{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:44:40Z","timestamp":1792629880633,"version":"4.5.0"},"reference-count":64,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"12","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2024,3,22]]},"abstract":"<jats:p>\n            In a phenotypical screen of 56 acute myeloid leukemia (AML) patient samples and using a library of 10,000 compounds, we identified a hit with increased sensitivity toward\n            <jats:italic>SF3B1<\/jats:italic>\n            -mutated and adverse risk AMLs. Through structure-activity relationship studies, this hit was optimized into a potent, specific, and nongenotoxic molecule called UM4118. We demonstrated that UM4118 acts as a copper ionophore that initiates a mitochondrial-based noncanonical form of cell death known as cuproptosis. CRISPR-Cas9 loss-of-function screen further revealed that iron-sulfur cluster (ISC) deficiency enhances copper-mediated cell death. Specifically, we found that loss of the mitochondrial ISC transporter\n            <jats:italic>ABCB7<\/jats:italic>\n            is synthetic lethal to UM4118.\n            <jats:italic>ABCB7<\/jats:italic>\n            is misspliced and down-regulated in\n            <jats:italic>SF3B1<\/jats:italic>\n            -mutated leukemia, creating a vulnerability to copper ionophores. Accordingly, ABCB7 overexpression partially rescued\n            <jats:italic>SF3B1<\/jats:italic>\n            -mutated cells to copper overload. Together, our work provides mechanistic insights that link ISC deficiency to cuproptosis, as exemplified by the high sensitivity of\n            <jats:italic>SF3B1<\/jats:italic>\n            -mutated AMLs. We thus propose\n            <jats:italic>SF3B1<\/jats:italic>\n            mutations as a biomarker for future copper ionophore\u2013based therapies.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adl4018","type":"journal-article","created":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T17:58:43Z","timestamp":1711130323000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":47,"title":["<i>SF3B1<\/i>\n            mutations provide genetic vulnerability to copper ionophores in human acute myeloid leukemia"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5381-3546","authenticated-orcid":true,"given":"C\u00e9line","family":"Moison","sequence":"first","affiliation":[{"name":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, 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Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3492-0759","authenticated-orcid":true,"given":"Simon","family":"Fortier","sequence":"additional","affiliation":[{"name":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1216-3240","authenticated-orcid":true,"given":"Isabel","family":"Boivin","sequence":"additional","affiliation":[{"name":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6143-6620","authenticated-orcid":true,"given":"Rodrigo","family":"Mendoza-Sanchez","sequence":"additional","affiliation":[{"name":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, 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