Innovative evaluation of selinexor and JQ1 synergy in leukemia therapy via C-MYC inhibition
Abstract Background Acute myeloid leukemia (AML) remains a therapeutic challenge due to drug resistance and relapse. Selinexor, an XPO1 inhibitor, shows limited efficacy as monotherapy, necessitating combination strategies. JQ1, a BET inhibitor targeting MYC, may synergize with Selinexor to enhance...
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2025-05-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06525-z |
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| author | Pei-Hong Wang Chu-Hong Hu Jia-Qi Fan Jia-Jun He Ting-Fen Deng Yan-Li Xu Yu-Jun Dai Shun-Qing Wang |
| author_facet | Pei-Hong Wang Chu-Hong Hu Jia-Qi Fan Jia-Jun He Ting-Fen Deng Yan-Li Xu Yu-Jun Dai Shun-Qing Wang |
| author_sort | Pei-Hong Wang |
| collection | DOAJ |
| description | Abstract Background Acute myeloid leukemia (AML) remains a therapeutic challenge due to drug resistance and relapse. Selinexor, an XPO1 inhibitor, shows limited efficacy as monotherapy, necessitating combination strategies. JQ1, a BET inhibitor targeting MYC, may synergize with Selinexor to enhance antileukemic effects. Methods AML cell lines, primary patient samples, and xenograft models (MLL-AF9, CDX, PDX) were treated with Selinexor and JQ1 alone or combined. Synergy was assessed via viability assays (Compusyn/SynergyFinder), apoptosis (flow cytometry/Western blot), and C-MYC suppression (qPCR/CRISPR). In vivo efficacy was evaluated by tumor burden (flow cytometry) and survival. Results The combination demonstrated strong synergy (CI < 1, HSA > 10) across AML models, with > 80% inhibition in cell lines and primary samples. Mechanistically, it suppressed C-MYC (protein/mRNA), induced apoptosis (cleaved PARP), and arrested cell cycle. In vivo, the combination reduced leukemic burden in bone marrow, spleen, and liver, extending survival in xenografts. PDX models confirmed efficacy in primary AML cells. Conclusions Selinexor and JQ1 synergistically target AML by dual C-MYC inhibition, offering a promising strategy to overcome resistance. Further clinical evaluation is warranted. |
| format | Article |
| id | doaj-art-510010fdd4eb45cab17a6749ac93b488 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-510010fdd4eb45cab17a6749ac93b4882025-08-20T03:52:55ZengBMCJournal of Translational Medicine1479-58762025-05-0123111410.1186/s12967-025-06525-zInnovative evaluation of selinexor and JQ1 synergy in leukemia therapy via C-MYC inhibitionPei-Hong Wang0Chu-Hong Hu1Jia-Qi Fan2Jia-Jun He3Ting-Fen Deng4Yan-Li Xu5Yu-Jun Dai6Shun-Qing Wang7Department of Hematology, Guangzhou First People’s Hospital, Institute of Blood Transfusion and Hematology, Guangzhou Medical UniversityDepartment of Hematology, Guangzhou First People’s Hospital, Institute of Blood Transfusion and Hematology, Guangzhou Medical UniversityDepartment of Hematology, Guangzhou First People’s Hospital, Institute of Blood Transfusion and Hematology, Guangzhou Medical UniversityState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Hematology, Guangzhou First People’s Hospital, Institute of Blood Transfusion and Hematology, Guangzhou Medical UniversityDepartment of Hematology, Guangzhou First People’s Hospital, Institute of Blood Transfusion and Hematology, Guangzhou Medical UniversityState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Hematology, Guangzhou First People’s Hospital, Institute of Blood Transfusion and Hematology, Guangzhou Medical UniversityAbstract Background Acute myeloid leukemia (AML) remains a therapeutic challenge due to drug resistance and relapse. Selinexor, an XPO1 inhibitor, shows limited efficacy as monotherapy, necessitating combination strategies. JQ1, a BET inhibitor targeting MYC, may synergize with Selinexor to enhance antileukemic effects. Methods AML cell lines, primary patient samples, and xenograft models (MLL-AF9, CDX, PDX) were treated with Selinexor and JQ1 alone or combined. Synergy was assessed via viability assays (Compusyn/SynergyFinder), apoptosis (flow cytometry/Western blot), and C-MYC suppression (qPCR/CRISPR). In vivo efficacy was evaluated by tumor burden (flow cytometry) and survival. Results The combination demonstrated strong synergy (CI < 1, HSA > 10) across AML models, with > 80% inhibition in cell lines and primary samples. Mechanistically, it suppressed C-MYC (protein/mRNA), induced apoptosis (cleaved PARP), and arrested cell cycle. In vivo, the combination reduced leukemic burden in bone marrow, spleen, and liver, extending survival in xenografts. PDX models confirmed efficacy in primary AML cells. Conclusions Selinexor and JQ1 synergistically target AML by dual C-MYC inhibition, offering a promising strategy to overcome resistance. Further clinical evaluation is warranted.https://doi.org/10.1186/s12967-025-06525-zJQ1SelinexorAMLC-MYCMLL-AF9 bone marrow transplantation modelPDX mouse model |
| spellingShingle | Pei-Hong Wang Chu-Hong Hu Jia-Qi Fan Jia-Jun He Ting-Fen Deng Yan-Li Xu Yu-Jun Dai Shun-Qing Wang Innovative evaluation of selinexor and JQ1 synergy in leukemia therapy via C-MYC inhibition Journal of Translational Medicine JQ1 Selinexor AML C-MYC MLL-AF9 bone marrow transplantation model PDX mouse model |
| title | Innovative evaluation of selinexor and JQ1 synergy in leukemia therapy via C-MYC inhibition |
| title_full | Innovative evaluation of selinexor and JQ1 synergy in leukemia therapy via C-MYC inhibition |
| title_fullStr | Innovative evaluation of selinexor and JQ1 synergy in leukemia therapy via C-MYC inhibition |
| title_full_unstemmed | Innovative evaluation of selinexor and JQ1 synergy in leukemia therapy via C-MYC inhibition |
| title_short | Innovative evaluation of selinexor and JQ1 synergy in leukemia therapy via C-MYC inhibition |
| title_sort | innovative evaluation of selinexor and jq1 synergy in leukemia therapy via c myc inhibition |
| topic | JQ1 Selinexor AML C-MYC MLL-AF9 bone marrow transplantation model PDX mouse model |
| url | https://doi.org/10.1186/s12967-025-06525-z |
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