Identification of ANXA1 as a Novel Upstream Negative Regulator of Notch1 Function in AML
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.
Authors
- Jian Kang (ORCID: https://orcid.org/0000-0001-9998-4975)
- Xirong Guo (ORCID: https://orcid.org/0000-0003-4873-8832)
- Tao Chen (ORCID: https://orcid.org/0000-0003-4614-4440)
- Caiyun Fu (ORCID: https://orcid.org/0000-0003-4090-885X)
- Yuanting Jin (ORCID: https://orcid.org/0000-0002-1001-2158)
- Yudie Lv
- Tianyi Zhu (ORCID: https://orcid.org/0000-0001-9291-8975)
- Hongzhang Wu
- Bing Yang (ORCID: https://orcid.org/0000-0001-6739-2932)
- Gang Shao (ORCID: https://orcid.org/0000-0003-1068-6790)
- Yihai Cao (ORCID: https://orcid.org/0000-0003-1308-0065)
- Zhibin Yan
- Junjie Ma (ORCID: https://orcid.org/0000-0002-8449-6917)
- Shuyuan Zhang (ORCID: https://orcid.org/0000-0002-6220-5998)
- Lei Wang (ORCID: https://orcid.org/0000-0002-5065-8447)
- Yiting Zheng (ORCID: https://orcid.org/0000-0003-2351-6707)
- Nanxi Wang (ORCID: https://orcid.org/0000-0002-0949-708X)
- Zeyu Sun (ORCID: https://orcid.org/0000-0003-1846-8069)
- Jianhu Li
- Hemiao Huang
- Xi Wang (ORCID: https://orcid.org/0000-0003-1835-8441)
- Huafeng Wang (ORCID: https://orcid.org/0009-0008-0306-9106)
Institutions
- Nanjing University of Chinese Medicine (CN)
- Zhejiang Sci-Tech University (CN)
- The University of Melbourne (AU)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peter MacCallum Cancer Centre (AU)
- Karolinska Institutet (SE)
- Zhejiang Cancer Hospital (CN)
- Hangzhou DAC Biotech (China) (CN)
- Hangzhou Cancer Hospital (CN)
- First Affiliated Hospital Zhejiang University (CN)
- China Jiliang University (CN)
- Zhejiang University (CN)
- Lanzhou University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-10-24
- DOI
- https://doi.org/10.1002/advs.202409726
- Citations
- 3
- Primary Topic
- S100 Proteins and Annexins
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Zhejiang Province