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We found that inhibiting AGTR1 sensitized AML to chemotherapy and protected the heart against chemotherapy-induced cardiotoxicity in a human AML cell\u2013transplanted mouse model. These effects were regulated by the AGTR1-Notch1 axis in AML cells and cardiomyocytes from mice. In mouse cardiomyocytes, AGTR1 was hyperactivated by AML and chemotherapy. AML leukemogenesis increased the expression of the angiotensin-converting enzyme and led to increased production of angiotensin II, the ligand of AGTR1, in an MLL-AF9\u2013driven AML mouse model. In this model, the AGTR1-Notch1 axis regulated a variety of genes involved with cell stemness and chemotherapy resistance. AML cell stemness was reduced after\n            <jats:italic>Agtr1a<\/jats:italic>\n            deletion in the mouse AML cell transplant model. Mechanistically,\n            <jats:italic>Agtr1a<\/jats:italic>\n            deletion decreased \u03b3-secretase formation, which is required for transmembrane Notch1 cleavage and release of the Notch1 intracellular domain into the nucleus. Using multiomics, we identified AGTR1-Notch1 signaling downstream genes and found decreased binding between these gene sequences with Notch1 and chromatin enhancers, as well as increased binding with silencers. These findings describe an AML\/CVD association that may be used to improve AML treatment.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adl5931","type":"journal-article","created":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T17:58:10Z","timestamp":1718819890000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":7,"title":["Inhibiting AGTR1 reduces AML burden and protects the heart from cardiotoxicity in mouse models"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7381-9776","authenticated-orcid":true,"given":"Yi","family":"Pan","sequence":"first","affiliation":[{"name":"Center for Precision Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA."},{"name":"Ellis Fischel Cancer Center at MU Health Care, University of Missouri, Columbia, MO 65212, 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