Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy

作者全名："Zhou, Qiao; Zhang, Jiamin; Zhang, Jingsong; Liang, Simin; Cai, Duo; Xiao, Han; Zhu, Yu; Xiang, Wenqiong; Rodrigues-Lima, Fernando; Chi, Jianxiang; Guidez, Fabien; Wang, Li"

作者地址："[Zhou, Qiao; Zhang, Jiamin; Zhang, Jingsong; Liang, Simin; Cai, Duo; Xiao, Han; Zhu, Yu; Xiang, Wenqiong; Wang, Li] Chongqing Med Univ, Dept Hematol, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400000, Peoples R China; [Rodrigues-Lima, Fernando] Univ Paris Cite, Unite Biol Fonct & Adaptat, CNRS, UMR 8251, Paris, France; [Chi, Jianxiang] Karaiskakio Fdn, Ctr Study Hematol Malignancies, Nicosia, Cyprus; [Guidez, Fabien] Univ Bourgogne, uB AgroSup, INSERM, UMR1231, 7 Blvd Jeanne dArc 21079 DIJON, F-21000 Dijon, France"

通信作者："Wang, L (通讯作者)，Chongqing Med Univ, Dept Hematol, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400000, Peoples R China."

来源：BIOLOGY DIRECT

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001136808800001

JCR分区：Q1

影响因子：5.5

年份：2024

卷号：19

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：BRAF; Vemurafenib; Senescence; HIPPO signaling pathway; MDS; AML

摘要："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 prognosis. The BRAF inhibitor-Vemurafenib (VEM) could significantly induce senescence, proliferation inhibition and apoptosis 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 expression holds promise as a prognostic indicator and potential therapeutic target for individuals with AML and MDS."

基金机构："Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission"

基金资助正文：Not applicable.