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R\/R AML salvage treatment with venetoclax (VEN)\u2009+\u2009azacitidine (AZA) results in overall response rates between 20% and 60%, and responses are not durable, highlighting the need for new therapies. Here, we report elevated mTORC1 signaling in AraC\u2010resistant AML cell lines, primary AML patient samples, and patient\u2010derived xenograft (PDX) AML cells derived from patients at relapse postchemotherapy. The CDK9 inhibitor AZD4573 suppresses mTORC1 signaling and downregulates c\u2010MYC and MCL\u20101, inducing AraC\u2010resistant AML cell death. AZD4573 in combination with VEN\u2009+\u2009AZA significantly increases AML cell death compared to any of the two\u2010drug combinations and suppresses AML progenitor cells but spares normal hematopoietic progenitor cells. The efficacy of this triple combination remains even with a 10\u2010fold reduction of VEN concentration. The roles of MCL\u20101 and c\u2010MYC in the three\u2010drug combination were confirmed by knockdown. This study demonstrates that AZD4573 enhances the activity of VEN\u2009+\u2009AZA against AraC\u2010resistant AML by downregulating c\u2010MYC and MCL\u20101 and to a lesser extent cellular respiration.<\/jats:p>","DOI":"10.1002\/1878-0261.70124","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T10:43:59Z","timestamp":1758019439000},"page":"555-572","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Inhibition of\n                    <scp>CDK<\/scp>\n                    9 enhances\n                    <scp>AML<\/scp>\n                    cell death induced by combined venetoclax and azacitidine"],"prefix":"10.1002","volume":"20","author":[{"given":"Shuangshuang","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Pediatric Hematology Children's Medical Center, The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Oncology Wayne State University School of Medicine  Detroit MI USA"},{"name":"Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute Wayne State University School of Medicine  Detroit MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaban Asfar","family":"Azmi","sequence":"additional","affiliation":[{"name":"Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute Wayne State University School of Medicine  Detroit MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avanti","family":"Gupte","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology Children's Hospital of Michigan  Detroit MI USA"},{"name":"Department of Pediatrics Central Michigan University College of Medicine  Mt. 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