Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy
Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy
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DOI：
10.1186/s13062-023-00451-0
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发表时间：
2024
期刊：
影响因子：
5.5
通讯作者：
Li Wang
中科院分区：
文献类型：
--
作者：
Qiao Zhou;Jiamin Zhang;Jingsong Zhang;Simin Liang;Duo Cai;Han Xiao;Yu Zhu;Wenqiong Xiang;Fernando Rodrigues‐Lima;Jianxiang Chi;Fabien Guidez;Li Wang
Background The outcome of Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remain dismal despite the development of treatment. Targeted therapy is gaining more and more attention in improving prognosis..Methods Expression of BRAF was analyzed by RT‐qPCR in AML and MDS patients. Cells viability treated by drugs was measured by CCK‐8 assay. Network pharmacology and RNA‐sequence were used to analyze the mechanism of drugs and verified in vitro and xenograft tumor model..Results Here we showed that BRAF was overexpressed in AML and MDS patients, and correlated with poor progno‐ sis. The BRAF inhibitor‐Vemurafenib (VEM) could significantly induce senescence, proliferation inhibition and apopto‐ sis in AML cells, which can be enhanced by Bortezomib (BOR). This inhibitory effect was also verified in CD34 + cells derived from AML patients. Mechanistically, we showed that VEM combined with BOR could turn on HIPPO signaling pathway, thereby inducing cellular senescence in AML cells and xenograft mouse..Conclusions Taken together, our findings demonstrate a significant upregulation of BRAF expression in AML.and MDS patients, which is associated with unfavorable clinical outcomes. We also discovered that the BRAF inhibitor Vemurafenib induces cellular senescence through activation of the HIPPO signaling pathway. Analysis of BRAF expres‐ sion holds promise as a prognostic indicator and potential therapeutic target for individuals with AML and MDS.
