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It is overexpressed in solid tumors and considered a key target in cancer therapy. NPM1 mutations are the most common genetic abnormalities in acute myeloid leukemia (AML), where they are found in about 30% of patients. In AML, NPM1 mutations result in the cytoplasmic localization of the mutant protein NPMc+. Although NPM1 mutations are known to drive AML, the underlying mechanisms are not fully understood. In this study, we found that primary leukemia cells from NPM1\u2010mutated AML patients exhibited elevated intracellular calcium levels compared with cells from NPM1 wild\u2010type AML patients. Our investigation revealed that NPMc+ interacts with the calcium channel Orai1, disrupting calcium homeostasis in AML cells. Notably, we identified that the N\u2010terminal region of NPM1 contains a calcium\u2010binding domain that directly interacts with Orai1, facilitating calcium influx. Targeting NPMc+, Orai1, or the NPMc+\/Orai1 complex using small\u2010molecule inhibitors significantly reduced calcium influx, inhibited calcium\u2010related signaling pathways, and suppressed the proliferation of NPM1\u2010mutated AML cells. These findings uncover a novel mechanism in which NPMc+ interacts with Orai1, disrupting calcium homeostasis and promoting AML progression. This presents a promising therapeutic strategy targeting the NPMc+\/Orai1\u2010mediated calcium imbalance in NPM1\u2010mutated AML.<\/jats:p>","DOI":"10.1111\/febs.70508","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T09:49:03Z","timestamp":1774345743000},"page":"5221-5240","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The interaction between\n                    <scp>NPMc<\/scp>\n                    + and Orai1 induces abnormal calcium influx to facilitate leukemogenesis"],"prefix":"10.1111","volume":"293","author":[{"given":"Wenhao","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences Hubei University of Medicine  Shiyan China"},{"name":"Department of Integrated Medicine, Sinopharm Dongfeng General Hospital Hubei University of Medicine  Shiyan 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