The synergy of TPL and selinexor in MLL-R acute myeloid leukemia via Rap1/Raf/MEK pathway-mediated MYC downregulation
MLL gene rearrangement recurrently occurs in acute myeloid leukemia (MLL-r AML), which is closely associated with chemotherapy insensitivity and unfavorable clinical outcomes. More importantly, there are limited therapeutic options for the management of patients with MLL-r AML, thus necessitating no...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
|
| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523325001305 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849730325547057152 |
|---|---|
| author | Manman Deng Peicui Huang Lijuan Wang Yuelong Jiang Zhenling Guo Hongpeng Duan Jie Zha Haijun Zhao Guowei Li Bing Xu |
| author_facet | Manman Deng Peicui Huang Lijuan Wang Yuelong Jiang Zhenling Guo Hongpeng Duan Jie Zha Haijun Zhao Guowei Li Bing Xu |
| author_sort | Manman Deng |
| collection | DOAJ |
| description | MLL gene rearrangement recurrently occurs in acute myeloid leukemia (MLL-r AML), which is closely associated with chemotherapy insensitivity and unfavorable clinical outcomes. More importantly, there are limited therapeutic options for the management of patients with MLL-r AML, thus necessitating novel effective treatment strategies. In this study, we demonstrated that low doses of triptolide (LD TPL) and the XPO1 inhibitor selinexor exerted synergistic therapeutic effects on poor-outcome MLL-r AML in vitro, ex vivo and in vivo. Induction of mitochondrial outer membrane permeabilization (MOMP) and initiation of the mitochondrial apoptotic pathway were closely involved in the therapeutic synergy of LD TPL in combination with selinexor against MLL-r AML. Mechanistically, MYC downregulation mediated by the Rap1/Raf/MEK/ERK pathway rather than by PI3K/AKT signaling was implicated in the synergistic activity of the combined regimen. In addition, the induction of DNA damage also contributed to the synergistic effects of the combined regimen on MLL-r AML. In summary, our findings suggest that LD TPL in combination with selinexor might represent a promising therapeutic approach for the treatment of MLL-r AML. However, future clinical trials are mandatory to draw a decisive conclusion. |
| format | Article |
| id | doaj-art-6b2106fba2af4aebb3ac3edb7cddcaae |
| institution | DOAJ |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-6b2106fba2af4aebb3ac3edb7cddcaae2025-08-20T03:08:55ZengElsevierTranslational Oncology1936-52332025-07-015710239910.1016/j.tranon.2025.102399The synergy of TPL and selinexor in MLL-R acute myeloid leukemia via Rap1/Raf/MEK pathway-mediated MYC downregulationManman Deng0Peicui Huang1Lijuan Wang2Yuelong Jiang3Zhenling Guo4Hongpeng Duan5Jie Zha6Haijun Zhao7Guowei Li8Bing Xu9Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, ChinaDepartment of Hematology, Huizhou Municipal Central Hospital, Huizhou, 516001, PR ChinaDepartment of Emergency, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, ChinaDepartment of Hematology, Huizhou Municipal Central Hospital, Huizhou, 516001, PR ChinaDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, ChinaDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, ChinaDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, China; Corresponding authors at: Department of Hematology, the First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen University, No.55, Zhenhai Road, Siming District, Xiamen, Fujian 361003, China.Department of Hematology, Huizhou Municipal Central Hospital, Huizhou, 516001, PR China; Corresponding author at: Department of Hematology, Huizhou Municipal Central Hospital, Huizhou, 516001, PR China.Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, China; Corresponding authors at: Department of Hematology, the First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen University, No.55, Zhenhai Road, Siming District, Xiamen, Fujian 361003, China.MLL gene rearrangement recurrently occurs in acute myeloid leukemia (MLL-r AML), which is closely associated with chemotherapy insensitivity and unfavorable clinical outcomes. More importantly, there are limited therapeutic options for the management of patients with MLL-r AML, thus necessitating novel effective treatment strategies. In this study, we demonstrated that low doses of triptolide (LD TPL) and the XPO1 inhibitor selinexor exerted synergistic therapeutic effects on poor-outcome MLL-r AML in vitro, ex vivo and in vivo. Induction of mitochondrial outer membrane permeabilization (MOMP) and initiation of the mitochondrial apoptotic pathway were closely involved in the therapeutic synergy of LD TPL in combination with selinexor against MLL-r AML. Mechanistically, MYC downregulation mediated by the Rap1/Raf/MEK/ERK pathway rather than by PI3K/AKT signaling was implicated in the synergistic activity of the combined regimen. In addition, the induction of DNA damage also contributed to the synergistic effects of the combined regimen on MLL-r AML. In summary, our findings suggest that LD TPL in combination with selinexor might represent a promising therapeutic approach for the treatment of MLL-r AML. However, future clinical trials are mandatory to draw a decisive conclusion.http://www.sciencedirect.com/science/article/pii/S1936523325001305MLL rearrangement (MLL-r)Acute myeloid leukemia (AML)TriptolideXPO1 inhibitor selinexorSynergyMYC |
| spellingShingle | Manman Deng Peicui Huang Lijuan Wang Yuelong Jiang Zhenling Guo Hongpeng Duan Jie Zha Haijun Zhao Guowei Li Bing Xu The synergy of TPL and selinexor in MLL-R acute myeloid leukemia via Rap1/Raf/MEK pathway-mediated MYC downregulation Translational Oncology MLL rearrangement (MLL-r) Acute myeloid leukemia (AML) Triptolide XPO1 inhibitor selinexor Synergy MYC |
| title | The synergy of TPL and selinexor in MLL-R acute myeloid leukemia via Rap1/Raf/MEK pathway-mediated MYC downregulation |
| title_full | The synergy of TPL and selinexor in MLL-R acute myeloid leukemia via Rap1/Raf/MEK pathway-mediated MYC downregulation |
| title_fullStr | The synergy of TPL and selinexor in MLL-R acute myeloid leukemia via Rap1/Raf/MEK pathway-mediated MYC downregulation |
| title_full_unstemmed | The synergy of TPL and selinexor in MLL-R acute myeloid leukemia via Rap1/Raf/MEK pathway-mediated MYC downregulation |
| title_short | The synergy of TPL and selinexor in MLL-R acute myeloid leukemia via Rap1/Raf/MEK pathway-mediated MYC downregulation |
| title_sort | synergy of tpl and selinexor in mll r acute myeloid leukemia via rap1 raf mek pathway mediated myc downregulation |
| topic | MLL rearrangement (MLL-r) Acute myeloid leukemia (AML) Triptolide XPO1 inhibitor selinexor Synergy MYC |
| url | http://www.sciencedirect.com/science/article/pii/S1936523325001305 |
| work_keys_str_mv | AT manmandeng thesynergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT peicuihuang thesynergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT lijuanwang thesynergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT yuelongjiang thesynergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT zhenlingguo thesynergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT hongpengduan thesynergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT jiezha thesynergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT haijunzhao thesynergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT guoweili thesynergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT bingxu thesynergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT manmandeng synergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT peicuihuang synergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT lijuanwang synergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT yuelongjiang synergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT zhenlingguo synergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT hongpengduan synergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT jiezha synergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT haijunzhao synergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT guoweili synergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation AT bingxu synergyoftplandselinexorinmllracutemyeloidleukemiaviarap1rafmekpathwaymediatedmycdownregulation |