Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy
Abstract 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 patient...
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| Format: | Article |
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BMC
2024-01-01
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| Series: | Biology Direct |
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| Online Access: | https://doi.org/10.1186/s13062-023-00451-0 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Qiao Zhou |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-08T16:22:22Z |
| format | Article |
| id | doaj.art-69e8887508ba4eca80fcd4c8700ef8c4 |
| institution | Directory Open Access Journal |
| issn | 1745-6150 |
| language | English |
| last_indexed | 2024-03-08T16:22:22Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Biology Direct |
| spelling | doaj.art-69e8887508ba4eca80fcd4c8700ef8c42024-01-07T12:15:07ZengBMCBiology Direct1745-61502024-01-0119111610.1186/s13062-023-00451-0Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapyQiao Zhou0Jiamin Zhang1Jingsong Zhang2Simin Liang3Duo Cai4Han Xiao5Yu Zhu6Wenqiong Xiang7Fernando Rodrigues-Lima8Jianxiang Chi9Fabien Guidez10Li Wang11Department of Hematology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Hematology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Hematology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Hematology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Hematology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Hematology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Hematology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Hematology, The First Affiliated Hospital of Chongqing Medical UniversityUnité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS UMR 8251Center for the Study of Hematological Malignancies, Karaiskakio FoundationUMR1231 Inserm/uB/AgroSup, Université de BourgogneDepartment of Hematology, The First Affiliated Hospital of Chongqing Medical UniversityAbstract 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.https://doi.org/10.1186/s13062-023-00451-0BRAFVemurafenibSenescenceHIPPO signaling pathwayMDSAML |
| spellingShingle | 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 Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy Biology Direct BRAF Vemurafenib Senescence HIPPO signaling pathway MDS AML |
| title | Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy |
| title_full | Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy |
| title_fullStr | Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy |
| title_full_unstemmed | Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy |
| title_short | Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy |
| title_sort | vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the hippo signaling pathway implications for potential targeted therapy |
| topic | BRAF Vemurafenib Senescence HIPPO signaling pathway MDS AML |
| url | https://doi.org/10.1186/s13062-023-00451-0 |
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