang Guanghao Luo Xiaobei Hu Gaoya Xu Tao Wang

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.

Guanfacine

Clinical efficacy

10.1038/s41467-023-37381-4

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Citations (2)

Integrative proteogenomic and pharmacological landscape of acute myeloid leukaemia

Science Bulletin (2024)

Hanlin Wang Jun‐Yu Xu Tao Wang Gaoya Xu Guanghao Luo

Myeloid leukaemia

Proteogenomics

10.1016/j.scib.2024.11.020

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