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...
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creator | 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 |
description | 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. |
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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.</description><identifier>ISSN: 2198-3844</identifier><identifier>EISSN: 2198-3844</identifier><identifier>DOI: 10.1002/advs.202409726</identifier><identifier>PMID: 39447086</identifier><language>eng</language><publisher>Germany</publisher><ispartof>ADVANCED SCIENCE, 2024-10, p.e2409726</ispartof><rights>2024 The Author(s). 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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.</description><issn>2198-3844</issn><issn>2198-3844</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNpNkUFPwkAQRjdGIwS5ejR79FLc2Q7t9kiIKAliYiThtlnaWayWLnZbjP_eIkg8zWTy5k0yH2PXIAYghLwz2c4PpJAoklhGZ6wrIVFBqBDP__Ud1vf-XQgBwzBGUJesEyaIsVBRly2nGZV1bvPU1LkrubN8NF-OgBvPDZ-7HRV8sfV1RWbD57RuqR3xF1o3haldtefnrk7fgE-aMv1V5CUfPc2u2IU1haf-sfbYYnL_On4MZs8P0_FoFqQSVB1IYwEgBCMRI8BoaJWVEVqI0CASUJxAZFFZlMKoLMbYZCgxSUxmKSMb9lhw8Pov2jYrva3yjam-tTO5Po4-2o60UvFQipa_PfDbyn025Gu9yX1KRWFKco3XIUgxTML2RosODmhaOe8rsic5CL0PQO8D0KcA2oWbo7tZbSg74X_vDn8A-4J_vg</recordid><startdate>20241024</startdate><enddate>20241024</enddate><creator>Shao, Gang</creator><creator>Wang, Xi</creator><creator>Zheng, Yiting</creator><creator>Ma, Junjie</creator><creator>Wang, Lei</creator><creator>Yan, Zhibin</creator><creator>Sun, Zeyu</creator><creator>Zhang, Shuyuan</creator><creator>Wu, Hongzhang</creator><creator>Lv, Yudie</creator><creator>Huang, Hemiao</creator><creator>Li, Jianhu</creator><creator>Zhu, Tianyi</creator><creator>Yang, Bing</creator><creator>Wang, Nanxi</creator><creator>Chen, Tao</creator><creator>Guo, Xuancheng</creator><creator>Jin, Yuanting</creator><creator>Kang, Jian</creator><creator>Wang, Huafeng</creator><creator>Cao, Yihai</creator><creator>Fu, Caiyun</creator><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope><orcidid>https://orcid.org/0000-0003-1308-0065</orcidid></search><sort><creationdate>20241024</creationdate><title>Identification of ANXA1 as a Novel Upstream Negative Regulator of Notch1 Function in AML</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c218t-2af11131a24461465f8f264f164a44e1e7916f48f420a8d747ad42499adfedef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shao, Gang</creatorcontrib><creatorcontrib>Wang, Xi</creatorcontrib><creatorcontrib>Zheng, Yiting</creatorcontrib><creatorcontrib>Ma, Junjie</creatorcontrib><creatorcontrib>Wang, Lei</creatorcontrib><creatorcontrib>Yan, Zhibin</creatorcontrib><creatorcontrib>Sun, Zeyu</creatorcontrib><creatorcontrib>Zhang, Shuyuan</creatorcontrib><creatorcontrib>Wu, Hongzhang</creatorcontrib><creatorcontrib>Lv, Yudie</creatorcontrib><creatorcontrib>Huang, Hemiao</creatorcontrib><creatorcontrib>Li, Jianhu</creatorcontrib><creatorcontrib>Zhu, Tianyi</creatorcontrib><creatorcontrib>Yang, Bing</creatorcontrib><creatorcontrib>Wang, Nanxi</creatorcontrib><creatorcontrib>Chen, Tao</creatorcontrib><creatorcontrib>Guo, Xuancheng</creatorcontrib><creatorcontrib>Jin, Yuanting</creatorcontrib><creatorcontrib>Kang, Jian</creatorcontrib><creatorcontrib>Wang, Huafeng</creatorcontrib><creatorcontrib>Cao, Yihai</creatorcontrib><creatorcontrib>Fu, Caiyun</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>SwePub</collection><collection>SwePub Articles</collection><jtitle>ADVANCED SCIENCE</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shao, Gang</au><au>Wang, Xi</au><au>Zheng, Yiting</au><au>Ma, Junjie</au><au>Wang, Lei</au><au>Yan, Zhibin</au><au>Sun, Zeyu</au><au>Zhang, Shuyuan</au><au>Wu, Hongzhang</au><au>Lv, Yudie</au><au>Huang, Hemiao</au><au>Li, Jianhu</au><au>Zhu, Tianyi</au><au>Yang, Bing</au><au>Wang, Nanxi</au><au>Chen, Tao</au><au>Guo, Xuancheng</au><au>Jin, Yuanting</au><au>Kang, Jian</au><au>Wang, Huafeng</au><au>Cao, Yihai</au><au>Fu, Caiyun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of ANXA1 as a Novel Upstream Negative Regulator of Notch1 Function in AML</atitle><jtitle>ADVANCED SCIENCE</jtitle><addtitle>Adv Sci (Weinh)</addtitle><date>2024-10-24</date><risdate>2024</risdate><spage>e2409726</spage><pages>e2409726-</pages><issn>2198-3844</issn><eissn>2198-3844</eissn><abstract>Abnormal Notch1 expression has an important role in tumorigenesis. 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title | Identification of ANXA1 as a Novel Upstream Negative Regulator of Notch1 Function in AML |
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