Shao Gang, Wang Xi, Zheng Yiting, Ma Junjie, Wang Lei, Yan Zhibin, Sun Zeyu, Zhang Shuyuan, Wu Hongzhang, Lv Yudie, Huang Hemiao, Li Jianhu, Zhu Tianyi, Yang Bing, Wang Nanxi, Chen Tao, Guo Xuancheng, Jin Yuanting, Kang Jian, Wang Huafeng, Cao Yihai, Fu Caiyun
Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China.
Department of Oncology, No.903 Hospital of PLA Joint Logistic Support Force, Hangzhou, 310013, China.
Adv Sci (Weinh). 2024 Dec;11(48):e2409726. doi: 10.1002/advs.202409726. Epub 2024 Oct 24.
Abnormal Notch1 expression has an important role in tumorigenesis. However, upstream control mechanisms for Notch1 are still insufficiently understood. Acute myeloid leukemia (AML) is one of the most common and lethal blood malignancies with limited possibilities for treatment. Thus, new therapeutic targets are urgently needed to improve current ineffective therapies. Herein, high Annexin A1 (ANXA1) expression is found correlated with hyperproliferation of AML cells, and then ANXA1 is identified as a novel negative regulator of Notch1 function in AML. Mechanistically, ANXA1 directly bound to the intracellular domain of Notch1 (NICD) to target this tumor suppressor for degradation. Furthermore, NICD executed its tumor suppressive function through activation of the p15 promoter. Thus, ablation of the Notch1-p15-mediated tumor suppression by ANXA1 provided a novel mechanism of AML proliferation. In human AML patients, a mutual exclusive relation is discovered between ANXA1 and Notch1/p15, corroborating mechanistic discovery. On the basis of these results, it is reasonably speculated that targeting ANXA1 would provide an effective approach for treatment of AML. In support of this new therapeutic paradigm, provided proof-of-concept data by antagonizing ANXA1 using NICD inhibitory peptides.
异常的Notch1表达在肿瘤发生中起重要作用。然而，Notch1的上游调控机制仍未得到充分理解。急性髓系白血病（AML）是最常见且致命的血液恶性肿瘤之一，治疗选择有限。因此，迫切需要新的治疗靶点来改善当前无效的治疗方法。在此，发现高膜联蛋白A1（ANXA1）表达与AML细胞的过度增殖相关，随后ANXA1被确定为AML中Notch1功能的新型负调节因子。机制上，ANXA1直接与Notch1的细胞内结构域（NICD）结合，靶向该肿瘤抑制因子进行降解。此外，NICD通过激活p15启动子发挥其肿瘤抑制功能。因此，ANXA1对Notch1-p15介导的肿瘤抑制的消融提供了AML增殖的新机制。在人类AML患者中，发现ANXA1与Notch1/p15之间存在相互排斥关系，证实了机制上的发现。基于这些结果，合理推测靶向ANXA1将为AML治疗提供一种有效方法。为支持这一新的治疗模式，使用NICD抑制肽拮抗ANXA1提供了概念验证数据。
