{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T06:17:04Z","timestamp":1793945824356,"version":"4.8.0"},"reference-count":70,"publisher":"American Society of Hematology","issue":"3","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,7,17]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Acute myeloid leukemia (AML) that evolves from myeloproliferative neoplasm (MPN) is known as post-MPN AML. Current treatments do not significantly extend survival beyond 12 months. B-cell lymphoma-extra large (BCL-xL) has been found to be overexpressed in leucocytes from patients with MPN, making it a potential therapeutic target. We investigated the role of BCL-xL in post-MPN AML and tested the efficacy of DT2216, a platelet-sparing BCL-xL proteolysis-targeting chimera, in preclinical models of post-MPN AML. We found that BCL2L1, the gene encoding BCL-xL, is expressed at higher levels in patients with post-MPN AML than in those with de novo AML. Single-cell multiomics analysis revealed that leukemia cells harboring both MPN-driver and TP53 mutations exhibited higher BCL2L1 expression and elevated scores for leukemia stem cell, megakaryocyte development, and erythroid progenitor than wild-type cells. BH3 profiling confirmed a strong dependence on BCL-xL in post-MPN AML cells. DT2216 alone, or in combination with standard AML\/MPN therapies, effectively degraded BCL-xL, reduced the apoptotic threshold, and induced apoptosis in post-MPN AML cells. DT2216 effectively eliminated viable cells in JAK2-mutant AML cell lines, induced pluripotent stem cell\u2013derived hematopoietic progenitor cells, primary samples, and reduced tumor burden in cell line\u2013derived xenograft model in vivo by degrading BCL-xL. DT2216, either as a single agent or in combination with azacytidine, effectively inhibited the clonogenic potential of CD34+ leukemia cells from patients with post-MPN AML. In summary, our data indicate that the survival of post-MPN AML is BCL-xL dependent, and DT2216 may offer therapeutic advantage in this high-risk leukemia subset with limited treatment options.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024027117","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T16:13:05Z","timestamp":1743437585000},"page":"341-355","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":37,"title":["Efficacy of a novel BCL-xL degrader, DT2216, in preclinical models of\n                    <i>JAK2<\/i>\n                    -mutated post-MPN AML"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9129-4125","authenticated-orcid":false,"given":"Zhe","family":"Wang","sequence":"first","affiliation":[{"name":"1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX"},{"name":"2State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0979-026X","authenticated-orcid":false,"given":"Anna","family":"Skwarska","sequence":"additional","affiliation":[{"name":"3Department of Medicine (Oncology), Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8882-7146","authenticated-orcid":false,"given":"Gowri","family":"Poigaialwar","sequence":"additional","affiliation":[{"name":"3Department of Medicine (Oncology), Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, 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