{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T04:57:50Z","timestamp":1793941070073,"version":"4.8.0"},"reference-count":37,"publisher":"American Society of Hematology","issue":"18","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,10,30]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are among the most aggressive and chemotherapy-refractory myeloid neoplasms, with a median overall survival of &amp;lt;6 months. An enormous unmet need exists to develop novel therapeutic strategies, and understand resistance mechanisms to suboptimal existing therapies for this disease. In 2 parallel, phase 2 clinical trials that combined eprenetapopt with azacitidine in TP53-mutated MDS\/AML, we observed complete remission rates of 40% to 50%, and molecular remission rates of 38%. However, unless allogeneic stem cell transplant was performed, relapse inevitably occurred. To understand the mechanisms of secondary resistance responsible for this, we genotyped sequential clinical trial samples, conducted a genome-wide CRISPR screen in TP53-mutated leukemia cells, and identified XPO1 as a therapeutically tractable mediator of resistance. We demonstrate that XPO1 is overexpressed in patient samples after eprenetapopt and azacitidine treatment, elucidate the mechanism by which this occurs, and determine that it is necessary and sufficient for resistance to combination therapy. Finally, we validate in a variety of model systems, including a novel patient-derived xenograft model of TP53 mutant MDS, that eprenetapopt in combination with XPO1 inhibitors can overcome this resistance, providing preclinical rationale that this novel combination strategy is a viable therapeutic approach in patients with TP53 mutant MDS\/AML.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025028803","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T20:16:56Z","timestamp":1753906616000},"page":"2244-2258","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":11,"title":["XPO1 drives resistance to eprenetapopt and azacitidine and can be targeted in\n                    <i>TP53<\/i>\n                    -mutated myeloid malignancies"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9211-6304","authenticated-orcid":false,"given":"Traci L.","family":"Kruer","sequence":"first","affiliation":[{"name":"1Department of Clinical Science, Moffitt Cancer Center, Tampa, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Quintana","sequence":"additional","affiliation":[{"name":"1Department of Clinical Science, Moffitt Cancer Center, Tampa, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Newman","sequence":"additional","affiliation":[{"name":"1Department of Clinical Science, Moffitt Cancer Center, Tampa, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3380-6989","authenticated-orcid":false,"given":"Meghan","family":"Ferrall-Fairbanks","sequence":"additional","affiliation":[{"name":"2J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1463-1458","authenticated-orcid":false,"given":"Ling","family":"Zhang","sequence":"additional","affiliation":[{"name":"3Department of Pathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"McLemore","sequence":"additional","affiliation":[{"name":"1Department of Clinical Science, Moffitt Cancer Center, Tampa, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surendra","family":"Neupane","sequence":"additional","affiliation":[{"name":"1Department of Clinical Science, Moffitt Cancer Center, Tampa, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Yang","sequence":"additional","affiliation":[{"name":"4Division of Hematology, Sylvester Comprehensive Cancer 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