Xue Qing, Zhang Ming, Mo Yixiao, Jiao Bo, Liu Xuan, Jiang Minghao, Zhou Yu, Tan Yun, Li Huimin, Zhang Jianming, Zhang Qianqian, Li Yunqi, Li Jianfeng, Ma Xiaofang, Jing Duo-Hui, Mi Jian-Qing, Wang Jin, Chen Zhu, Shen Shu-Hong, Chen Sai-Juan
Shanghai 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 Medicine, Shanghai, China.
Department of Hematology/Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Signal Transduct Target Ther. 2025 Jul 23;10(1):230. doi: 10.1038/s41392-025-02310-y.
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 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.
MEF2D融合在预后不良的B细胞前体急性淋巴细胞白血病（BCP-ALL）的一种特殊亚型中被发现。在本研究中，我们分别使用携带MEF2D::HNRNPUL1（MH）和MEF2D::BCL9（MB）这两种主要MEF2D融合的细胞系和体外细胞模型进行了高通量药物筛选。我们鉴定出CUDC-907是一种高效的PI3K/HDAC双靶点抑制剂，在诱导强大杀伤力的同时对表达MEF2D融合的细胞保持选择性，显示出显著疗效。CUDC-907有效诱导凋亡并促进前B细胞受体信号的下调。我们发现PI3K-AKT信号通路、HDAC9和BCL2的过度激活促成了MEF2D融合（+）BCP-ALL的持续状态。重要的是，CUDC-907通过靶向MEF2D融合的整合途径发挥双重调节功能。它抑制PI3K-CREB途径和融合基因表达，同时抑制由MEF2D融合-HDAC轴调节的转录活性。CUDC-907在体外携带不同MEF2D融合变体的患者样本中显示出显著疗效。此外，该化合物的有效性和安全性在MH/NRAS BCP-ALL小鼠模型和MB患者来源的异种移植（PDX）模型中均得到证实，优于传统疗法。这些结果支持双途径抑制在MEF2D融合（+）BCP-ALL中的治疗潜力，并表明CUDC-907是具有相似分子依赖性的融合驱动白血病精准治疗的有希望候选药物。
