Molecular mechanisms of unique therapeutic potential of CUDC-907 for MEF2D fusion-driven BCP-ALL
Abstract MEF2D fusions are found in a special subtype of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis. In this study, we conducted high-throughput drug screenings using cell line and ex vivo cell model harboring, respectively, MEF2D::HNRNPUL1(MH) and MEF2D::BCL9(MB), t...
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Nature Publishing Group
2025-07-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02310-y |
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| author | Qing Xue Ming Zhang Yixiao Mo Bo Jiao Xuan Liu Minghao Jiang Yu Zhou Yun Tan Huimin Li Jianming Zhang Qianqian Zhang Yunqi Li Jianfeng Li Xiaofang Ma Duo-Hui Jing Jian-Qing Mi Jin Wang Zhu Chen Shu-Hong Shen Sai-Juan Chen |
| author_facet | Qing Xue Ming Zhang Yixiao Mo Bo Jiao Xuan Liu Minghao Jiang Yu Zhou Yun Tan Huimin Li Jianming Zhang Qianqian Zhang Yunqi Li Jianfeng Li Xiaofang Ma Duo-Hui Jing Jian-Qing Mi Jin Wang Zhu Chen Shu-Hong Shen Sai-Juan Chen |
| author_sort | Qing Xue |
| collection | DOAJ |
| description | Abstract MEF2D fusions are found in a special subtype of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis. In this study, we conducted high-throughput drug screenings using cell line and ex vivo cell model harboring, respectively, MEF2D::HNRNPUL1(MH) and MEF2D::BCL9(MB), the two major MEF2D fusions. We identified CUDC-907 as a highly potent dual-target inhibitor of PI3K/HDAC, demonstrating remarkable efficacy in inducing robust lethality while maintaining selectivity for MEF2D fusion-expressing cells. CUDC-907 effectively induced apoptosis and promoted the down-regulation of pre-BCR signaling. We discovered that the hyperactivation of the PI3K-AKT signaling pathway, HDAC9, and BCL2 contributed to the sustained state of MEF2D fusion (+) BCP-ALL. Importantly, CUDC-907 exerted dual regulatory function by targeting the integrative pathways of MEF2D fusions. It suppressed the PI3K-CREB pathway and fusion gene expression, while simultaneously inhibited transcriptional activity regulated by the MEF2D fusion-HDAC axis. CUDC-907 demonstrated remarkable efficacy in patient samples carrying distinct MEF2D fusion variants in vitro. Furthermore, this compound’s effectiveness and safety were confirmed in both MH/NRAS G12D BCP-ALL mouse model and MB patient-derived xenograft (PDX) model, outperforming conventional therapies. These results support the therapeutic potential of dual-pathway inhibition in MEF2D fusion (+) BCP-ALL and suggest CUDC-907 as a promising candidate for precision treatment in fusion-driven leukemias with similar molecular dependencies. |
| format | Article |
| id | doaj-art-8708ef9c13084c008e53e609f557d55e |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-8708ef9c13084c008e53e609f557d55e2025-08-20T04:02:45ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-07-0110111410.1038/s41392-025-02310-yMolecular mechanisms of unique therapeutic potential of CUDC-907 for MEF2D fusion-driven BCP-ALLQing Xue0Ming Zhang1Yixiao Mo2Bo Jiao3Xuan Liu4Minghao Jiang5Yu Zhou6Yun Tan7Huimin Li8Jianming Zhang9Qianqian Zhang10Yunqi Li11Jianfeng Li12Xiaofang Ma13Duo-Hui Jing14Jian-Qing Mi15Jin Wang16Zhu Chen17Shu-Hong Shen18Sai-Juan Chen19Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Hematology/Oncology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong UniversityShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Hematology/Oncology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong UniversityShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineAbstract MEF2D fusions are found in a special subtype of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis. In this study, we conducted high-throughput drug screenings using cell line and ex vivo cell model harboring, respectively, MEF2D::HNRNPUL1(MH) and MEF2D::BCL9(MB), the two major MEF2D fusions. We identified CUDC-907 as a highly potent dual-target inhibitor of PI3K/HDAC, demonstrating remarkable efficacy in inducing robust lethality while maintaining selectivity for MEF2D fusion-expressing cells. CUDC-907 effectively induced apoptosis and promoted the down-regulation of pre-BCR signaling. We discovered that the hyperactivation of the PI3K-AKT signaling pathway, HDAC9, and BCL2 contributed to the sustained state of MEF2D fusion (+) BCP-ALL. Importantly, CUDC-907 exerted dual regulatory function by targeting the integrative pathways of MEF2D fusions. It suppressed the PI3K-CREB pathway and fusion gene expression, while simultaneously inhibited transcriptional activity regulated by the MEF2D fusion-HDAC axis. CUDC-907 demonstrated remarkable efficacy in patient samples carrying distinct MEF2D fusion variants in vitro. Furthermore, this compound’s effectiveness and safety were confirmed in both MH/NRAS G12D BCP-ALL mouse model and MB patient-derived xenograft (PDX) model, outperforming conventional therapies. These results support the therapeutic potential of dual-pathway inhibition in MEF2D fusion (+) BCP-ALL and suggest CUDC-907 as a promising candidate for precision treatment in fusion-driven leukemias with similar molecular dependencies.https://doi.org/10.1038/s41392-025-02310-y |
| spellingShingle | Qing Xue Ming Zhang Yixiao Mo Bo Jiao Xuan Liu Minghao Jiang Yu Zhou Yun Tan Huimin Li Jianming Zhang Qianqian Zhang Yunqi Li Jianfeng Li Xiaofang Ma Duo-Hui Jing Jian-Qing Mi Jin Wang Zhu Chen Shu-Hong Shen Sai-Juan Chen Molecular mechanisms of unique therapeutic potential of CUDC-907 for MEF2D fusion-driven BCP-ALL Signal Transduction and Targeted Therapy |
| title | Molecular mechanisms of unique therapeutic potential of CUDC-907 for MEF2D fusion-driven BCP-ALL |
| title_full | Molecular mechanisms of unique therapeutic potential of CUDC-907 for MEF2D fusion-driven BCP-ALL |
| title_fullStr | Molecular mechanisms of unique therapeutic potential of CUDC-907 for MEF2D fusion-driven BCP-ALL |
| title_full_unstemmed | Molecular mechanisms of unique therapeutic potential of CUDC-907 for MEF2D fusion-driven BCP-ALL |
| title_short | Molecular mechanisms of unique therapeutic potential of CUDC-907 for MEF2D fusion-driven BCP-ALL |
| title_sort | molecular mechanisms of unique therapeutic potential of cudc 907 for mef2d fusion driven bcp all |
| url | https://doi.org/10.1038/s41392-025-02310-y |
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